- - - - -


- - - - -


- - - - TUESDAY, JUNE 18, 1996

- - - - -

The Committee met pursuant to adjournment in the Superior Room, The Renaissance Madison Hotel, Seattle, Washington, at 8:30 a.m., Joyce C. Lashof, Chair, presiding.






HOLLY L. GWIN, Deputy Director/Counsel


JOSEPH S. CASSELLS, Senior Advisor for Medical and Clinical Affairs

KATHI E. HANNA, Senior Advisor for Policy Implementation

THOMAS C. McDANIELS, JR., Policy Analyst

343 A G E N D A


Call to Order 345

Joyce C. Lashof

Assessing Reproductive Health 345

in Special Populations

Adolfo Correa, 345

Johns Hopkins University

Questions and answers 360

Betty Mekdeci, 368

Association of Birth Defect

Children, Inc.

Questions and answers 386

Linda Shortridge-McCauley, 409

Oregon Health Sciences University

Questions and answers 426

Diagnosis, Defining Syndromes, 432

Determining Prevalence, and Surveillance

Lewis Holmes, 432

Massachusetts General Hospital

Questions and answers 451

Larry Edmonds, 456

Centers for Disease Control

and Prevention

Questions and answers 474


AGENDA (Continued): PAGE

Genetic Services, Referral, and Outreach: 487

Department of Veterans Affairs

Thomas L. Garthwaite 487

Deputy Undersecretary for Health

Questions and answers 494

Genetic Services, Referral, and Outreach: 512

Department of Defense

Diana Tabler 512

Deputy Assistant Secretary,

Health Services Financing

Donald Johnson, 523

Bremerton Naval Hospital

Robert Jarrett, 528

Madigan Army Medical Center

Questions and answers 532

345 1 P R O C E E D I N G S

2 (8:30 a.m.)

3 MS. LASHOF: I think we're ready to

4 get started.

5 We changed the order of presentations

6 this morning because of schedules, and so let me

7 start with Dr. Adolfo Correa. We're very happy you

8 could join us.




12 MR. CORREA: Thank you for inviting

13 me.

14 This morning what I'd like to do is

15 to present two studies of reproductive effects in

16 relation to occupational and environmental exposures

17 and some of the methodologic issues that these kinds

18 of studies raise.

19 The first study will be -- or is

20 about an investigation of reproductive health in

21 semiconductor manufacturers in two manufacturing

22 plants in the northeastern -- northeastern United

346 1 States. The second one is a case-controlled study

2 of cardiac defects and environmental factors

3 conducted in the States of Maryland, northern

4 Virginia, and Washington. D.C.

5 In 1988 Pastidas and colleagues

6 reported an increased risk of spontaneous abortions

7 among women working in a semiconductor manufacturing

8 plant, and that led to two additional studies to

9 elucidate those -- that association.

10 One study was conducted by

11 investigators at University of California, Davis and

12 University of Massachusetts at Lowell, and they

13 investigated, I believe, fourteen plants across the

14 United States.

15 The second study was conducted by

16 investigators at Johns Hopkins University. And I

17 was involved with this study, and we evaluated the

18 reproductive health of workers at two plants.

19 The specific aims of the Johns

20 Hopkins study were, one, to examine the reproductive

21 outcomes of female workers and the couples, of male

22 workers in relation to work areas -- specifically

347 1 semiconductor clean-room manufacturing area, other

2 manufacturing, and non-manufacturing areas -- and

3 also to examine the relation between reproductive

4 outcomes and work with specific processes or

5 chemicals in the clean-room manufacturing area.

6 For this study we used a

7 retrospective cohort design, and then also a short

8 or small prospective cohort design to try to

9 corroborate some of the results of the historic

10 cohort study.

11 For the historic cohort study we

12 identified the active workers from employment

13 records in 1989, we recruited workers -- that is,

14 female workers and male workers and their wives.

15 And we specifically excluded workers who had had

16 surgical sterilization prior to 1980.

17 The unit of observation in this study

18 was a pregnancy conceived between 1980 and 1989

19 during employment in these two plants. The

20 information on pregnancies was obtained on

21 interviews of the female workers and the wives of

22 male workers. And the information on exposures was


1 obtained by interviews of the workers to elicit

2 details of histories, as well as from records in the

3 plant that indicated the processes and agents used

4 in different settings of the plant. And I'll spend

5 a few minutes on the job histories because this was

6 very crucial for our study.

7 Just a word about semiconductor

8 manufacturing. This is a very complex, multi-step

9 process that involves the working with these silicon

10 wafers. They're discs that resemble compact discs.

11 And on these discs a number of processes are carried

12 out, including the application of photoresistive and

13 photosensitive material. As shown here, this is for

14 the silicon wafer with photoresist on it. Then this

15 silicon wafer is exposed to light. That is shown

16 through this particular pattern that has the

17 semiconductor circuits, and this leads to the

18 imprinting of these microelectronic circuits on the

19 wafers. This process is then followed by a number

20 of other developmental -- development processes and

21 chemical exposures.

22 This slide shows a worker in one of

349 1 these plants. And the things I want to emphasize

2 are that this worker is wearing a cap, a mask, a

3 special suit to prevent the release of particles

4 that might contaminate the products and damage the

5 products.

6 The air in this environment is

7 circulated through special exhaust systems to remove

8 the number of particles in the air, also to prevent

9 damage to the circuits. So these environments are

10 called clean-room manufacturing rooms.

11 Traditionally in an occupational

12 study, exposure assessment is based on the job

13 histories that are then translated into potential

14 exposures that the workers may have incurred over

15 time. And in this study we had also employment

16 records for all the workers. This shows the

17 effective dates when a particular transition in the

18 worker's employment status took place, their

19 position title, and the department name.

20 We felt that this information would

21 not necessarily enable us to capture the variability

22 in processes that the two workers may have had

350 1 performing the same job title or having the same job

2 title, and that over time in this industry there

3 were a number of changes that would not be reflected

4 by the job titles. So we decided to combine this

5 with other techniques to try to obtain a more

6 detailed history of exposures.

7 We showed this employment record to

8 each worker and asked the worker to identify the

9 periods of time during which he or she performed the

10 same tasks, and that defined for us jobs.

11 Then for each one of those jobs we

12 asked the worker to tell us a little bit about that

13 job, the dates that that job was held, the building

14 in which that job was performed, and department or

15 area. And then within one -- within each one of

16 those jobs we also asked information about the

17 processes that the worker performed or worked on,

18 and the tools within each process.

19 This represents one of the memory

20 cues that we used to help the workers remember the

21 processes in the clean-room and for the particular

22 processes or tools that they may have worked in. So

351 1 we used a number of cognitive techniques to try to

2 help the workers remember the tasks they performed.

3 We also had records from the plants

4 that indicated to us what chemicals were required

5 for each one of these processes, so this allowed us

6 to construct what we called the process/chemical

7 matrix. That would enable us to tell, for any given

8 worker performing certain processes at a given point

9 in time, what chemical exposures that worker may

10 have had.

11 We were also interested in specific

12 chemicals, in particular the short-chain ethylene

13 glycol ethers, because of their known toxicity.

14 They're readily absorbed by inhalation or dermal

15 contact. They have reproductive and developmental

16 -- developmental toxicity. And in the study of

17 Pastidas where work with photolithography had been

18 identified as a risk factor, the question was

19 whether these chemicals were involved there.

20 In our study we found from the

21 records of the plants that the glycol ethers, here

22 represented by cellusolve acetate and dyline, were

352 1 present and photo- -- photo-applied in an area of

2 semiconductor clean-room manufacturing called

3 photo-apply. That is where photolithography takes

4 place.

5 But the concentrations were low. The

6 air concentrations were low. So we thought that if

7 there was going to be enough variation in exposure

8 between the workers, that would not be accounted by

9 inhalation, that it would have to -- it would have

10 to come from differentiations, differences in dermal

11 contact.

12 So if we wanted to conduct an

13 exposure assessment of expose- -- in relation to

14 ethylene glycol ethers, we wanted to rely, then, on

15 the time that the workers spent in photolithography

16 as an indication of the potential for exposure to

17 the ethylene glycol ethers. And for that purpose,

18 then we looked at the processes within a given job

19 and said that if the worker performed only

20 photoresist processes that require ethylene glycol

21 ethers, the potential for exposure to these

22 chemicals was high.

353 1 If the worker worked on these

2 processes as well as other processes, then the

3 potential for exposure was moderate, since that

4 meant that the worker would spend less time on the

5 photoresist ethylene glycol ether processes.

6 If the worker performed processes

7 that used other solvents, other than those involving

8 photoresist or -- we felt that the potential for

9 exposure to these chemicals was low.

10 And if the worker worked in processes

11 that really require no chemicals or solvents, we

12 felt the potential for exposure there was going to

13 be none.

14 So this information that we collected

15 retrospectively allowed us to conduct different

16 exposure classification systems, one based on area

17 such as clean-room, other manufacturing, non-

18 manufacturing, or more specific classification

19 systems, and including the one that I just

20 described, the exposure to ethylene glycol ethers in

21 photoresist.

22 So with this information, we linked


1 the reproductive histories that we obtained by

2 interview to the chronology of area processes that

3 the workers had been working on at the time of

4 conception. That allowed us to divide these

5 pregnancies into these three exposure groups by

6 area.

7 We also linked the processes at

8 conception with the process chemical matrix in

9 semiconductor clean-room manufacturing, to give us

10 an indication of the potential for exposure to these

11 chemicals, the ethylene glycol ethers.

12 And so we ended up with four groups

13 of pregnancies: those with a high potential for EG

14 exposure, those with medium potential for exposure,

15 those with low potential for exposure, and those

16 with no potential for exposure.

17 The analysis by -- of reproductive

18 outcomes by area showed no variation, no consistent

19 variation of spontaneous abortions, subfertility,

20 low birth weight, prematurity, or malformations, by

21 semiconductor clean-room manufacturing, and other

22 manufacturing and non-manufacturing. So I'm going

355 1 to present only the results of the analysis we

2 conducted within the clean-room workers.

3 This table shows the number of

4 pregnancies to female clean-room employees and the

5 number of pregnancies to the wives of male clean-

6 room employees during the study period, and the

7 numbers of spontaneous abortions, as well as the

8 percents of spontaneous abortions for those

9 pregnancies. And we have here percents or rates

10 that are comparable to those reported in other

11 studies that have been on interview data.

12 When we actually looked at the rate

13 of spontaneous abortions in female employees by

14 potential for exposure to these short-chain glycol

15 ethers, we observe, however, that there was some

16 variation in the rate of spontaneous abortions. We

17 in fact saw an increase in the rate of spontaneous

18 abortions with potential for exposure -- almost a

19 threefold increase in risk in the high-exposure

20 group, compared to the no-exposure group.

21 We looked also at the variation in

22 spontaneous abortions among the wives of male

356 1 employees with potential for exposure to these

2 chemicals. And in this group we didn't observe any

3 variation with exposure.

4 We also examined subfertility -- that

5 is, the delayed time to conception, or taking more

6 than a year to conceive -- among the female

7 employees in relation to these chemicals. And we

8 increased an increase in the risk of subfertility

9 with potential for exposure to these chemicals --

10 almost a fivefold increase in risk in the high-

11 exposure group, compared to the no -- no-exposure

12 group.

13 We examined subfertility in the

14 couples, of male workers, in relation to these

15 chemicals, and in this case we also observed an

16 increase in the rate of subfertility, although the

17 rate was less dramatic here than for the female

18 employees.

19 So in summary, in this study of

20 semiconductor manufacturers we observe an increased

21 risk of spontaneous abortion among female employees,

22 and increased rates of subfertility among female

357 1 employees, and among couples, of male employees, in

2 relation to potential exposure to the short-chain

3 glycol ethers or photoresist mixtures.

4 This study has a number of strengths.

5 One is that it was large enough to allow us to look

6 at spontaneous abortions and subfertility in

7 relation to these chemicals.

8 The data on spontaneous abortions

9 was validated through medical records, and we were

10 able to confirm that 94 percent of those on whom we

11 had medical records, the diagnosis was confirmed.

12 There was -- time to pregnancy had

13 relatively good consistency when we looked at some

14 of the questions, several questions that we asked

15 about this.

16 Our exposure assessment was conducted

17 independent of pregnancy outcome ascertainment.

18 And we had detailed and reliable work

19 histories.

20 Specific measures of exposure that

21 were time-dependent and allowed us to rank exposures

22 to the short-chain glycol ethers and to conduct

358 1 exposure response analysis.

2 Our results are consistent across

3 plants, and are consistent with the known toxicology

4 of these chemicals.

5 The limitations of this study are

6 several.

7 One is that we were really unable to

8 examine the independent effects of the short-chain

9 glycol ethers, of the effects -- possible effects of

10 the photoresist chemical mixtures that -- in which

11 they were present.

12 We didn't have a biomarker to

13 indicate exposure to these chemicals.

14 We don't know what the critical

15 exposure period for subfertility is.

16 And we didn't have a large enough

17 sample size of pregnancies to allow us to look at

18 malformations. The numbers that we found were very

19 small, to -- for an adequate analysis.

20 Okay. The second study I'd like to

21 turn to --

22 MS. LASHOF: I --


1 MR. CORREA: Yes?

2 MS. LASHOF: I would suggest that you

3 summarize the second study very rapidly, because you

4 have about five minutes left.

5 MR. CORREA: Very well.

6 In the second study, of congenital

7 malformations of the heart, we found that there were

8 no associations between the heart defects and many

9 environmental factors that we looked at when we

10 considered the cardiac defects as a group.

11 But when we examined diagnostic

12 groups and specific paternal exposures, we found

13 associations between specific diagnostic groups and

14 paternal exposures, such as ionizing radiation in

15 jewelry-making. And there were some suggestions of

16 a dose-response effects and interaction with family

17 history -- that is, family history increased

18 susceptibility to these -- some of these defects.

19 Now, that study was an exploratory

20 study, so the results could be interpreted as being

21 due to chance. And I think additional studies are

22 needed to replicate those findings.


2 MS. LASHOF: Thank you very much.

3 Are there questions from the panel

4 first?

5 If not, let me ask just a couple.

6 Certainly the silicon -- the solvent

7 study, semiconductor industry study, is a very well

8 designed, very careful, and has many strengths; its

9 limitations you mentioned.

10 How would you evaluate our ability to

11 do anything as scientifically sound as that, and the

12 problems we're facing in looking at exposures in the

13 Gulf War veterans?

14 MR. CORREA: I don't know enough

15 about the Gulf War veterans, but my -- the limited

16 knowledge that I have tells me that it's probably a

17 more complicated type of exposure setting. I don't

18 know what the different exposures might have been,

19 but my impression is that there may have been

20 several. The -- but I'm not sure that it's really

21 necessarily that much more complicated, as -- than

22 this study that we did. I think that there are some

361 1 similarities there.

2 Now, the one -- one advantage, I

3 think, in the Gulf War's setting is that there was

4 limited time of exposure. I think that that -- that

5 may facilitate the exposure assessment. We had to

6 look at a nine-, ten-year period. And I think

7 that's more difficult to recall the information.

8 The -- in the Gulf War setting there

9 is a fair amount of publicity now about the possible

10 relationship between exposure and outcomes. So the

11 recall of particular jobs or tasks or potential

12 exposures there may be subject to some effect from

13 outcomes -- that is, there might be some recall bias

14 that -- but that might be addressed, I think, in

15 some -- with some looking, including some questions

16 that specifically look at that possibility of

17 recall.

18 I think that sample size is probably

19 going to be an issue.

20 MS. LASHOF: Yeah.

21 MR. CORREA: A big issue.

22 MS. LASHOF: And in the result of the

362 1 spontaneous abortions, this was among people in the

2 high exposure, during the period of their exposure.

3 Is there any aftereffect of people who've worked in

4 high exposure areas then move out? How long would

5 you expect the effects to linger?

6 MR. CORREA: We haven't actually

7 examined that, and that's actually one of the

8 questions that remains: are the effects that we

9 observed -- that we observed in this setting chronic

10 or reversible? And if they're reversible, how

11 quickly are they reversed? I couldn't tell you

12 that.

13 MS. LASHOF: So those that you did

14 report on all were being exposed at that time?

15 MR. CORREA: Yes.

16 MS. LASHOF: And you have no data,

17 then, at this point, but you are planning to follow

18 that up?

19 MR. CORREA: We have the -- we have

20 the data in this study that may enable us to look at

21 subsequent pregnancies within the time period in

22 relation to past exposures. But we haven't analyzed

363 1 that.

2 MS. LASHOF: Okay. Thank you very

3 much.

4 Any other questions? Marguerite?

5 MS. KNOX: Yeah, I have a question.

6 When you were categorizing the chemicals, what made

7 you put the -- you categorize "other solvents" along

8 with the ECG as a low possibility risk.

9 MR. CORREA: Yes.

10 MS. KNOX: How did you decide upon

11 that?

12 MR. CORREA: Okay. We knew that the

13 category of "other solvents" -- we had four

14 categories: the high, the medium --

15 MS. KNOX: Medium.

16 MR. CORREA: -- that used EG and

17 other solvents; that was medium. And then we had

18 other solvents as the low.

19 We knew that at one plant that did

20 not include the glycol ethers. At the other plant

21 the glycol ethers had been used in a very limited

22 manner. That was from the records at the plant. So

364 1 we decided to consider that as low, rather than none

2 or medium. Because it really -- we felt that there

3 was really little potential for exposure, definitely

4 in one plant, and in the other one, very low

5 potential.

6 I don't know if that clarifies the

7 question.

8 MS. KNOX: Well, it just makes you

9 wonder, looking at -- say for instance, we've got

10 four veterans. We're looking at pyridostigmine

11 bromide and DEET, and the combination of that, those

12 two drugs together. And I just wondered if you --

13 if you combined the chemical that you were talking

14 about with another solvent, would it be more potent

15 or less potent, or did you -- you know, did you

16 investigate that?

17 MR. CORREA: We didn't investigate

18 that, but that is a very important question, because

19 we -- it is possible that in the presence of other

20 solvents, that these glycol ethers might be absorbed

21 more quickly, and maybe their effect potentiated.

22 And if -- and in fact, the glycol ethers were always


1 present in association with the photoresist

2 mixtures, the particular -- the specific nature of

3 which we don't know. And so it is possible that

4 those mixtures enhance the absorption as well as the

5 effects, but there's no way for us to know that.

6 MS. LASHOF: Let me follow that up,

7 then, a little bit. The glycol ethers you selected

8 as the possible culprit based on pharmacology or

9 toxicology before, and the solvents -- the other

10 solvents you had no reason to suspect them, so that

11 you considered them as not germane to the study, and

12 put them with the control? Is that correct or

13 incorrect?

14 MR. CORREA: No, no; I didn't have

15 time to really go into detail here, but --

16 MS. LASHOF: Yeah, I know. We cut

17 you short, and then we ask you tough questions and

18 -- but that gives you the chance to do that, anyway.

19 MR. CORREA: Yes.

20 We actually examined about twenty-

21 eight chemicals specifically in this plant,

22 chemicals that were used in high volume that had

366 1 known prior reproductive toxicity, and for which

2 there was potential for exposure. And we found that

3 really, of all of those, it didn't -- it seemed like

4 only the glycol -- glycol ethers, or those chemicals

5 that were used in conjunction with the glycol

6 ethers, were suggested in association.

7 MS. LASHOF: And what kind of

8 examinations did you do with the twenty-eight? I'm

9 trying to see what we can draw out of this that will

10 be applicable to the Gulf War.

11 MR. CORREA: Yeah. We did -- you

12 know, compared rates of people exposed to the

13 particular -- each particular chemical, versus the

14 rates among those who were not exposed to that

15 particular chemical.

16 It's not -- it's difficult, because

17 within these reference groups you may end up with

18 individuals who are exposed to other chemicals that

19 may be toxic, so you may dilute some associations.

20 If you try to use a common reference

21 group that has no exposure to any chemicals, you may

22 have very small numbers. We did both analyses, and

367 1 in both analyses we found the same -- similar

2 results, so --

3 MS. LASHOF: I see. Thank you very

4 much.

5 Any further questions?

6 If not, thank you very much.

7 Oh, I'm sorry, Joe; I didn't see your

8 hand.

9 MR. CASSELLS: Just to further

10 clarify the categorization with the ethylene glycol,

11 basically it's a categorization of time of exposure

12 potential? Is that correct? If they did the jobs

13 that were --

14 MR. CORREA: Yes.

15 MR. CASSELLS: Related strictly to

16 the time of use of that?

17 MR. CORREA: At time of conception.

18 Yes, at the time of --

19 MR. CASSELLS: And if they did other

20 tasks, it was a matter of time relationships?

21 MR. CORREA: Right.

22 MR. CASSELLS: Thank you.

368 1 MR. CORREA: At time of conception.

2 We also looked at other times: before conception,

3 after conception.

4 MS. LASHOF: Thank you very much.

5 Appreciate it.

6 Betty Mekdeci. Very happy to have

7 you with us this morning.




11 MS. MEKDECI: Good morning. I'd like

12 to thank the members of the Committee for bringing

13 me here all the way from Florida. I appreciate it

14 very much.

15 The Association of Birth Defect

16 Children, the organization that I direct, is a

17 national non-profit organization started in 1982.

18 We provide information to parents all over the

19 country about all kinds of birth defects. We do

20 national parent-matching, connecting families of

21 similar birth defects. And we sponsor a project

22 called the National Birth Defect Registry.

369 1 The National Birth Defect Registry

2 was really begun because of the poor quality of data

3 on birth defects we have at the national level.

4 According to a General Accounting

5 report that was done for Senator John Glenn, there's

6 very poor quality data all around the country on

7 birth defects. In fact, while 2 to 3 percent of

8 birth defects are detectable at birth, one major

9 study found that continued monitoring for seven

10 years after birth found up to 16 percent birth

11 defects. That was the Columbia -- the Collaborative

12 Perinatal Project, which was a prospective study of

13 50,000 pregnancies at twelve medical centers in the

14 United States.

15 Next chart, please.

16 This same report surveyed a group of

17 experts who said that up to 60 percent of birth

18 defects are of unknown origin, but 74 percent of

19 these experts believed that 25 percent or more would

20 be eventually linked to environmental exposures of

21 one kind or another.

22 Although linking and finding the


1 total incidence rate of birth defects is a major

2 challenge, even a greater challenge is trying to

3 link particular birth defects with particular

4 exposures.

5 According to a major text on birth

6 defects, Congenital Defects, by Saxen and Rappala,

7 overall incidence of birth defects may not be able

8 to detect specific causes. And in fact, thalidomide

9 we kind of call the great-granddaddy of teratogens,

10 did not cause an increase in the total number of

11 birth defects.

12 In fact, all the major teratogens, or

13 most of the major teratogens that have been

14 identified to date, have been identified by the

15 mechanism Dr. Brent mentioned yesterday, the alert

16 practitioner. That is, a doctor or doctors begin to

17 see a pattern of birth defects in a group of

18 children and begin a retrospective analysis of what

19 might be a common factor in the background of these

20 children. This includes, but is not exclusive to,

21 thalidomide, rubella, fetal alcohol syndrome, fetal

22 hydantoin syndrome, valparoic acid syndrome, methyl

371 1 mercury, PCBs, lithium, DES, radiation, and others.

2 We decided with the National Birth

3 Defect Registry to try to adapt the process of the

4 alert practitioner in a broad way by taking advanced

5 computer technology and database design to look at

6 large numbers of cases from all over the country.

7 We began this project in 1991 by

8 designing an interrelational database and an

9 original twelve-page questionnaire. Our

10 questionnaire is divided, not just by overall

11 syndrome names, but by birth defects by body system.

12 We have the ability to collect literally thousands

13 of combinations of birth defects in this way, and to

14 examine syndromes, not just by the name they've been

15 given, but by the components of those syndromes.

16 The development of the original

17 project took over a year, with multiple reviews by

18 outside experts. The American Legion gave us a

19 grant for pilot-testing of the project. And we

20 distributed 5,000 questionnaires to our entire

21 mailing list, which was at that point consisted of

22 families with children with birth defects, state and

372 1 national developmental disability programs, support

2 groups, and medical research centers and other

3 people working with birth defect populations. Of

4 this original mailing, 1,200 registry questionnaires

5 were returned for databasing.

6 One inducement to participate in this

7 project and complete our lengthy questionnaire is

8 our parent-matching component. In fact, I would say

9 that as many parents participate to be matched

10 participate because they may have some idea about

11 what caused their child's birth defects.

12 The first environmental issue that we

13 addressed with the database was the ongoing

14 controversy regarding Agent Orange and birth

15 defects. Although 65,000 cases of adverse

16 reproductive outcome had been reported to the court

17 during the Agent Orange litigation, nobody seemed to

18 have any idea what these reports consisted of.

19 There was no tally made, no examination of the case

20 reports.

21 So under a contract from the State of

22 New Jersey and working with the New Jersey Agent

373 1 Orange Commission, we added an additional page to

2 the questionnaire, and we did send that page to all

3 5,000 of the original participants on service in

4 Vietnam.

5 In 1992 the Association and the New

6 Jersey Commission made a dual report to the National

7 Academy of Science committee appointed to review the

8 health effects of herbicides and dioxin in veterans

9 and their children. At that point we compared the

10 disabilities in 800 Vietnam veterans' children to

11 400 non-veterans' children in the database. And to

12 do this, we convert these cases into cases per

13 hundred in the database, so that we'll have some

14 comparative. We put these statistics into Harvard

15 Graphics charts. And at the first instance we do

16 some basic things, and then New Jersey did some

17 statistical work.

18 Today the charts that I'm going to

19 present are just the first level.

20 You can go ahead with the next chart.

21 And I want to emphasize that we have

22 found this pattern of disabilities in veterans'

374 1 children from the first time we analyzed 300 cases.

2 Now we have almost 2,000 cases. And it hasn't

3 changed. We haven't added a condition, nor have we

4 subtracted a condition.

5 In the first chart you'll see we have

6 increases in a variety of childhood cancers.

7 Next chart, please.

8 We have consistent increases in

9 allergic conditions of a variety of kinds.

10 We have impressive increases in

11 growth disorders.

12 Persistent skin problems. And notice

13 particularly the "acne-like rash"; this is not

14 teenage acne. These are unusual acne-like skin

15 manifestations in strange parts of these children's

16 bodies.

17 Next, please.

18 Increases in attention deficit

19 disorders.

20 Increases in all areas of learning

21 and -- learning problems.

22 Consistent and impressive differences

375 1 in emotional and behavioral disorders.

2 And a variety of miscellaneous

3 conditions which are very consistent with some of

4 the effects of chronic fatigue syndrome.

5 We also have increases in endocrine

6 disorders, benign tumors, and cysts, but I didn't

7 want to take up the time with too much Agent Orange

8 today.

9 The National Academy referenced our

10 report in their book Veterans And Agent Orange, and

11 they did indicate that we had found some increases.

12 They had two problems with our data collection. One

13 was the potential for recall bias, and the second

14 was for self-selection.

15 So after their report, our

16 organization brought together a team of seven

17 national experts -- they didn't know each other;

18 they came from all different disciplines in

19 different parts of the country. We brought in

20 people who had expertise in reproductive

21 epidemiology, biometrics, environmental biology,

22 genetics, endocrinology, biochemistry, obstetrics


1 and gynecology, and developmental biology. We

2 brought them down to Orlando. We laid the project

3 before them and said, "What do you think? We'll

4 just do what we say it can do, and are we doing it

5 the right way?" They didn't let me talk, which is

6 an achievement in itself, and they settled down to

7 work.

8 And they came up with a consensus

9 statement in support of what we were doing. And

10 that is looking for potential clusters of birth

11 defects associated with potential exposures. This

12 does not constitute proof. This simply is pointing

13 a direction to start looking.

14 They also decided that they wanted to

15 redesign the questionnaire to make some of our

16 questions less biased, to add some component for

17 medical records, to get medical records to confirm

18 diagnoses. They recommended trend testing, to

19 continue looking at things as we gathered numbers

20 and to help offset self-selection processes. And

21 they asked us to do a different type of outreach for

22 the project that would reach more families for the

377 1 parent-matching component where they didn't have a

2 biased idea of what might have caused their child's

3 birth defects.

4 So at that point we started to

5 advertise the registry's parent-matching component

6 in the premier national disability magazine,

7 Exceptional Parent. Since that time our figures for

8 Agent Orange in our registry is -- our registry is

9 over 3,000 cases now. Our Agent Orange cases

10 represent over 1,600.

11 We have the same pattern. It has not

12 changed. It has stated consistent all along. The

13 pattern --

14 Once we've found a pattern and it is

15 consistent as we double and redouble and redouble

16 the data, we go out and look other forms of more

17 highly controlled research: animal work, cell

18 culture work, studies that were recently done in

19 children at Times Beach. And we found support in

20 these studies for the patterns that we were finding.

21 And in fact, the 2,000-page EPA's

22 "Reassessment of Dioxin" also points out that

378 1 postnatal functional alterations involving learning

2 and developmental reproductive system are most

3 sensitive endpoints to the prenatal dioxin exposure,

4 as is the developing immune system and growth and

5 skin problems. So what we found in the veterans'

6 children is very consistent with other forms of

7 data. Still, I wouldn't say that we have cause and

8 effect here; that will require an actual case-

9 controlled study or a more refined epidemiological

10 effort.

11 At the same time that the committee

12 came down to look at the project, I wrote up the

13 question to them of the Gulf War cases that we were

14 starting to get, because we were starting to get

15 calls to our office of families who had served in

16 the Gulf and were having children with birth

17 defects. And I innocently asked the committee

18 "Should we make a special effort to collect this

19 data?" and they said, "Yes," so -- I wonder why. So

20 they added a new page on that, and this -- the page

21 on our questionnaire on Gulf War is based on

22 information that we got from Senator Riegle, Senator

379 1 Rockefeller, and other research that we did on our

2 own.

3 I didn't have time to do a new set of

4 charts for you, but I did bring the set that we did

5 in September.

6 Currently we have case reports from

7 227 male veterans in our database, 30 veterans where

8 both males and females served, and 13 where the

9 mothers only served.

10 I would venture to say that we hear

11 from about twice as many people as those who

12 actually returned the questionnaire. There's a

13 great concern in the veteran population,

14 particularly the active-duty military, about being

15 too active on this issue.

16 Although the case reports we have are

17 based on figures from September, I think they're

18 representative of what we are seeing. In this

19 instance, rather than show you all twenty-six charts

20 I would normally show you, I have condensed those

21 conditions that we have found increases in when we

22 compared the two groups in our database.

380 1 If you look down, these are cranial,

2 facial, and neurological problems. You'll see the

3 Goldenhar syndrome that has had a lot of

4 conversation. I'll talk about that more in a

5 minute. External ear anomalies are impressive. The

6 micrognathia and the bony defect of the skull often

7 is included within the Goldenhar. Craniosynostosis,

8 Dandy Walker cyst, microcephaly and anencephaly.

9 Next chart, please.

10 We are also seeing some impressive

11 differences in heart defects. And I don't need to

12 tell you that heart defects are among the more

13 common birth defects, so you have to look at a lot

14 of heart defects to demonstrate any linkage.

15 But one area that I am particularly

16 interested is -- in, is the hypoplastic left heart

17 syndrome, which is a rare birth defect. We also

18 recently have gotten some cases of hypoplastic right

19 heart syndrome.

20 Next chart, please.

21 Across the board in the veterans'

22 cases, we find a thread of immune dysfunction,


1 whether these are just functional birth defects or

2 children with severe structural problems. Chronic

3 upper respiratory infections, chronic thrush,

4 temperature instability -- these children spike

5 temperatures for no reason -- a frank immune

6 deficiency in some cases, skin color changes.

7 I added the hemangiomas and the

8 strawberry marks to this chart because part of the

9 new treatments for hemangioma is interferon, which

10 might suggest there is some immune basis for that.

11 Strawberry mark is a hemangioma, but it's a small

12 one, so most parents aren't given that technical

13 term. So we separate those out, but those

14 technically are all hemangiomas.

15 We have an impressive difference in

16 lung absence -- either absence or underdevelopment

17 in these cases.

18 Next chart, please.

19 And finally, this is kind of a duke's

20 mixture of gastrointestinal, genitourinary, and some

21 chromosomal problems that we are seeing differences

22 in at this point in time.

382 1 If we could go back to the first

2 chart for a minute and talk a minute -- back to the

3 chart 13; I'm sorry.

4 A lot of attention has been given to

5 the Goldenhar syndrome. We have twenty-four cases

6 of children in the database now who have external

7 ear anomalies. Any external ear anomaly case

8 technically can be termed a branchial arch syndrome.

9 Branchial arch syndrome anomalies can be autosomal

10 dominant, they can be sporadic, or they can be

11 multifactorial.

12 In the case of Goldenhar syndrome,

13 which is technically a branchial arch syndrome

14 deformity, there are, historically, some familial

15 cases in the literature. But there are also cases

16 that have been linked to well known teratogens:

17 thalidomide was connected with branchial arch

18 deformities, most particularly Goldenhar;

19 primadone, which is an antiseizure medication; and

20 of course, acutane.

21 Yesterday Dr. Araneta discussed the

22 problem with coming up with an accurate incidence

383 1 figure for Goldenhar syndrome, and she cited various

2 state registries, which we've looked at as well.

3 We have also looked at the

4 Collaborative Perinatal Project, because it was a

5 controlled and prospective study of a large number

6 of pregnancies. In that study of 50,000 pregnancies

7 they found one case in every 26,400.

8 Although I clearly can't say at this

9 point that Goldenhar is linked to the Gulf, I will

10 tell you that we can analyze every kind of exposure

11 in this database, from aspirin to how many

12 ultrasounds you had, to water you drank, to

13 co-factors, smoking, drinking, recreational drug

14 use. And we don't find this skewing with any other

15 exposure category, with the exception of one.

16 There are two things. When we

17 analyze Goldenhar, Gulf War service in the Gulf, and

18 living within an agricultural area during pregnancy

19 are the two things that we see increased right now.

20 Because we take this work very

21 seriously and we know the decisions families make

22 about their future reproductive life are very

384 1 serious ones to them, we don't do this lightly.

2 When we started seeing the increase

3 in Goldenhar, we did a special outreach to various

4 projects around the country that do parent-matching.

5 We obtained the names of 175 cases of children with

6 Goldenhar syndrome and sent questionnaires out. So

7 we have 65 cases, total, of Goldenhar in our

8 database. And we can actually go into just that

9 birth defect category and, conversely, look at the

10 distribution of various exposures. So we can look

11 at it backwards and forwards.

12 As difficult as it is to look for

13 potential increases in certain disabilities, it's

14 even more difficult when you look at the

15 multiplicity of exposures in the Gulf. According to

16 the GAO report, there were twenty-one different

17 reproductive toxicants in the Gulf -- everything

18 from pesticides, lead, and mercury, arsenic,

19 cadmium, the potential of chemical warfare agents,

20 not to mention multiple inoculations, pyridostigmine

21 bromide. So teasing out one of these from all the

22 others will be a real challenge, not to mention the

385 1 interactions or synergism that might exist between

2 various things.

3 However, we already have some

4 interesting little tickling things going on with the

5 data. And that is, in our Goldenhar cases, four of

6 our cases were in parents' fathers who were called

7 up for service, given all the preliminary

8 inoculations, but didn't go. So that's an

9 interesting little aside at this point.

10 For several years our organization

11 has been monitoring ongoing research on

12 immunotoxicology. And we have been looking at the

13 connection between immunotoxic agents and their

14 potential to be teratogens. Many of the agents in

15 the Gulf are toxic to immune function. And we have

16 come to think, or at least to hypothesize that an

17 immunotoxic agent at one level of exposure may cause

18 a severe structural birth defect, but more commonly

19 at lower levels may cause functional birth defects,

20 such as learning, attention, immune, endocrine, and

21 other problems.

22 Unfortunately, in the country today

386 1 we really don't monitor functional birth defects at

2 all, so we have no good handle on the statistics.

3 I appreciate you inviting me here

4 today, and I'd be most happy to answer any

5 questions. And we would like permission to submit a

6 more fully worked out report to you in written form.


8 MS. LASHOF: Thank you very much.

9 That's very interesting data, and by all means we'd

10 be anxious to receive any full report and any

11 additional information up until November, when we

12 have to put our report together.

13 MS. MEKDECI: Very well.

14 MS. LASHOF: After that, it may be

15 harder to incorporate it.

16 Questions. Marguerite?

17 MS. KNOX: I just have one. You said

18 there were four fathers who received the

19 vaccinations.

20 MS. MEKDECI: Yes. Right.

21 MS. KNOX: And those are anthrax and

22 botulinum, or just the anthrax? Do you know what


1 they received?

2 MS. MEKDECI: Well, the fathers

3 weren't -- no one that I'm aware of was told what

4 they received. They were -- they received the

5 inoculations.

6 Now, one of the cases is interesting,

7 in that the father received the inoculations state

8 -- stateside, and worked with gear that was

9 contaminated when it came back. He now is being

10 treated for Gulf War syndrome.

11 And another father was working in an

12 occupation where he was working with a lot of

13 chemicals in the particular occupation he was in,

14 but we don't know for sure -- I mean, in some cases

15 people think they know that they were exposed to

16 this or that.

17 One -- one area that I'm concerned

18 about is the gamma globulin shot. Pretty much

19 everybody who went over got gamma globulin. It's

20 made of multiple blood products. And while it's

21 screened for AIDS, it is not screened for all the

22 potential viruses that are out there today. And

388 1 there are a number of new immune-affecting viruses

2 that I have a particular interest in, particularly

3 human herpes virus 6, 7, and 8, not to mention some

4 mutations of the HIV virus. So that's a particular

5 concern. And I knew that all of them would have

6 gotten that.

7 MS. LASHOF: Let me try to better

8 understand your control groups.

9 MS. MEKDECI: Okay.

10 MS. LASHOF: I mean, obviously you're

11 not in a position to do the traditional case-

12 control groups.

13 MS. MEKDECI: Right.

14 MS. LASHOF: And most retrospective

15 studies where you find a defect thing, you look for

16 a child that was born the same day in the same

17 place, et cetera, and then look at exposures of

18 parents. And you're not able to do that.

19 Can you tell me a little more about

20 how you select who you're matching against? And

21 when it says, "Non-Gulf War," does that all-include?

22 And are they controlled in any other ways?

389 1 MS. MEKDECI: At this point in time

2 when we say, "Non-Gulf," what we do is, we compare

3 all the cases in a particular category to all the

4 cases that are not in that category in the database.

5 Now, that's a little tricky, because sometimes you

6 may be comparing apples to apples, if you're not

7 careful.

8 For instance, within the Gulf

9 exposures we have pesticides. So some of our other

10 -- but we can take that out. We can actually get

11 into removing those and putting those aside and

12 looking at them.

13 We don't have the illusion that our

14 data does anything more than look for clustering.

15 From that point, you can go -- you can go into a

16 random selection within the database, once the

17 numbers reach a certain critical mass. And in fact,

18 the New Jersey Commission is trying to get us to do

19 that on the Agent Orange, and we probably will.

20 But what we really think our data can

21 do is point a direction for case-control work that

22 would be done in the traditional way. Because I

390 1 realize that what we're doing is a little unusual,

2 although there are several studies that have used

3 malformed children as control groups -- in fact, the

4 Center for Disease Control has done that type of

5 study before.

6 MS. LASHOF: Okay. Second question:

7 specific -- well, on all of them, but let's take

8 Goldenhar as one you've looked at particularly.

9 What is the relationship of the cases that you have

10 of Goldenhar to the time at birth in relation to the

11 time of service? What duration period post-service

12 are you still seeing the --

13 MS. MEKDECI: The latest case of

14 Goldenhar that we have in the database was born in

15 1994.

16 I would like to point out that the

17 thirteen cases -- we have thirteen cases in the

18 database -- does not represent all the cases that we

19 have heard of. We have five cases that have called

20 us, but for reasons unknown to me just simply won't

21 return their questionnaires. So we can't count

22 those. But I can tell you we've heard from them.

391 1 MS. LASHOF: So the total number of

2 Goldenhar is only thirteen? Is that --

3 MS. MEKDECI: We have thirteen in the

4 database that have been classified by a medical

5 professional as Goldenhar. Within our ear anomaly

6 cases we have another four or five that have facial

7 asymmetry, the ear anomaly, a vertebral column

8 problem, that in my mind could technically be

9 classified as Goldenhar. But I don't have the

10 expertise to put them in that category. We can just

11 tell you that we have that combination of defects.

12 MS. LASHOF: And how many Goldenhar

13 do you have in non-Gulf --

14 MS. MEKDECI: In the non-Gulf we

15 would have thirteen -- well, sixty-five minus

16 thirteen -- what would that be? Fifty-two.

17 MS. LASHOF: Okay. So percentage-

18 wise, you have thirteen Goldenhar with --

19 MS. MEKDECI: In the Gulf.

20 MS. LASHOF: In the Gulf.

21 MS. MEKDECI: Yes.

22 MS. LASHOF: And fifty-odd in the


1 non-Gulf.

2 MS. MEKDECI: Right.

3 MS. LASHOF: And the total congenital

4 defects in the non-Gulf are -- I mean, how big is

5 your non-Gulf sample --


7 MS. LASHOF: -- and your Gulf sample?

8 MS. MEKDECI: Our non-Gulf sample --

9 our Gulf sample in the charts that I showed you was

10 194 cases, and the non-Gulf sample was -- I don't

11 remember the figure -- 2,100 and some-odd at that

12 time.

13 MS. LASHOF: Yeah. Yeah. Okay.

14 That's a very significant difference.

15 MS. MEKDECI: Yeah, different. It's

16 very -- and it's especially different because we

17 didn't just let things come into the database on

18 Goldenhar. We actually went out searching to bring

19 in cases to look at it in a thorough way.

20 Ordinarily, if we had just left it alone, we

21 wouldn't have nearly that many cases of Goldenhar in

22 our non-exposed, because they wouldn't have come in

393 1 like that. We actually searched them out.

2 MS. LASHOF: But what time period?

3 What age ranges were there in your non-Gulf

4 Goldenhar --

5 MS. MEKDECI: I can't tell.

6 MS. LASHOF: -- versus your --

7 MS. MEKDECI: I can't tell you that

8 today. I would have to do that.

9 MS. LASHOF: Yeah.

10 MS. MEKDECI: We were --

11 MS. LASHOF: It would be important

12 that we're not talking about completely different

13 time periods.

14 MS. MEKDECI: Oh, absolutely.

15 Absolutely. Actually, when we do a

16 report, we do go into all of that, and actually go

17 into some statistics work. But I just didn't have

18 time.

19 MS. LASHOF: Yeah; sure.

20 MS. MEKDECI: We were hoping to get

21 more of those cases that are out into the database

22 before we did a report for you.

394 1 MS. LASHOF: Okay. Well, we'll look

2 forward to receiving that.

3 Another question I have is: I think

4 your criticism that we don't have a national birth

5 defects registry is a very solid one. Would you be

6 supportive of federal legislation requiring that we

7 have a national birth defects registry, and require

8 that all birth defects be reported?

9 MS. MEKDECI: That would certainly

10 depend on who they were going to get to do it.

11 (Laughter.)


13 MS. MEKDECI: I have to tell you,

14 I've been doing this for twenty years, and I have

15 some -- I'm sure there are some salt-of-the-earth

16 people at CDC, but I've had some very unfortunate

17 experiences with CDC on a variety of issues.

18 I want to add a little addendum. In

19 1984 I was diagnosed with chronic encephalopathy and

20 immune deficiency. I have had pretty much all the

21 symptoms that Gulf War veterans have had. And in

22 fact, I was exposed to one of the chemicals that was

395 1 on the federal list of procurement for the Gulf. I

2 know what these families are going through.

3 Unfortunately for them, they didn't

4 happen to go to the doctor that I went to. I was

5 diagnosed by a doctor who was formerly the head of

6 the American Academy of Allergy and Immunology. I

7 was diagnosed very quickly. No one ever told me I

8 was crazy. No one ever suggested that I had PTSD.

9 I had some very serious immune problems. They did

10 suggest I needed to be tested multiple times for

11 AIDS. I have had some of the most sophisticated

12 immune system testing available. I've been on

13 experimental treatment. I'm not dead. I think I am

14 reasonably coherent most of the time, although

15 things like this make me a little -- a little

16 uncomfortable.

17 I've done a lot of research on this.

18 I hope that every member of this Committee has seen

19 this book and read it. Because in your analysis,

20 not only of the Gulf War birth defects, but your

21 analysis of Gulf War syndrome, this is a very

22 valuable tool.

396 1 I believe that these veterans have

2 something going on. I don't know what it is;

3 perhaps no one does at this point. But I can tell

4 you definitively that there is treatment and there

5 is diagnosis available. And I don't believe they're

6 getting it, from what I'm hearing from the veterans

7 I'm talking to. And they certainly are not getting

8 the quality of care that I have gotten.

9 MS. HANNA: Can I ask a question?

10 MS. LASHOF: Yes, please, Kathi.

11 MS. HANNA: I have a question about

12 your initial mailing group.

13 MS. MEKDECI: Yes.

14 MS. HANNA: You had mentioned you had

15 5,000 people.

16 MS. MEKDECI: Yes.

17 MS. HANNA: And that's where you

18 collected your first set of data?

19 MS. MEKDECI: Right.

20 MS. HANNA: Can you just explain a

21 little bit more who is --

22 MS. MEKDECI: Where that came from?

397 1 MS. HANNA: Yeah, where the -- who

2 those --

3 MS. MEKDECI: Sure.

4 MS. HANNA: Who those recipients are?


6 MS. HANNA: And you had mentioned

7 that one category is medical centers or whatever.

8 And they receive a questionnaire?

9 MS. MEKDECI: Yes. What we did is --

10 our mailing list grew from its infancy. We started

11 with eighty families working out of a utility room

12 many years ago. Our mailing list is now over

13 12,000. But at the point that we did this, we had

14 5,000. I'm not sure how it's grown; it's grown like

15 Topsy. We have federal programs, we have state

16 programs, we have support groups, we have libraries.

17 They just come. I don't know how they get us. We

18 have twenty-two countries, although we didn't send

19 the questionnaires to the twenty-two countries.

20 We actually had a state developmental

21 disability program send us all the labels for the

22 children they had served that year, which shocked


1 the heck out of me.

2 But the reason we sent it to medical

3 centers for that purpose, we actually got states

4 that were interested, we got professionals who were

5 interested. We were trying to send it out broadly

6 to see how it would fly. And it did very well,

7 considering it was --

8 MS. HANNA: And the questionnaire, is

9 that similar to the questionnaire that you submitted

10 to us?

11 MS. MEKDECI: It's similar, except

12 the original questionnaire that we sent out didn't

13 have the Gulf War page or the Agent Orange page.

14 Now, we have also rewritten a few of

15 the questions since that time. You think that you

16 have things perfectly designed until you've sent out

17 a bunch, and then you find out something needs to be

18 changed as far as the wording, certain little

19 things. And of course, the committee reworded a few

20 things that they thought could be better said, so --

21 MS. HANNA: But the questions on the

22 questionnaire are --

399 1 MS. MEKDECI: Essentially the same,

2 yes.

3 MS. HANNA: Right. But they're

4 directed to an individual --

5 MS. MEKDECI: Correct.

6 MS. HANNA: -- concerning their

7 reproductive --

8 MS. MEKDECI: Correct.

9 MS. HANNA: So let's say a caseworker

10 or whatever the disability agents --

11 MS. MEKDECI: It goes to directly to

12 the family.

13 MS. HANNA: They then can copy it and

14 give it to --

15 MS. MEKDECI: Well, they don't copy

16 it; these are not copied. Each one of these is

17 coded by a number.

18 MS. HANNA: But they could request

19 additional surveys?

20 MS. MEKDECI: They can request

21 additional ones. We now have an 800 line where

22 anyone in the country who wants one of these can

400 1 call up day or night, twenty-four hours a day, and

2 we'll send out the packet to them, and then they can

3 send it back.

4 When they send it back, if they

5 choose, we'll do the parent-matching. They don't

6 have to do parent-matching, or at any point we can

7 cut that off if they don't want to do parent-

8 matching.

9 We don't match by exposures. Because

10 if we start that, we'll be accused of setting up

11 litigation or rabble-rousing or I don't know what.

12 So we just match by conditions. At this point we

13 can match by major condition or up to five separate

14 components of a condition. As the database grows,

15 we'll be able to go to more and more. We can --

16 eventually maybe we can match by twenty conditions.

17 But we try to give them a sufficient number of

18 contacts.

19 MS. HANNA: So all of the people --

20 all of the individuals that return the questionnaire

21 are returning it because they have a child --

22 MS. MEKDECI: That's right.

401 1 MS. HANNA: -- with a birth defect?

2 MS. MEKDECI: That's correct.

3 MS. HANNA: Okay.

4 MS. MEKDECI: That's correct, yes.

5 MS. LASHOF: On the parent-matching,

6 you're matching them for the conditions, putting

7 parents in touch with each other.

8 MS. MEKDECI: Correct. Correct.

9 MS. LASHOF: And they have a choice

10 of saying yes, they want to be matched --

11 MS. MEKDECI: Right.

12 MS. LASHOF: -- or "Please don't give

13 my name to anybody" --

14 MS. MEKDECI: Absolutely.

15 MS. LASHOF: -- "under the sun" or

16 whatever?

17 MS. MEKDECI: Absolutely. There's a

18 question on here we have highlighted in red, and if

19 at any point they want to change that -- let's say

20 they've done parent-matching and they don't want to

21 do it any more, they can call us up and we just

22 change that Yes to a No, and that's the end of it.

402 1 We have had a lot of good feedback on

2 the parent-matching. The parents are very excited.

3 If we send a match that they don't like, they send

4 it back and have us rematch by a different

5 condition. They're very enthusiastic. Because one

6 of the things about having a child with a birth

7 defect is, it's a very isolating type of challenge.

8 And there's nothing like talking to somebody who's

9 either been through it, going through it -- it just

10 gives you, you know, some support system.

11 Unfortunately, for most categories of

12 birth defects there are no support groups. You

13 know, for the larger categories, yes. But most

14 things, there are no support groups. So we try to

15 give parents that emotional cushion, if you will.

16 MS. LASHOF: Let me try one more

17 question on Goldenhar, if I may.

18 MS. MEKDECI: Surely.

19 MS. LASHOF: Have you found anything

20 else other than Gulf War that -- and even before the

21 Gulf War came into the picture, when you were

22 looking at --


1 MS. MEKDECI: Yes. When we --

2 MS. LASHOF: -- branchial arch --

3 MS. MEKDECI: When we analyze our

4 total Goldenhar cases, we do find living in an

5 agricultural area to be impressively skewed. And

6 I'm not sure what the meaning of that is. My guess

7 would be pesticides, but that might be a little

8 prejudiced, so --

9 MS. LASHOF: Yeah. When you say,

10 "living in an agricultural area," have you been able

11 to break it down to those who were actively engaged

12 in agricultural --

13 MS. MEKDECI: We haven't done that.

14 MS. LASHOF: -- activities --

15 MS. MEKDECI: We haven't done that.

16 MS. LASHOF: -- versus those who just

17 live there?

18 MS. MEKDECI: We have a -- within --

19 I believe it's within three miles of an agricultural

20 area. And we haven't broken it down.

21 One of the things that the project

22 will do is, if we find something like that that

404 1 we're interested in, we can do another questionnaire

2 and go back. Because we have a question "Can we get

3 back to you for further research?" So our committee

4 at any point can go back to them and say, "All

5 right, now, let's find out: are you working in

6 farming? Are they farming next door?"

7 MS. LASHOF: Farm, yeah.

8 MS. MEKDECI: You know, "What's been

9 going on?"

10 MS. LASHOF: "Are you using

11 pesticides yourself?"

12 MS. MEKDECI: "Are you using

13 pesticides in your home?" We do ask that question,

14 "Are you using pesticides in your home, in your

15 office?" -- whatever.

16 MS. LASHOF: Thank you very much.

17 Tom?

18 MR. McDANIELS: When your association

19 receives queries from Gulf veterans about the

20 incidence of birth defects in their offspring, what

21 type of education and information do you give out on

22 the incidence of environmentally-produced birth

405 1 defects?

2 MS. MEKDECI: Okay.

3 The most difficult questions that we

4 handle at our office are "I served in the Gulf" or

5 "I was exposed to this" or "What's going to happen?

6 Am I going to have a child with a birth defect?" --

7 a tough question for us to have to answer.

8 And what I tell parents routinely is

9 this: all known teratogens -- even if we had

10 identified something in the Gulf, all of them only

11 affect a minority of children. With thalidomide it

12 was 20 percent, with dilantin it's about 5 percent,

13 fetal alcohol syndrome is one percent of those

14 exposures in the country. So when you're looking at

15 environmental birth defects, fortunately, even if

16 you took 100 women and exposed them all, only a

17 minority would be impacted.

18 So I always tell them that "The

19 chances are always greater than not that you're not

20 going to have a problem. However, everybody is at

21 risk in our country of having a child with a birth

22 defect. Most of us don't ever think about it. I

406 1 certainly never thought about it. And if this is a

2 problem for you, if the child -- if your child is

3 born with a birth defect, if that's going to be a

4 problem for you, then you need to think about

5 getting pregnant altogether, because none of us get

6 a gilt-edged guarantee."

7 We can't tell them at this point that

8 we have seen an increase, or an increase over the

9 base line from exposures in the Gulf. We can tell

10 them that we're seeing some interesting clusters;

11 we're not sure what that means yet. But I can't

12 tell them to not have a child because they served in

13 the Gulf. I can tell them that everyone is at risk

14 of having a child with a birth defect.

15 MR. McDANIELS: And do they tend to

16 understand that? Does that tend to assuage their

17 fears?

18 MS. MEKDECI: They always seem --

19 yes, they do. They seem to feel better. In fact,

20 we get very nice letters, you know, that "Gee, it

21 was wonderful that you talked to us." And I can

22 talk to parents, because I have a son with a birth

407 1 defect. I've been there -- going through it. He's

2 twenty-one now; we've been through all the ages and

3 stages. And I can tell them, too, that it's not the

4 worst thing in the world that ever happens to you.

5 Of course, that also depends on the type of birth

6 defect. You know, with David, he's able to go to

7 school and work and everything. So I have a

8 particular insight.

9 I don't think anyone ever calls our

10 office and comes away horrified by anything we've

11 told them. I think they feel relieved. And I think

12 if you talk to some of the families, they would

13 share that with you.

14 MS. LASHOF: Marguerite?

15 MS. KNOX: Would you give us that

16 1-800 number that you spoke of earlier?

17 MS. MEKDECI: Sure. Sorry; I'm

18 getting a little hoarse. It's 1-800 313-2232. And

19 the 1-800 number, we've recently changed that.

20 We've had some problems with funding

21 in the last year, because half of our funds come

22 from the federal campaign, and this year,

408 1 unfortunately, there was the federal work stoppage

2 during the campaign, so a lot of organizations, not

3 just ours, suffered from that.

4 We are now -- we offer free

5 information on the line, and we do market several

6 kits that we're trying to use to pay for the

7 information line, so that we have everything

8 supported. So if you call that line, you'll have a

9 component where you can get free information about a

10 birth defect, you can get a free questionnaire

11 packet. You can order an Agent Orange information

12 package for a $15 donation. You can order a Gulf

13 War package, an environmental birth defect package.

14 Or you can become a member over the line.

15 I think we've caught the same thing.

16 MS. LASHOF: It's contagious.

17 Okay. Thank you very much.

18 MS. MEKDECI: Thank you.

19 MS. LASHOF: We do appreciate your

20 coming.

21 MS. MEKDECI: I appreciate it.

22 MS. LASHOF: And we look forward to


1 receiving further information from you.

2 MS. MEKDECI: Thank you.

3 MS. LASHOF: The next presenter is

4 Linda Shortridge-McCauley.




8 MS. McCAULEY: Betty was hoarse at

9 the end of her talk and I'm hoarse at the beginning

10 of mine, so bear with me.

11 MS. LASHOF: Well, hopefully, you'll

12 get better by the end.

13 MS. McCAULEY: Good morning, Madam

14 Chairman and members of the Committee. My name is

15 Linda McCauley, and I'm a scientist at the Oregon

16 Health Sciences University Center for Research on

17 Occupational and Environmental Toxicology and lead

18 epidemiologist of the Portland Environmental Hazards

19 Research Center, a joint research enterprise of OHSU

20 and the Portland Veteran Affairs Medical Center.

21 I've been asked to speak to you this

22 morning on the assessment of reproductive health in

410 1 special populations, specifically those having

2 occupational or environmental exposures to chemical,

3 physical, or psychological factors. Knowledge of

4 the potential reproductive toxicity of even rather

5 common occupational exposures is limited, as we've

6 heard frequently yesterday and this morning.

7 Assessing the impact, the health impact of exposures

8 to mixtures of chemicals and other types of agents

9 represents an extraordinary epidemiological

10 challenge.

11 Reproductive health effects have been

12 documented in populations defined by particular

13 workplace or environmental exposures. As discussed

14 yesterday, some of the best known associations

15 between environmental exposures and these health

16 effects are: lead salts and spontaneous abortions

17 and decreased fertility; DBCP; carbon disulfide;

18 also reports on spontaneous abortion increases with

19 workers exposed to anesthetic gases; and

20 reproductive effects in populations exposed to anti-

21 neoplastic drugs. The difficulty of delineating

22 relationships between environmental exposures and

411 1 reproductive health problems is increased when

2 exposures are multifactorial -- exactly what we're

3 dealing with with the experience of veterans of the

4 Persian Gulf War.

5 Second overhead, please.

6 At the Portland Environmental Hazards

7 Center we've designed a study that's looking

8 specifically at an array of different factors that

9 were present in the Gulf, including chemical and

10 biological exposures from petroleum products,

11 solvents, smoke, insect repellents, pyridostigmine

12 bromide, vaccines, vectors, diet, water. Physical

13 and psychological exposures include sand and heat,

14 and crowded living conditions and stress, and

15 perceptions of exposure to danger. It creates a

16 very complex picture. And it's difficult to look at

17 traditional reproductive epidemiological studies and

18 try to figure out a sane way to approach this, this

19 population.

20 Next overhead, please.

21 In an ideal situation when you're

22 trying to look at exposure determination, there are

412 1 four components that help you begin to get a true

2 picture of what happened in relation to exposure.

3 But five years after the war,

4 exposure determination presents a particularly

5 difficult task. Real-time measures are not

6 available: it's impossible to verify exposures to

7 vaccines, PB, insecticides, solvents, and infection

8 agents, for the large majority of veterans. We have

9 no work records to verify these exposures, and

10 self-reports are extremely problematic. We do have

11 data on smoke dispersion, but exposure to smoke can

12 only be correlated to troop unit movements, and not

13 movements of individuals in the theater of

14 operations.

15 Exposures may be gleaned, in part,

16 from an analysis of duties. But there are thousands

17 of codes for the types of work that the troops were

18 engaged in in the theater of operations. And

19 another important component is that there's no

20 details of the work outside of the usual duties

21 recorded in any systematic manner.

22 Some of the chemicals of specific

413 1 interest in the Persian Gulf War theater of

2 operations are PB and vaccines and pesticides.

3 However, none of these agents are known to induce

4 male-mediated genetic effects. Exposure to

5 alkylating agents associated with chemical warfare,

6 notably mustard gas, could theoretically have the

7 potential of causing germ cell damage. However, we

8 do not have confirmed documentation of any airborne

9 levels of these agents in the theater of operations.

10 Sparse information exists on the body

11 burden of environmental contaminants that our

12 veterans were exposed to in the theater, with the

13 exception of lead exposures and some troops exposed

14 to depleted uranium. Indeed, the problems of

15 exposure assessment seem insurmountable, at least in

16 comparison to methods routinely used in studies of

17 exposure and health effects in working populations.

18 We do, however, have an opportunity

19 to compare and contrast groups of veterans who had

20 disparate sets of potential exposures, because they

21 were deployed in the theater of operations for

22 distinct, identifiable periods.


1 And the Portland Environmental

2 Hazards Research Center, as you may already know, is

3 using this approach to assess risk factors and

4 unexplained illness in deployed Persian Gulf War

5 veterans. This research program was designed and

6 funded to focus on unexplained illness in veterans,

7 specifically cognitive problems, fatigue, and

8 musculoskeletal complaints -- not reproductive

9 problems. But the exposure determination issues are

10 relevant for whatever health condition that you're

11 focusing on.

12 Next overhead, please.

13 This overhead, which some of you have

14 already seen from previous presentations by Dr.

15 Spencer, head of our -- the Center for Occupational

16 and Environmental Toxicology -- it illustrates the

17 relationship between discrete deployment periods and

18 unique sets of chemical, biological, physical, and

19 psychological factors.

20 For example, those who were deployed

21 during the period of December 31st, 1990 to March

22 1st, 1991 may have been exposed to a unique set of

415 1 factors that included PB, special vaccines,

2 munitions, stress from combat and chemical warfare

3 alarms, and exposure to enemy prisoners of war. By

4 contrast with this Desert Storm period, veterans who

5 served only in the Desert Shield or desert cleanup

6 would have experienced quite different exposures,

7 which included the absence of PB and special

8 vaccines. Other factors, such as smoke from the oil

9 well fires, overlapped two deployment periods.

10 Although focusing on distinct

11 deployment time periods does not address all

12 exposures of interest in this population, it does

13 provide an excellent mechanism to determine

14 differences between risk of disease in relation to

15 some of the key exposures of interest.

16 As I mentioned before, the Portland

17 Environmental Hazards Research Center's mission is

18 to look at the impact of environmental hazards

19 encountered in military service on human health.

20 And we look at this mission both in terms of hazards

21 in the past, in the present, and in the future. And

22 our initial focus has been on unexpected

416 1 illnesses,but we are cognizant of the reproductive

2 problems that veterans are reporting, and are

3 looking at our research program to see how it might

4 be adapted to more specifically address these health

5 problems.

6 The next slide shows the framework

7 for the Portland Environmental Hazards Center, which

8 is a joint effort between OHSU and the Portland VA

9 Medical Center. There is an epidemiology core. We

10 coordinate with the Persian Gulf Registry. We have

11 a multidisciplinary team of clinicians,

12 epidemiologists, biostatisticians, and also some

13 scientists who specialize in the area of biological

14 markers. We have a protozoa disorder study.

15 And then we have research projects

16 that are laboratory-based in the areas of

17 neuropsycho- -- neuropsychology, neuroendocrinology,

18 neurotoxicology, and genetic toxicology.

19 The epidemiology core -- I want to

20 give you a little more detail on exactly the

21 population that we're accessing to identify the risk

22 factors for unexplained illness. We're focusing on

417 1 veterans from the northwest United States who were

2 deployed to the Persian Gulf region during the

3 approximate one-year period after August 1990.

4 We're using data provided by the U.S. Department of

5 Defense as our sampling frame. A stratified random

6 sample of subjects has been selected, and they are

7 being mailed a self-completion questionnaire.

8 Now, we grouped our population into

9 strata according to the deployment periods that I

10 described previously. And those deployment periods,

11 again, are the Desert Shield only, the Desert Storm

12 only, and the desert cleanup only, and then veterans

13 serving in a combination of those time periods.

14 We had to use a purposeful

15 oversampling of those, what we call the clean

16 deployment periods, because if you look at the total

17 deployed veteran population, each of those clean

18 deployment periods were less than 10 percent of --

19 each were less than 10 percent of the total

20 population.

21 We've designed a sampling strategy in

22 which 50 percent of the veterans that we will be

418 1 contacting will have served in only one of these

2 clean specific deployment periods. And the other 50

3 percent of our sample includes veterans who served

4 in a combination of time periods, with an

5 oversampling of women and reservists.

6 This overhead shows that at the time

7 of deployment to the Gulf, there were approximately

8 24,000 veterans who listed Oregon or Washington as

9 their home state of residence. To be able to

10 contact these veterans and to bring them in for

11 clinical studies, we focused on only those veterans

12 who still remain in the Northwest, which is

13 approximately 8,000. We're mailing the survey to a

14 randomly selected, stratified sample of 3,000

15 veterans.

16 We're mailing the questionnaires in

17 waves. Because we follow the responders to the

18 questionnaires with tele- -- a random selection of

19 responders are contacted to participate in our

20 clinical case-control studies, so we're doing the

21 questionnaire mailing in waves so that there's not a

22 long time lapse between the time that they receive

419 1 the questionnaire, perhaps are interested in

2 participating in the research, and then will come in

3 and participate in the clinical component.

4 Women comprise 7 percent --

5 approximately 50,000 of the total PGW deployed

6 population. Of the 8,000 veterans in our Northwest

7 cohort, 535, only 6 percent are women. We are

8 contacting all of these women in our -- in our

9 survey, and this will only increase our proportion

10 to 12 percent females. While this rather low

11 percentage hampers our efforts to explore the

12 relationship between risk factors and unexplained

13 illness in veteran -- female veterans, it presents

14 severe limitations in investigations of reproductive

15 health effects in females.

16 Though the major aim of our survey is

17 to contact this random population-based sample to

18 study unexplained illness, we're sensitive to the

19 concern of many veterans regarding the status of

20 their reproductive health, and receive and answer

21 many inquiries and questions regarding reproductive

22 health from veterans who hear of our Center.


1 We have included reproductive health

2 components on our survey questionnaire. These items

3 are similar to those that are included in the VA

4 National Prevalence Survey currently in progress and

5 the CDC-Iowa study. We purposely looked at those

6 questionnaires in our development phase so that we

7 would have comparable measures.

8 Our questionnaire contains self-

9 reported pregnancy histories and outcomes, including

10 stillbirths and spontaneous abortions, the health of

11 children, the inability to conceive, decreased

12 libido, menstrual function, use of contraceptives,

13 sexually transmitted diseases, and abnormal Pap

14 smears. The survey instrument also includes in-

15 depth components on exposures in the Persian Gulf,

16 military history, family history, lifestyle factors,

17 and occupational -- current occupation and

18 occupational history.

19 It's important to remember that our

20 survey is not designed to compare rates of illness,

21 including specific reproductive outcomes in deployed

22 troops, to rates in non-deployed troops. We're

421 1 specifically looking at the deployed population.

2 The inclusion of these items on this survey is

3 designed to assess the general reproductive health

4 of a limited sample of deployed veterans. We do not

5 have specific hypotheses regarding exposures in the

6 theater of operations and reproductive outcomes.

7 The next slide, please.

8 We knew, going into the study, that

9 we would not have the sample size to do reproductive

10 effects with any success. If we achieve a 70

11 percent response rate to our mailed survey -- and as

12 you may have heard from some of the other research

13 going on in the country, achieving a 70 percent

14 response rate is going to be a champagne day in

15 Portland. But if we were to get 70 percent

16 response, we expect to have approximately 400

17 pregnancies conceived after March 1991.

18 Now, while these data could be

19 potentially leaked with -- linked with pregnancy

20 outcome data from other studies, our study alone, as

21 shown on this overhead, does not have the power to

22 do anything statistically to detect differences

422 1 between deployment groups.

2 We project that we may have the

3 sample size to compare rates of infertility among

4 responders in the different deployment strata, and

5 perhaps to do some analysis of spontaneous abortion

6 rates if female veterans and spouses of male

7 veterans are combined. This would be preliminary

8 analysis only; we would not have the sample size to

9 do any multifactorial types of analyses.

10 Even with obtaining these

11 reproductive data, as Dr. Correa mentioned today in

12 the very well designed semiconductor study at Johns

13 Hopkins, we will not -- to verify the spontaneous

14 abortion rates would be quite a challenge in a

15 population-based survey like this. So verification

16 would be extremely difficult.

17 And also, we have no time-

18 specificity. These are pregnancies that basically

19 occurred after the veterans returned home. We

20 really don't have pregnancies that occurred while

21 the exposures were taking place.

22 From our population-based survey

423 1 design, we've been able to obtain a sample of

2 veterans, of whom 90 percent have not previously

3 sought medical attention in the VA or DOD

4 registries. This population is highly mobile, and

5 requires intensive follow-up of non-responders to

6 achieve representative samples.

7 From the responders to our survey,

8 we're recruiting 250 subjects reporting symptoms of

9 unexplained illness and 250 health controls who will

10 participate in the clinical evaluation component of

11 our study. The response rate for the clinical

12 evaluation component has been very positive: 80

13 percent of the questionnaire responders have agreed

14 to be contacted for future studies, and enrollment

15 rates for the clinical case-control study are

16 approximately 80 percent. That's for veterans

17 living within fifty miles of our Center. We'll have

18 to do satellite clinics as we move out into other

19 areas of the Northwest. The participation rates for

20 cases and controls are comparable, to date.

21 During our clinical evaluation of

22 cases and controls we obtain samples of blood,

424 1 lymphocytes, and skin to assess DNA damage and

2 repair, in a study being conducted by Dr.Glen Kisby

3 at OHSU. Two questions are being asked by Dr.

4 Kisby: one, the first, is to try to determine if

5 there's evidence of greater DNA damage in tissues

6 from cases versus controls, in particular DNA damage

7 that could be linked to exposure to alkylating

8 agents; secondly, we will attempt to ascertain if

9 the DNA-repair capacity of cases differ from that of

10 controls.

11 As was discussed yesterday, could

12 chemicals associated with the Persian Gulf War have

13 produced infertility or genetically altered

14 offspring in the male veteran population? We are

15 currently considering an extension of Dr. Kisby's

16 DNA research into the area of germ cell

17 cytogenetics.

18 DNA-repair systems are present in

19 spermatogonia and spermatocytes. There is a need to

20 develop and validate semen markers of genetic

21 toxicity and induced mutations, including DNA

22 adducts in mature sperm. Studies of DNA repair have


1 been performed also on spermatogenic cells by

2 measuring the unscheduled DNA synthesis required to

3 repair an excised length of damaged DNA. While the

4 results of these studies may indicate the presence

5 of abnormal DNA in sperm, the origin of the damage

6 is not thereby indicated.

7 CROET also has available in-house a

8 DNA-repair-deficient mouse model which might have

9 utility in screening chemical agents for gonadotoxic

10 effects. Such research endeavors could benefit, not

11 only the veterans of the Persian Gulf War, but also

12 future military and civilian populations and their

13 families.

14 In conclusion, the Portland

15 Environmental Hazards Research Center's primary goal

16 is to identify risk factors associated with

17 unexplained illness. But we recognize the concerns

18 of veterans of the Persian Gulf War regarding their

19 reproductive health and the health of their families

20 and offspring. We really welcome opportunities to

21 collaborate with other researchers, particularly in

22 the area of achieving sample sizes needed for

426 1 epidemiological investigations. And we welcome

2 opportunities to expand our research program to

3 include specific laboratory investigations of the

4 cytogenetic potential of exposures encountered by

5 veterans of the Persian Gulf War and by servicemen

6 and women of the future.

7 Thank you for the opportunity to

8 present our program.


10 MS. LASHOF: Thank you very much, Dr.

11 McCauley.

12 Are there questions for Dr. McCauley?

13 Joe?

14 MR. CASSELLS: Yes, I have two

15 questions to begin with.

16 In your earlier part of the

17 presentation you indicated in the pre-combat, the

18 Desert Shield environment, there was absent

19 botulinum toxoid, absent anthrax, absent PB. My

20 understanding is that anthrax and botulinum were, in

21 fact, administered prior to Desert Storm during the

22 time of Desert Shield. Is that accurate?

427 1 MS. McCAULEY: Towards the end of

2 Desert Shield, but not in the group that were

3 deployed in the August/September/October -- the

4 buildup period. We've not had any documentation of

5 that.

6 MR. CASSELLS: Anthrax is, I think, a

7 three -- for a full course of immunization, is a

8 three-shot at various intervals.

9 MS. McCAULEY: No; the anthrax was a

10 special pre-combat type of preparation vaccine, and

11 not part of the routine, that vaccine series that

12 everyone would get.

13 MR. CASSELLS: Right; I understand.

14 I'm just getting some -- trying to get some feel for

15 at what point in time anthrax was given.

16 MS. McCAULEY: We believe it was not

17 in the early fall period, that clearly there was

18 some -- they began giving vaccines toward the end of

19 the Desert Shield period for people who were going

20 to remain in the theater.

21 But this Desert Shield group is a

22 very interesting group. They may have gone over two

428 1 or three times for short periods of time, or were

2 there for a specific purpose, and were in the

3 buildup period and then were returned back to the

4 United States before the combat. So they had the

5 environmental exposures, but they really were not

6 part of the combat picture.

7 MR. CASSELLS: Okay. Considering the

8 limitations, the considerable limitations you have

9 put upon the information that you can get relative

10 to reproductive effects of these exposures in the

11 veterans population you're looking at, at best, what

12 do you think your study can do?

13 MS. McCAULEY: Well, I think, as

14 pointed out yesterday, if there are male-mediated

15 genetic effects, it's -- you should be able to see

16 those effects in infertility rates. And some of the

17 population studies, the Portland study and some

18 others that are being conducted in the United

19 States, need to look at those rates, and

20 particularly if we have samples of non-deployed

21 troops, as a first cut, to see if there's any

22 evidence. It's going to be much easier, probably,

429 1 to assess an effect on fertility than it's going to

2 be in terms of an effect on birth defects.

3 MR. CASSELLS: Specifically.

4 MS. McCAULEY: So I think that that

5 is an area that merits attention.

6 In spontaneous abortion rates, again,

7 it's just not similar to a lot of occupational

8 studies where you look specifically at pregnancies

9 that are conceived while the exposure is taking

10 place. It's just a very different type of

11 phenomenon that we're dealing with with the Persian

12 Gulf War.

13 MR. CASSELLS: So --

14 MS. McCAULEY: But I think as a -- I

15 think as a first cut, those are two things that we

16 should look at in populations.

17 MR. CASSELLS: So at best, you may be

18 able to generate a hypothesis?

19 MS. McCAULEY: It'd be interesting to

20 see if post-Persian Gulf War there was a difference

21 in fertility rates in these deployment strata. That

22 would lead to some interesting speculation about

430 1 exposures and effects. But you don't know unless

2 you do that preliminary look at the data.

3 MS. LASHOF: All right.

4 MS. KNOX: What are you doing in

5 particular to attract veterans to filling this

6 survey out? How are you going about advertising

7 that to veterans?

8 MS. McCAULEY: We don't really

9 advertise. The sample is randomly selected, and

10 they receive the questionnaire, follow-up post card,

11 then a replacement questionnaire. And then we are

12 phoning all non-responders. This is something that

13 we did not anticipate having to do, but our -- after

14 the three contacts our response rate was 53 percent.

15 And so by contacting non-responders, we're trying to

16 push that up --

17 MS. KNOX: A little higher.

18 MS. McCAULEY: -- between 60 and 70

19 percent. We're also giving a $10 incentive to

20 return the questionnaire, to complete and return the

21 questionnaire. There's a $50 incentive to come in

22 for clinical exams.


1 MS. LASHOF: Any other questions?

2 Tom?

3 MR. McDANIELS: In terms of branch of

4 service, is your -- this population representative

5 of the Desert Storm and Desert Shield population?

6 MS. McCAULEY: Yes. Our data are

7 comparable to the general frequency distributions in

8 the DOD database.

9 MR. McDANIELS: Okay. I was just

10 concerned that with the Northwest population you

11 might have an overrepresentation of Navy personnel

12 and different exposures for them.

13 MS. McCAULEY: It doesn't appear to

14 be, no. I think this -- the Northwest cohort

15 included people who were stationed all over the

16 United States, but listed Oregon and Washington as

17 their home state of record at the time of

18 deployment, so it's not just people who were just

19 stationed here. So we're not seeing any distinct

20 differences in the branch of service.

21 MS. GWIN: Thanks very much, Dr.

22 McCauley.

432 1 MS. McCAULEY: Thank you.

2 MS. GWIN: We'll start our next panel

3 now on diagnosis, defining syndromes, determining

4 prevalence, and surveillance.




8 MR. HOLMES: Shall we start?

9 MS. GWIN: Dr. Holmes, thank you.

10 MR. HOLMES: Thank you. I appreciate

11 the opportunity to make my presentation. I'm here

12 as a geneticist and teratologist. I spend my time

13 trying to learn how to identify environmental causes

14 of birth defects, and I spend time trying to

15 identify specific malformations, either hereditary

16 or environmentally-induced. So my role is that of

17 the clinician, who presumably would -- could, in any

18 proposed assessment of Gulf War veterans' children,

19 assess whether there is a distinctive phenotype or

20 not.

21 As you know from the presentations

22 already been made, that the exposures known to be

433 1 human teratogens have been recognized as producing a

2 distinctive pattern of abnormalities, and this would

3 be the role of the clinician.

4 In the slides I have in the carousel,

5 I want to present four things:

6 The definition that I think could be

7 used for major malformations, as opposed to minor

8 anomalies;

9 The prevalence, as we've seen it in

10 our own studies, of major birth defects;

11 Some observations about how one

12 identifies a syndrome and the problems in that

13 process;

14 And then I'd like to make the final

15 pitch about the fact that major birth defects are

16 now being shown to have many etiologies, and that

17 heterogeneity of the phenotype is the rule rather

18 than the exception.

19 All of these are points arguing

20 against any cursory, long-distance analysis of large

21 data sets that can't consider these points. So

22 let's go through this, these slides.

434 1 Operationally, everyone struggles

2 with the definition of a major malformation. And

3 I'm showing you data that comes from hospital data,

4 a hospital-based active malformation surveillance

5 program. One of the things I would make a pitch to

6 consider, if you're proposing large birth defect

7 surveillance, you need -- you're going to need a

8 subset of folks who are able to look closely at the

9 affected children themselves.

10 We've used this cumbersome definition

11 -- it works. It's structural. It has -- it has

12 surgical, medical, or cosmetic importance. And you

13 have to distinguish it from the much more numerous

14 minor anomalies and normal variations. I submitted

15 a handout that I'll use to follow -- I'll follow

16 along that handout in my comments. But this will be

17 one of the points I'd like to illustrate, that the

18 structural major abnormalities are the key that

19 we're talking about.

20 Frequency. We carried out at Brigham

21 and Women's Hospital in Boston an analysis of the

22 birth defects identified in children through ten

435 1 years of our active hospital surveillance. You'll

2 see that in this ten-year period 69,000 infants were

3 born, and the overall prevalence rate was just a

4 little over 2 percent.

5 We carried out something that hadn't

6 been done before we did this, which is, break it

7 down by recognized cause. You can see -- everyone

8 always talks about the unknowns. Clearly, there's

9 still a large group that's unknown. The different

10 categories of recognized causes are listed. There

11 clearly is a group of about 25 percent that's in the

12 strictly genetic category. And another large group

13 -- we only put in this category conditions where the

14 data available from large studies were consistent

15 with the understanding of multifactorial

16 inheritance.

17 Now, you'll notice the parentheses.

18 One of the advantages of a hospital-based

19 surveillance program is that you can identify

20 elective terminations for structural abnormalities,

21 a problem that all the data sets that have been

22 discussed so far have had to struggle with.


1 We're finding at this hospital about

2 a third now of all the children with major birth

3 defects, the abnormalities have been identified in

4 utero. And so there's a steady increase in the

5 number of elective terminations. If you're dealing

6 with a data set that doesn't include elective

7 terminations, you obviously have an enormous problem

8 of "What am I missing?"

9 This data analysis was completed in

10 '85. So if you look for the data for, say 1995, the

11 numbers in parentheses will be much higher. This

12 table comes from -- this paper is in the materials I

13 submitted to the panel.

14 Race makes a difference. You can see

15 here, not data from us, but from CDC, showing the

16 obvious variation between two large racial groups

17 that are available to them in the greater

18 metropolitan area where they carry out their active

19 surveillance program.

20 Another thing that makes a big

21 difference is excluding minor anomalies and normal

22 variations. These are some that, if written into

437 1 the hospital medical record, would be very common.

2 A Sidney line is one of the creases on the palm of

3 your hand; you're probably more familiar with the

4 simian crease. But the point is, when you're doing

5 studies like this, you know birthmarks and minor

6 anomalies are very common, and you're pointedly

7 excluding those from your tabulation.

8 Now some comments about the

9 clinician's role and the specificity of the

10 phenotype. These things make a difference. Noting

11 not just that there's syndactyly, but that it's

12 webbing between the third and fourth fingers in the

13 hand and the same in the feet -- this is a specific

14 genetic phenotype. And if you had a generic

15 syndactyly group, it would miss that specificity:

16 the mother had the same thing.

17 Here's another child. You can see

18 how when you take pictures of infants and children,

19 you end up with larger magnification of the holder's

20 hand than you do of the poor child, who's not too

21 interested in the photograph being taken. The

22 fourth and fifth finger here are webbed together.

438 1 And the point is, this is obviously distinctively

2 different from the one I showed before.

3 And then here's a third variation.

4 Here the child has -- you'd probably say, "Well,

5 gee, that arm is a bit turned" -- that's because

6 there's underdevelopment of the radius -- and the

7 webbing is between the first and second fingers.

8 This is a totally different disorder. This is a

9 child who actually had the Holt-Oram syndrome where

10 the father and several siblings had shortening of

11 the radius to various degrees, and this one happened

12 to have syndactyly of the first and second fingers.

13 So the specificity is important for

14 the major problems. And it's equally important to

15 exclude things that are usually categorized as minor

16 anomalies of no great significance.

17 One of the things that bedevils

18 surveillance programs is that webbing between the

19 second and third toes, which is extremely common,

20 gets listed with the same weight as the things I

21 just showed you. And it's clearly a trivial finding

22 with low predictive value of any associated major

439 1 birth defect.

2 Polydactyly. We heard yesterday the

3 comment that race makes a big difference. This kind

4 of polydactyly is much more -- ten times more common

5 in blacks than in whites. It has no great medical

6 significance, but shows up on all the birth

7 certificates in passive medical systems.

8 In terms of recognizing a syndrome,

9 that kind of polydactyly is very different from this

10 one, which doesn't show, which is -- there's a thumb

11 here with an extra bone, which I think will show up

12 better in the X-ray. This is called preaxial

13 polydactyly, on the other side of the hand, where

14 there is an extra bone in the thumb. So in terms of

15 recognizing syndromes, those that have postaxial

16 polydactyly over here, like in the previous child,

17 picture of the little infant, there's some entities

18 that have postaxial polydactyly. This is showing you

19 preaxial. So the record has to be specific enough

20 to note where the polydactyly is and the nature of

21 the polydactyly, or else you'll miss the whole

22 point.

440 1 Now, here is an example of -- I'm

2 going to show you a few syndromes with some of the

3 problems that would bedevil the listing of these in

4 medical records.

5 This woman has a condition that's

6 associated with normal intelligence and lifespan,

7 but some terrible birth defects -- shortening of the

8 forearm, with shortening particularly of the radius,

9 missing the thumb, sometimes index finger. This

10 individual would be recognized easily from a medical

11 record because of the severity of the problem.

12 By contrast, other members of the

13 family who have the gene will simply have these very

14 prominent thumbs. And this would be the part of the

15 phenotype that would be easily missed. So here's an

16 example of a genetic condition. If you were

17 considering, as Dr. Brent pointed out, that the

18 exposure might be mutagenic, this would be the kind

19 of thing that you'd need to be able to address in

20 your surveillance system.

21 Here's another genetic disorder that

22 would be a candidate for being increased among

441 1 individuals exposed to a potential mutagen. You can

2 see here it's a young child whose external ear is

3 deformed in a way that would be considered mild to

4 moderate, but is -- this kind of severity is often

5 associated with significant hearing loss.

6 For the surveillance issue, would it

7 be recognized that she had a pit here in her neck?

8 You can see the tape from the surgery that she's

9 had, already had on the other side, where these

10 branchial cleft cysts were being removed. The

11 association with the external ear malformation and

12 the cyst makes this a specific entity. So there has

13 to be enough ability to spot this.

14 And here's her mother. And even

15 though it's obvious to us, sitting here today, she's

16 got the less cosmetic scar from the removal of her

17 cysts, and the very obvious abnormality of her ears.

18 She didn't realize that what this is is a genetic

19 condition until her children were found to be

20 affected. That's -- this is the disorder. It's now

21 pretty well recognized by clinical geneticists. A

22 lot of the care providers aren't familiar with it,


1 but it's a fairly well-delineated condition.

2 Another example, a child is born with

3 an imperforate anus. That's obviously a serious

4 malformation from many standpoints. If it's

5 associated with this kind of ear deformity -- this

6 is the kind of ear deformity associated with

7 imperforate anus, and hands like this that Drs.

8 Townes and Brocks reported many years ago. It's now

9 recognized as a specific entity. Here again you

10 have the polydactyly, where the thumb simply has an

11 extra bone in here, shown on the radiograph. So

12 that would be the kind of phenotype you'd be wanting

13 to rule out if you were looking at a record of a

14 child with imperforate anus.

15 Well, we've talked a lot about

16 Goldenhar syndrome. And I just wanted to show

17 visually the issue of variation in phenotype, with

18 some commonality of the components: the asymmetric

19 lower face with a hypoplastic mandible; the ear

20 deformities can be quite variable, often as severe

21 as a very poorly developed external ear; varying

22 degrees of pits and tags in front of the ears; an

443 1 asymmetric mouth; some lesions on the eye that are

2 called epibulbar dermoid; and occasionally a variety

3 of other malformations such as vertebral anomalies

4 or heart defects.

5 So if you were trying to pick this

6 up, you'd be looking for a variety of outcomes, and

7 you'd certainly need to have the benefit of somebody

8 examining the child who was familiar with things

9 like this.

10 So this will show you what microtia

11 looks like, severe end of the spectrum; sometimes

12 the ears are not nearly so malformed. Here's

13 obviously a much more normally formed ear, but in

14 association with these dramatic tags in front of the

15 ear. You probably wouldn't be sure of it, but the

16 side of the mouth here is extending around further

17 than it should. That's what macrostomia means. And

18 here's a newborn who's got the microtia on one side,

19 and you can see -- while asleep, you can see the

20 macrostomia very easily.

21 The key is that the person who's

22 writing the material on the form is sensitive to

444 1 these findings. The problem with this kind of work

2 is that busy pediatricians -- and with discharge

3 earlier and earlier, you can imagine it's harder for

4 everyone to get the thorough exam that might be

5 needed to settle the presence or absence of some of

6 these findings.

7 Dr. Olney yesterday was commenting

8 that the key to recognizing the Goldenhars in the

9 cases they surveyed was that someone took the time

10 to do the consultation exam that really was the key

11 to settling that it was, indeed, Goldenhars.

12 The epibulbar dermoid doesn't cause

13 any pain or any problems, but it creeps out in a way

14 that scares you that it's going to impede the pupil

15 of the eye. But fortunately, that usually does not

16 cause problems. I wasn't sure how well that would

17 project, and I put in another slide from an older

18 boy showing the same thing.

19 Okay, so that shows you a lot of

20 specific examples.

21 When we went through our data set, we

22 identified in these years, through about 160,000

445 1 births, six infants with the Goldenhars phenotype.

2 And I think you can appreciate the issue of

3 variability as you look at the pluses across the

4 table here. Yes, microtia occurred frequently, but

5 not in all infants. The tags were also common, but

6 not in all, and so forth. The smallness of the

7 mandible is the key finding -- occasional cleft lip

8 or palate, occasional vertebral anomalies, and a

9 variety of other malformations.

10 You might not have noticed when you

11 quickly scanned this the point I'm making here about

12 transfer status. When you work at a tertiary

13 hospital, you have to exclude the women who hadn't

14 planned to deliver there, because that's a bias of

15 being at a tertiary center.

16 One of the mothers had had prenatal

17 screening that picked up that the child was

18 stillborn, and came simply for termination of

19 pregnancy after fetal demise. The other had

20 hydrocephalus diagnosed, had planned to deliver at

21 another hospital. So if you're establishing

22 prevalence rates, you've got to be able to do that,

446 1 and you'd exclude these two cases from your

2 estimates of prevalence, and come out with roughly

3 four in 160,000.

4 MS. LASHOF: That's a lower incidence

5 than many others we've heard so far, isn't it?

6 MR. HOLMES: Well, statistically I

7 don't know whether most -- the larger data sets that

8 have similar quality in the data will come in at one

9 in 25,000. And we haven't done a calculation of

10 whether our one in 40,000, out of 106,000, is

11 significantly different from one in 25,000, out of,

12 say, 950,000 births, so -- but I think it

13 illustrates the impact of prenatal detection of,

14 obviously, the stillbirth.

15 So you come back to this group. What

16 you'd expect to see -- I'd like to make the next

17 point about phenotypic heterogeneity, which

18 obviously pushes a child around in the apparent

19 etiology, depending on how you put the things

20 together.

21 The first point I would make concerns

22 the well-known disorder of spina bifida, shown here


1 on the right. We've looked at the data over many

2 years. This is an old slide, but it make the point.

3 Everyone is very familiar with anencephaly and

4 encephaloceles and spina bifida. Most of these

5 conditions are now being diagnosed prenatally. The

6 pregnancies typically do not get to term, so they

7 would be missed if you were not including elective

8 terminations for birth defects.

9 Down at the bottom is a key point:

10 out of the children being surveyed here, 10 percent

11 had, in association with a neural tube defect,

12 either a chromosome abnormality or were part of a

13 specific syndrome, many of which are hereditary.

14 And so if you were looking at neural tube defects,

15 heart defects, any group you want to name, being

16 able to separate out the chromosome abnormalities,

17 separate out the autosomal recessive disorders, is

18 very crucial before you allege an environmental

19 exposure.

20 Just another example. We're just

21 starting a sample of the apparent association of

22 limb deficiencies and the prenatal procedure of

448 1 chorionic villus sampling. Here is a visual

2 illustration of what a mixed group of infants' limb

3 deficiencies are.

4 My colleagues in epidemiology always

5 like to lump these children together. And our

6 concern is that it's a very heterogeneous group. So

7 if you had in your study limb deficiencies as a

8 single outcome, look at what a mixture you'd have:

9 disorders due to dominant or recessive genes,

10 chromosome abnormalities, specific syndromes, then

11 the much smaller group that would be relevant to

12 your alleged environmental exposure.

13 So just to complete the point about

14 etiologic heterogeneity, let's go back to the entity

15 that I mentioned earlier, the microtia, which is a

16 feature of Goldenhars. And this child actually is

17 one of that group of children.

18 If we looked at the 160,000 births

19 and said, "Okay, let's just focus on microtia,"

20 would that lead us to the Goldenhars? I think you

21 can see here very vividly that it's quite a mixed

22 group of infants. There are -- there were, out of

449 1 the 160,000 births, fourteen with just isolated

2 micro- -- microtia, eleven who had microtia as part

3 of multiple malformations.

4 You can see that there were dominant

5 and recessive genes accounting for one subgroup;

6 chromosome abnormalities is another group; specific

7 syndromes, which included Goldenhars. The impact of

8 twinning, which is a major issue for some birth

9 defects is shown here. And then there are a lot of

10 unknown etiology. So if you -- if you used microtia

11 as if it were Goldenhars, you can see how you'd

12 misrepresent the data. You'd have twenty-five

13 infants listed, only four of whom really had this

14 disorder.

15 Finally, the impact of minor

16 anomalies, which bedevils surveillance programs,

17 because the people extracting medical records have

18 difficulty excluding minor features from major ones.

19 And the minor features are much more common.

20 Here's an infant who on one side of

21 his face has big preauricular tags, on the other

22 side has very small preauricular tags. When we did

450 1 many years ago a study of the prevalence of minor

2 features, you can see how very common these are,

3 whether it's the tags in front of the ear, on the

4 ear lobe, or in other regions.

5 So in summary, what I've done is make

6 a pitch for the need for folks involved in looking

7 at the birth defects, who are sensitive to the many

8 etiologies of common birth defects and would be able

9 to exclude the much more common and less significant

10 minor physical features.

11 If out of this, these hearings, there

12 is a proposal made to examine Gulf War-exposed

13 children, or fathers who were exposed in the Gulf

14 War, or mothers, I would stress the fact that we've

15 learned the hard way from other studies of exposures

16 that simply coming up with an exam protocol doesn't

17 solve the problem. Because folks, well-meaning,

18 who've got the same definition in front of them,

19 we've shown in other studies they don't find the

20 same frequency, because that internal definition

21 overrides whatever is written on the paper. And

22 you'd need to be sure you had a small number of

451 1 examiners, and they'd need to be given the

2 opportunity to see whether there really is anything

3 distinctive about the phenotype or not.

4 Thank you.


6 MS. LASHOF: Thank you very much.

7 Questions? Kathi?

8 MS. HANNA: Dr. Holmes, in your

9 studies and when you're trying to determine

10 etiologies, you obviously have to go back and

11 collect extensive family histories sometimes --

12 MR. HOLMES: Sure.

13 MS. HANNA: -- pregnancy histories.

14 Can you give us any idea of the amount of time that

15 has to be spent? And once you have a diagnosis and

16 you're trying to collect data to try to determine if

17 etiology can be determined, how much time does it

18 take per case, very roughly? And what kind of

19 people are needed to collect that kind of data and

20 those histories?

21 MR. HOLMES: Well, if you look at the

22 way this is done, there is the exhaustive "spend an

452 1 hour getting the pedigree" approach, versus focusing

2 on the immediate family. If you look in the reprint

3 I enclosed with this, there's a list of the

4 frequency with which the child, even with genetic

5 disorders, is a total surprise to healthy parents,

6 and there is no family history. And there are

7 X-linked causes of malformations, but most are

8 dominant and recessives. And the immediate family

9 is the key.

10 And so what I would -- what I do when

11 I do this kind of work is have an individual

12 designated who will do the pregnancy history review

13 with the mother, do the pedigree, confirm it with

14 both parents, pursue anything in the close members

15 of the family that seems worth pursuing, but not go

16 into exhaustive detail on distant relatives, because

17 that really doesn't help you very much.

18 And that individual can be trained to

19 do this work. A college graduate who is motivated,

20 interested, and organized is a starting point.

21 Obviously, the more experienced the person, the more

22 help they would be. But you don't have to have


1 someone who is coming at this with a lot of

2 postgraduate training.

3 MS. LASHOF: To confirm the diagnosis

4 of Goldenhar, how extensive would the exam --

5 MR. HOLMES: How many features have

6 to be there?

7 MS. LASHOF: Who would we need?

8 Would we have to bring every case to you, or send

9 you to each one to examine them to confirm? It

10 strikes me that if indeed Betty Mekdeci's group has

11 nineteen Goldenhars in Gulf War veterans,

12 considering how many births there have been, if

13 these were all Goldenhar, it would probably be

14 significant. But how are we going to find out

15 whether they would meet the criteria to compare to

16 these incidence figures?

17 MR. HOLMES: Well, whether the

18 prevalence rate is increased would be a separate

19 issue. But this -- there are lots of clinicians who

20 do this. The key is that the person who examines

21 the child has the knowledge up front of what they're

22 looking for. You know, there's a sensitization

454 1 issue that goes on when you learn how to do this.

2 And so if you pick people who are experienced

3 clinicians, all of whom are aware of -- have

4 participated in developing whatever protocol they're

5 going to use, there are lots of people who could do

6 it.

7 I think the key, as I would suggest,

8 is that the examiner be unaware of who was who, and

9 that if there is a group of children who are --

10 whose fathers served in the Gulf War, with birth

11 defects, that there be a comparable group who have

12 similar malformations, whose fathers didn't serve,

13 and that some consideration go into trying to decide

14 how to match them, so that there wouldn't be an

15 obvious difference in severity or something like

16 that in the group. And then let the experienced

17 individuals do the exam.

18 Because if you look at what we've

19 learned from other environmental causes of birth

20 defects, there should be some specificity to the

21 phenotype. And if there isn't, that's helpful. And

22 you know, they'd examine the children blindly,

455 1 figuratively speaking, and then --

2 (Laughter.)

3 -- the data would be pulled together

4 and you'd be able to speak to that point.

5 I think geographic constraints are an

6 issue. You'd want to -- if you have a group of

7 folks that are in the Pacific Northwest, there are

8 lots of people who are well-trained clinicians,

9 could do this in the Pacific Northwest.

10 The thing I'd want to caution you

11 about, which I mentioned earlier, is, we tried in

12 other studies to have everyone agree on an exam

13 protocol, and that doesn't solve the problems of

14 variations from examiner to examiner. That's just a

15 real fact of life in this work. I doubt that it

16 would be a fact of life for the outcomes I showed

17 for Goldenhars. Saying whether an epibulbar dermoid

18 was there or not is probably going to have a high

19 reproducibility level. I think subtleties like "Is

20 the bridge of the nose depressed?" "Are the

21 fingernails small?" -- that kind of subjectivity is

22 where you get in trouble with these protocols.

456 1 MS. LASHOF: Thank you very much.

2 MR. HOLMES: You're welcome.

3 MS. LASHOF: Very interesting.

4 Any other -- Joe?

5 MR. HOLMES: I was supposed to share

6 this, share the microphone with Larry Edmonds, who's

7 here, CDC.

8 MS. LASHOF: Yeah. Right. That's

9 what I --

10 MR. HOLMES: Which is going to get

11 all the money that comes out of this.

12 MS. LASHOF: I'll ask Larry to come

13 forward now.




17 MR. EDMONDS: Good morning. Thank

18 you very much for the invitation to address the

19 Committee.

20 My name is Larry Edmonds. I'm an

21 epidemiologist at the CDC in the Birth Defects

22 Branch. I've worked at CDC for a number of years,

457 1 and a majority of that time has been managing

2 surveillance activities in our branch. And in the

3 last few years I've been working with state health

4 departments on developing and implementing a

5 surveillance program.

6 I was asked by the staff to talk

7 about surveillance methodologies for birth defects

8 and talk about what we do at CDC and what's going on

9 in surveillance in the United States with state

10 health departments and other programs.

11 You've seen some of these slides

12 before, but I think it's important to talk about why

13 we're interested at CDC in birth defects and

14 prevention, in that you know that birth defects are

15 the leading cause of infant mortality.

16 I think it's important to point out

17 that -- how many children are affected each year

18 with a major birth defect. We talk about 3 or 4

19 percent, but that's a large number of infants that

20 are affected each year. So depending on how you

21 define a birth defect, 120- to 160,000 babies a

22 year.


1 Thirty percent of these infants are

2 admitted to a pediatric hospital. And the medical

3 cost associated with this is phenomenal. A recently

4 published article estimates that $8 billion lifetime

5 costs are associated with eight major -- eighteen

6 major malformations. So a baby born in 1992 -- that

7 will be with those eighteen malformations, the

8 lifetime cost will be that $8 billion.

9 And more importantly, I think now, is

10 that we're finding some prevention for birth

11 defects, most notably the recent discovery that

12 folic acid could prevent a large portion of spina

13 bifida and anencephalics. So I think that's the

14 positive note that we need to start with.

15 A definition, I think, is important

16 for "surveillance," and this is, I think, a

17 definition that CDC uses for a lot of their work:

18 it's the ongoing collection, analysis, and

19 interpretation of birth defect data essential for

20 the planning, implementation, and evaluation of

21 public health practice.

22 You asked me to address what we do at

459 1 CDC. This is kind of a flow diagram that points out

2 some of -- the building block is surveillance,

3 collecting good quality data, and then going to

4 epidemiologic studies, which you've heard a number

5 of. But let me back up to the surveillance systems.

6 In CDC we started in this activity

7 back in the late '60s, as a lot of countries in

8 Europe did, because of the thalidomide episode and

9 the knowledge that environmental agents can cause

10 birth defects. So we started a program, which I'll

11 go back to in a few minutes, in 1967. And so the

12 primary objective of most of these programs then was

13 to look for environmental influences.

14 And it's evolved in the last few

15 years, especially in state programs, that states are

16 very interested in identifying children that need

17 services, early intervention programs, and now we're

18 getting into trying to make sure we deliver and

19 evaluate prevention programs. So the objectives

20 have changed over time, although we're still very

21 interested in looking at the environmental

22 influences.

460 1 At CDC we do a lot of case-control

2 studies, and you're aware of a number of those: the

3 Vietnam veterans study, which was done a number of

4 years back. I don't want to go into all the studies

5 we've done. But the surveillance database is the

6 building block for doing these studies.

7 And more recently, the CDC is getting

8 into the prevention activities, as we're discovering

9 more and more things we can do. Folic acid is --

10 again, as I mentioned, one of our big focuses right

11 now in our branch, and fetal alcohol syndrome also,

12 the prevention.

13 I want to go over basic -- some basic

14 building blocks for what makes a good surveillance

15 system, some of the characteristics of a good

16 surveillance system.

17 Most importantly is that you identify

18 all the data sources you can to identify children

19 with birth defects, and as Lew, I think, has talked

20 about very, very well, that you need an accurate and

21 precise diagnosis. This is most critical -- not

22 just a birth defect, but all the birth defects --

461 1 and it's described very well.

2 And you need a classification system

3 that is meaningful. Major birth defects is one way,

4 all birth defects -- but more specifically getting

5 down to the specific birth defects or birth defects

6 that might be associated together.

7 A large database, that's important

8 for getting the numbers. I mean, you raised

9 questions about powers. So building a large

10 database is important.

11 It's very important that data be

12 timely and that it can be used and addressed in a

13 timely fashion, if you have a concern that you're

14 not looking at it two, three years down the line --

15 kind of the situation we're doing with the Gulf War

16 now.

17 You need to disseminate the data and

18 get it out to the public in a timely manner, that

19 people can use it and look at it.

20 Probably one of the most important

21 things about a good surveillance system is, you have

22 to have personal identifiers to do follow-up. And

462 1 this always causes a lot of concern, but you have to

2 have this to link to other data, to link records

3 among babies, among visits, and so on.

4 And because you have personal

5 identifiers, you need to develop a very well-

6 developed confidentiality system to protect the

7 patients' privacy.

8 What are the limitations of

9 surveillance? Well, the quality of the data, the

10 data we get, depends on the resources we expend.

11 And I'll show you a couple of different approaches

12 that we use at CDC. So the harder you work at it,

13 the better the data is going to be.

14 The case identification in a

15 surveillance system is dependent upon the quality of

16 the medical record. And Dr. Holmes has address

17 that, too. If we don't get down -- written down on

18 the medical record an accurate and precise

19 diagnosis, we can't collect that data.

20 And I think, you know, we need to

21 realize that we're not going to identify all cases.

22 Our goal is to try to get to 100 percent, and in

463 1 most cases we don't reach that goal. But we do very

2 well at it in some cases.

3 Talk about a case definition. And

4 this varies greatly among some of the states, as

5 I'll talk about later. But this is very important.

6 And Lew just went over this again: you need to

7 define what you consider a major malformation in

8 your surveillance program, what you're going to

9 include in the program. You need to define what a

10 minor malformation is, and whether you're going to

11 include it or not. There are certain conditions

12 that aren't included, as Dr. Holmes talked about:

13 the hemangiomas, polydactyly, and things like that.

14 If that's the only defect, a lot of times we exclude

15 those from our surveillance systems.

16 Other surveillance in special

17 settings may include other birth defects that aren't

18 in. At CDC we do major birth defects. Some states

19 require all malformations, because they're

20 interested in delivering services to children. A

21 number of state programs include biochemical and

22 genetic diseases that are mandated by law.


1 The age of the infant to be included

2 is important. I'll talk a little bit about

3 surveillance systems in newborn infants. And then

4 at CDC we have a surveillance system of infants up

5 to one year of age. So that can vary between

6 programs too, so -- but you need to define what

7 you're going to do: newborn one year, five year.

8 The gestational age. What are you

9 going to include? What's to meet your case

10 definition? Is it any product of conception? Which

11 becomes very difficult to do. I don't know if I

12 want to do all the ramifications of doing

13 surveillance like that. But most surveillance

14 programs in the U.S. now have a cutoff, something

15 like generally around twenty weeks of gestation, or

16 maybe a birth weight criteria, 500 grams or more.

17 So that needs to be spelled out in your surveillance

18 system: what will you count?

19 And again, as Lew talked about, now

20 prenatal diagnosis is very important. We know that

21 a number of states, 30 to 40 percent of neural tube

22 defects are now identified prenatally. And we

465 1 published that recently.

2 Where can you get data for

3 surveillance? Just -- I've given some more detail

4 in my written testimony about this, but just to

5 quickly review this.

6 The one obvious place is vital

7 records; every baby gets a birth certificate, and

8 all infants who die get a death certificate. This

9 is one source. It has a lot of problems, and the

10 sensitivity of this type of data is not very good.

11 It's probably 14 percent of the true population are

12 identified correctly on birth certificates.

13 Hospital records. This is becoming

14 one of the predominant ways that we identify

15 children. There are medical records, you got

16 discharge summaries, you got physical examinations

17 within hospital records. There may be consults with

18 a geneticist within the medical record. It could be

19 test results, be lab results, the karyotypes. So

20 these are all the things we look at in a medical

21 record.

22 There are many special data sources

466 1 that you can go to for surveillance. You can go to

2 the genetics clinics and identify children, go to

3 the perinatal centers to identify prenatally

4 diagnosed cases. And you can go to specialty

5 clinics. In Atlanta we have a very nice heart

6 center that sees the majority of children in

7 metropolitan area.

8 You can also go to existing data

9 sources. In this country now most states have a

10 statewide hospital discharge database that will

11 identify all hospital discharges, and you can look

12 at newborns in that database.

13 There's Medicaid data that you can

14 look at.

15 And now more and more the insurance

16 and HMO systems are building databases, and they're

17 interested in trying to look at this, especially for

18 prevention activities.

19 Trying to address some of the

20 different kinds of surveillance methods that are --

21 that are going on now or that have gone on in the

22 past. And one that was alluded to earlier and a lot

467 1 of you know about was the Collaborative Perinatal

2 Project. This was an ideal project. This would be

3 an ideal surveillance system, if we could do it.

4 You have a standard protocol: you go examine every

5 baby. This program followed 50,000 pregnancies, and

6 I'll come back to this and talk about the rates that

7 came out of that program.

8 You can review -- and this is

9 probably one of the most comprehensive surveillance

10 systems now, is to review medical records of

11 potential cases. And this can include records from

12 nurseries, NICUs, the specialty clinics that I

13 talked about, laboratories, and then all kinds of

14 screening programs. And I will come back and talk

15 about this with the Metropolitan Atlanta Program.

16 You can use hospital discharge

17 summaries and disease indexes to identify records.

18 Some states use that kind of approach. You can use

19 existing hospital discharge data.

20 The National Birth Defect Monitoring

21 Program, I'll talk about was a program like that.

22 And the uniform billing data is

468 1 something that exists currently.

2 Other approaches to ascertaining

3 birth defect data is, a number of states now are

4 developing legislative mandates. Probably the vast

5 majority of the programs have a law that mandates

6 birth defect reporting, and it requires hospitals

7 and physicians to report. In most of these states

8 that do that type of approach, they use some

9 supplemental interaction with the hospitals to

10 increase reporting.

11 And then you have states that link

12 data sources. They may have the hospital discharge

13 data, they may have the Medicaid data. Vital

14 records is one. So they link all these data sets.

15 And then, as I said earlier, we've

16 got vital statistics.

17 And then, a number of states are

18 developing specialized surveillance programs for

19 selected conditions. And that's looking at neural

20 tube defects; they're focusing on just one or two

21 malformations.

22 What kind of -- the data can vary


1 greatly with the intensity of surveillance effort.

2 And I wouldn't focus so much on the absolute numbers

3 on this slide, but the great variation of rates

4 depending on how much effort you put forward.

5 If you examine "Infant," you can get

6 a rate. The Collaborative Perinatal Project had a

7 rate of about 8 percent for major defects, had a

8 rate of around 15 percent for all defects. So lots

9 of minor malformations were identified.

10 Comprehensive hospital surveillance,

11 something like we do in Atlanta and they do in

12 California, the rate will be -- around 3 to 4

13 percent of babies will have a major defect. And

14 then you can start seeing the hospital reporting

15 systems. The rate, depending upon their methods --

16 some were 2 and a half to 3 percent.

17 And then as I alluded to earlier,

18 birth certificates don't do very well; they only

19 identify about one percent of the babies with a

20 birth defect.

21 So it can vary greatly, and so you

22 really know -- need to know how the data was

470 1 collected.

2 In metropolitan Atlanta, as I said

3 earlier, we started in the -- in the late '60s. And

4 Atlanta served as a prototype for a lot of other

5 surveillance systems now that are -- that are

6 operating in the U.S.

7 We monitor all births in metropolitan

8 Atlanta, around 40,000 births a year, and we look at

9 all live and stillborn infants who are diagnosed.

10 And we really focus on major malformations that are

11 diagnosed up to first year of life. And we use a

12 very intensive type of case-finding where we go to

13 multiple sources to find the cases in the hospitals

14 and specialty clinics. And we've used this database

15 over the years for doing a lot of epidemiologic

16 studies.

17 Another system that I think ought to

18 be looked at, especially when you come to my kind of

19 recommendation at the end there, is -- the Birth

20 Defect Monitoring Program might be an example of

21 what the DOD might look at for hospital discharge

22 data. This is a program that we had operational

471 1 from 1974 to '94, and it was a large database. It

2 monitored, in the early '80s, about 35 percent of

3 the births in the country, and the total time

4 period, about 20 percent. But this gave us good

5 national estimates of birth defects in the country,

6 and trends, and we used this for a number of

7 studies.

8 The company that provided this is now

9 out of business, and we're exploring new

10 alternatives to this, especially the uniform billing

11 data, as a possible surveillance system to replace

12 it.

13 This is what is going on in the U.S.

14 in state health departments. And I think this has

15 changed dramatically since the late '70s. In the

16 late '70s there were three states that had programs.

17 Currently there are well over thirty that have a

18 program or are trying to implement a program.

19 You see these blue states? They're

20 the states that have hospital or mandated reporting.

21 And then you see the intensive kinds cases they're

22 finding. There are about seven or eight of those

472 1 blue states that -- Atlanta and California and so

2 on. There's a lot -- I mean, I can't tell you how

3 much is going on. It's amazing in the last five

4 years how many states are interested in getting into

5 of this, not only for the epi' purposes, but for

6 prevention activities, intervention activities.

7 We're currently funding eleven states to develop

8 programs in this area.

9 Some of the other activities I think

10 you ought to be aware of that were at CDC is that

11 we're trying to build a national collaboration of

12 these state programs. We hope to have within the

13 next six months the first annual report of these

14 surveillance programs. We currently have data from

15 twenty of those states that we will include in this

16 first report. So I think we're trying to build this

17 national collaboration, and between the states.

18 We've done a number of studies with them. Chorionic

19 villus sampling was one of example recently.

20 Another thing that we're involved in

21 right now is risk factor surveillance. And we have

22 an ongoing case-control study in three states,

473 1 including Atlanta, to interview parents with major

2 birth defects on a number of risk factors. And we

3 hope to expand this very soon. We put out an RFA,

4 in fact, last week to hopefully fund three states to

5 develop a center of excellence and to do birth

6 defect research.

7 So I think this last bullet -- this

8 came out of legislation out of Congress that

9 mandated CDC to expand their efforts in trying to

10 develop a national collaboration and fund

11 surveillance activities and do research. So things

12 are improving. The resources are tight, but we are

13 able to get into new areas.

14 The last thing I'd like to talk about

15 is that -- our collaborations with the Navy and the

16 studies we're assisting them with is, I think -- it

17 brought it mind that it's time to kind of think

18 about in DOD starting to collect data in a more

19 uniform and standard manner and in a little more

20 proactive phase. And I think collecting a good

21 reproductive and fertility history on all active-

22 duty personnel would be a nice thing to have

474 1 available to you.

2 And I think another opportunity

3 exists, especially with TRICARE being implemented,

4 is -- this is the time to think about an ongoing

5 surveillance system of military personnel. You

6 heard us talk about looking at the Goldenhar with

7 the DOD data. But the civilian data, we haven't

8 looked at yet. And I think with TRICARE, it might

9 be the opportunity to think about this and see if it

10 is a reasonable thing to develop an ongoing

11 surveillance system.

12 Thank you.


14 MS. LASHOF: Thank you very much.

15 Let me ask you a question just

16 directly related to that approach.

17 So far, the efforts of trying to

18 identify whether there's increased birth defects

19 among Gulf War veterans are starting with the Gulf

20 War veterans and then looking at births and looking

21 at birth defects. What is the feasibility in your

22 collaborative birth defect registries to start with


1 birth defects --

2 MR. EDMONDS: Right.

3 MS. LASHOF: -- and look at what

4 percentage of those have fathers or mothers that

5 served in the Gulf War, and whether that's out of

6 proportion or not?

7 MR. EDMONDS: That could be done.

8 And Happy Araneta is trying to look at that by going

9 to a number of surveillance systems.

10 But another way we could do it too is

11 to try with this risk factor assessment. You know,

12 we'll be looking at occupational and things like --

13 including service. But the number's going to -- I

14 mean, the exposures, or the people who served in the

15 Gulf, are going to be pretty small in that

16 population. We've thought of -- tried to start

17 thinking about that. I mean, it's really a

18 difficult thing to try to do. I don't know whether

19 it's better to try to continue with what the Navy

20 has started and go on to the civilian populations,

21 or think about going to some of these states and try

22 to --

476 1 MS. LASHOF: Yeah. I mean, even with

2 what Dr. Araneta is trying to do, she's going to the

3 states, three states with birth defect registries,

4 but she's looking at all --

5 MR. EDMONDS: At all birth defects,

6 right.

7 MS. LASHOF: She's looking at all

8 birth defects and then trying to determine how many

9 came from the Gulf War --

10 MR. EDMONDS: Yes.

11 MS. LASHOF: -- or is she looking at

12 the Gulf War --

13 MR. EDMONDS: Yeah, they're linking

14 the manpower tapes to vital records in a number of

15 these states -- and Hawaii was the first example --

16 and then look at the registries and see how many of

17 them were -- had birth defects, and then look at

18 Gulf status versus non-deployment status.

19 MS. LASHOF: Yeah; but she's going --

20 she's going with non-deployed versus deployed, and

21 then to birth defects? Or she's starting with birth

22 defects?

477 1 MR. EDMONDS: Well --

2 MS. LASHOF: I'm confused.

3 MR. EDMONDS: She's starting with

4 being a veteran --

5 MS. LASHOF: Yes.

6 MR. EDMONDS: -- irrespective of

7 deployment, and then linking to vital records, then

8 identifying the children born to those children --

9 MS. LASHOF: Right.

10 MR. EDMONDS: -- then linking to the

11 registries.

12 MS. LASHOF: And then linking.

13 MR. EDMONDS: And then evaluating --

14 MS. LASHOF: I'm suggesting going the

15 other way. I'm asking whether it's -- whether one

16 would be able to detect a significant increase if it

17 were occurring in Gulf War veterans, if you started

18 at the other end. That is --

19 MR. EDMONDS: Well, that's kind --

20 MS. LASHOF: Started at the registry

21 and --

22 MR. EDMONDS: Right.

478 1 MS. LASHOF: -- said, "Okay, let's

2 look at every Goldenhar that's been reported last

3 year in the country," and determine how many of

4 those Goldenhar syndromes --

5 MR. EDMONDS: Served in --

6 MS. LASHOF: -- served in the Gulf.

7 MR. EDMONDS: I think that's -- I

8 don't know what the power calculation is on that --

9 probably not real great. But you could. You could

10 go --

11 MS. LASHOF: I would think the power

12 would be greater than the other way around.

13 MR. EDMONDS: It probably would be.

14 MS. LASHOF: That's my thought. And

15 that's why I raise it.

16 MR. EDMONDS: You could go to all

17 these states and ask them to identify the Goldenhar

18 cases. The problem is, you're going to run into

19 some of the things we did with the DOD database,

20 that only a few of those at this point have the

21 ability to really pull out the specific diagnosis,

22 'cause Goldenhar is buried in kind of a catchall

479 1 category. So in about seven or eight of those

2 states you could do that approach. I don't know

3 what the numbers would be. We could probably try to

4 figure that out. But then you could go to those, do

5 a case-control study with them.

6 MS. LASHOF: Yeah.

7 MR. EDMONDS: I don't know what the

8 power of that, off the top of my head, would be.


10 MR. EDMONDS: But the exposure is

11 probably not going to be that great, you know, the

12 serving in the Gulf. But I think those are the

13 kinds of things that we need to talk to the Navy

14 about, what --

15 MS. LASHOF: Yeah.

16 MR. EDMONDS: What's the next step,

17 and the most reasonable?

18 MS. LASHOF: I would think that's

19 worth -- appreciate it.

20 MR. EDMONDS: But we've offered the

21 Navy that we'll continue to assist them.

22 MR. HOLMES: I think one of the


1 things he hasn't specified, but CDC has expanded the

2 ICD coding system to try to allow you to have more

3 specificity in the ICD number that's used. And a

4 lot of the states are wedded to the old ICD

5 numbering codes, which lump. And that's where the

6 problems arise.

7 Would the seven states you're citing

8 use the expanded ICD codes?

9 MR. EDMONDS: Yes. And they would --

10 they represent somewhere around 25 percent of the

11 births in the country, somewhere between 20 and 25

12 percent. So it's a large sample. Yeah.

13 MS. LASHOF: Now, these states with

14 birth defect registries, are they then transmitting

15 that information to CDC?

16 MR. EDMONDS: Yes; this --

17 MS. LASHOF: Do you have in this

18 collaborative effort --

19 MR. EDMONDS: Yeah, we've just

20 started that.

21 MS. LASHOF: -- the results from all

22 the -- so you've just started that?

481 1 MR. EDMONDS: Right.

2 MS. LASHOF: And then what -- are

3 there any routine studies that you're doing on a

4 selected group of birth defects?

5 MR. EDMONDS: Right. That goes --

6 MS. LASHOF: Or how do you then

7 follow up, and what additional information do you

8 get from the parents for exposures, et cetera?

9 MR. EDMONDS: Well, the risk factors

10 surveillance study -- we're funding two of the

11 states, California and Iowa, and then in Atlanta,

12 where we're interviewing the parents of a number of

13 selected major malformations. And this in-depth

14 interview takes about an hour, looking at a lot of

15 the risk factors we currently know about, plus some

16 other ones that are -- that are suspect.

17 That database started about three

18 years ago, and we're -- the analysis of that has not

19 started. We hope to build up a large database for

20 analysis. The new centers we're going to fund that

21 will be -- one of the requirements of that is, they

22 also, whoever gets those awards, will contribute

482 1 cases-controls to that ongoing study. So that

2 hopefully we will have a good database to start

3 addressing concerns about risk factors for birth

4 defects.

5 MS. LASHOF: Could you comment about

6 any risk factors that you've identified since the

7 system is underway? Folic acid was one.

8 MR. EDMONDS: Folic acid, diabetes,

9 cocaine, smoking -- a number of studies like that

10 that -- we a number of years back funded a number of

11 states to look at toxic waste sites. They ended up

12 being predominantly drinking water studies. And

13 there were a number of things that came out of that,

14 that raised suspicions about exposures in public

15 drinking water of volatile organics and so on, and

16 byproducts of disinfection of water. There's a lot

17 of interest in our Center about trying to further

18 those studies.

19 MS. LASHOF: So that at this point

20 you can say that having this surveillance system in

21 effect has enabled you to identify specific risk

22 factors that we can do something about?

483 1 MR. EDMONDS: Yes. I think -- yeah,

2 the Vietnam study.

3 MS. LASHOF: We don't have that many

4 success stories.

5 MR. EDMONDS: No, we don't.

6 MS. LASHOF: To get them out --

7 MR. EDMONDS: I think the folic acid

8 study is one that came out of that.

9 MS. LASHOF: Pardon? Which one?

10 MR. EDMONDS: Folic acid --

11 MS. LASHOF: Uh-huh; yeah.

12 MR. EDMONDS: -- I think, came

13 directly out of that. Our study was one of many

14 that pinpointed that folic acid was effective in

15 preventing neural tube. So that's one of the

16 success stories.

17 MS. LASHOF: What percentage of

18 neural tube defects do we now believe are due to

19 folic acid deficiency?

20 MR. EDMONDS: Fifty percent.

21 MS. LASHOF: Fifty?

22 MR. EDMONDS: Or greater, that we

484 1 might be able to prevent that much.

2 MS. LASHOF: Uh-huh. Good. Thank

3 you.

4 Questions? Marguerite? Tom? Joe?

5 MR. CASSELLS: I just have one.

6 Given what you have both said this

7 morning and what we heard yesterday about the

8 difficulty of making the diagnosis in many instances

9 here of a major malformation, going back to the

10 Collaborative Perinatal Project where every infant

11 is examined, how many examiners are involved in

12 that?

13 Dr. Holmes, you indicated that there

14 were people out there who could do this.

15 MR. HOLMES: The problem with a

16 national -- the National Collaborative Perinatal

17 Project was, there were thirteen centers and lots of

18 examiners at each center. And this is back in the

19 early '60s, and I know I made extra money at the

20 time when I was an intern: they'd hand me the form,

21 I'd go do the exam. And that represented the

22 problems they got into, and the lack of consistency

485 1 in what everyone understood they were supposed to be

2 finding.

3 What I was suggesting was, you have

4 folks that are trained as -- they usually call

5 themselves dysmorphologists, meaning they focused on

6 understanding the causes of birth defects, and

7 they're sensitive to the outcomes we're talking

8 about. Those folks are all over the United States,

9 and you could just identify individuals

10 geographically that might be interested in

11 participating in this kind of work. I would

12 recommend that over the system used in the NCPP,

13 where people like me were given the form to do for

14 $10 or something like that.

15 MS. LASHOF: Started you off on a

16 whole new career, though, didn't it?

17 MR. HOLMES: Yes.

18 MR. CASSELLS: But is that -- is that

19 data at all useful, given those caveats?

20 MR. HOLMES: For minor features, no.

21 We've looked back -- when we did our tabulation of

22 the 70,000 births in terms of the frequency of the


1 various major malformations and the etiologies we

2 recognized, we wanted to know whether other data

3 sets had seen similar abnormalities.

4 And it was impressive to see that

5 between '65, when the NCPP ended, and when we were

6 doing this in '85, the number of entities we could

7 diagnose, which are on table 2 in that reprint you

8 have, has grown tremendously. And Dr. Brent

9 referred yesterday to the Mendelian inheritance in

10 man, this catalogue that has over -- since the

11 mid-'60s has shown this incredible growth in the

12 number of phenotypes identified. So the problem

13 with the NCPP is, its folks didn't know these

14 entities existed. So their descriptions might be

15 all right, but you're not sure.

16 MS. LASHOF: Okay. Thank you very

17 much.

18 We are running a little behind time,

19 as usual. We will resume at ten after and try to

20 make up at least five minutes. So ten after the

21 hour.

22 (Recess at 10:55 a.m. to 11:12 a.m.)

487 1 MS. LASHOF: I think we'll try to

2 resume our hearings now.

3 And I'm very pleased to welcome Dr.

4 Thomas Garthwaite, Deputy Undersecretary of Health

5 from the Veterans Affairs Agency.




9 MR. GARTHWAITE: Thank you, Dr.

10 Lashof, members of the committee, others interested

11 in Persian Gulf War illness. It is a pleasure to

12 meet with you today to provide you with information

13 on the Department of Veterans Affairs policies,

14 programs, and practices related to reproductive

15 health in veterans.

16 First, I'd like to assure you that

17 we're a system that welcomes inquiry from veterans.

18 We know the concerns about the effects of military

19 service on reproductive health are very significant

20 for veterans who served in the Persian Gulf, as well

21 as those who served in Vietnam, and those who were

22 exposed to ionizing radiation during World War II

488 1 and the ensuing cold war.

2 The training of our Persian Gulf

3 coordinators and registry physicians includes the

4 information available from research on reproductive

5 outcomes. A recent satellite video teleconference

6 included discussion of the only two scientifically

7 rigorous studies available at that time, and as was

8 discussed here yesterday, we recognize that those

9 studies also have limitations.

10 The first study was an investigation

11 of children born to Persian Gulf veterans of two

12 Mississippi Nation Guard units as published in

13 Military Medicine.

14 The second study is that, as

15 discussed yesterday by Dr. Cowan, the principal

16 investigator, who appeared on our satellite

17 broadcast and conference. He discussed his findings

18 from his survey of children born in military

19 hospitals to military parents who differed by

20 whether or not they were deployed to the Persian

21 Gulf or not. We all saw his most recent data during

22 yesterday's hearing.

489 1 It is our intention that physicians

2 make all credible information available to patients

3 in counseling them. We have some limitations.

4 VA statutory authority to deliver

5 reproductive health services to female veterans is

6 limited to specific services under the Women

7 Veterans Health Care Act of 1992, Public Law

8 102-588. This Act excludes services for

9 infertility, abortion, or pregnancy, including

10 prenatal care and delivery, unless the risks of

11 complications of pregnancy are increased by the

12 veteran's service-connected disability.

13 The only authority we have to provide

14 any evaluation to non-veterans, i.e., the spouse of

15 a Persian Gulf War veteran, was included in Public

16 Law 103-446, which expires September 30th, 1996.

17 Under this authority we are going to study 1,000

18 family members of Persian Gulf veterans as part of

19 the large VA Persian Gulf study described in one of

20 your previous meetings.

21 In addition, VA is providing free

22 health examinations to any individual who is the

490 1 spouse or child of a Persian Gulf veteran if the

2 veteran is listed in the Persian Gulf registry and

3 has an illness which cannot be dissociated from the

4 veteran's service in the Gulf, and who has granted

5 permission for the examination data to be included

6 in the Persian Gulf registry. These examinations

7 are being provided by university-affiliated

8 physicians contracted through thirty-two VA medical

9 centers. Individuals may register through the

10 Persian Gulf help line, and I remind all veterans

11 that it's 1-800 PGW -- Persian Gulf War -- VETS,

12 V-E-T-S. That's 749-8387.

13 It is estimated that 4,500 spouses

14 and children can be provided examinations within the

15 statutory spending limits. As of May 30th, 1996,

16 479 family members have registered for the

17 examination program. The examination program --

18 excuse me; the examinations are done using

19 standardized protocols. The adult examinations

20 include a CBC standard chem-20 panel on the

21 urinalyses. Information for physicians has been

22 sent out in a physicians' reference guide which has


1 been made available to members of your staff. A

2 follow-up letter is sent by the examining physician.

3 However, the law includes no provision for treatment

4 of any abnormalities detected during this

5 examination, which would have to be referred to the

6 individual's own physician. The results of the

7 examinations are entered into a scannable code sheet

8 for inclusion in the registry and analysis by VA's

9 Environmental Epidemiology and Environmental Agent

10 Services.

11 We've made multiple attempts to

12 outreach to Persian Gulf veterans. These are done

13 through articles in The Persian Gulf Review, which

14 is currently sent to every veteran in our registry;

15 through national -- regional; I'm sorry -- regional

16 and local media; through veterans service

17 organizations; the Persian Gulf help line, the

18 number I just gave; through VA Online, a Web page

19 that's one of the top five Web pages in terms of

20 access of all pages on the Web; and through registry

21 Gulf coordinators and physicians at local medical

22 centers.

492 1 In your letter of invitation you

2 specifically asked me to discuss the legislation for

3 spina bifida in the offspring of Vietnam veterans

4 which VA will be seeking. As you know, the National

5 Academy of Science in its second report, "Veterans

6 and Agent Orange, Update 1996," found there is

7 limited or suggestive evidence of an association

8 with exposure to Agent Orange and other herbicides

9 used in Vietnam with spina bifida in the offspring

10 of veterans who served in that conflict. On May

11 28th the President announced that the Department of

12 Veterans Affairs will be proposing legislation that

13 would provide an appropriate remedy for children of

14 Vietnam veterans with spina bifida.

15 The details of that legislation are

16 still being developed, and I will gladly provide a

17 copy to the Committee when it's available. Some of

18 the reasons that we can't provide it now are, there

19 are significant issues needing to be addressed in

20 that legislation including how to provide health

21 care to the offspring -- for example, should it be

22 through CHAMPVA, private insurance plans, contracted

493 1 care, Medicare, Medicaid, or others -- and what kind

2 of benefits would be provided, which may include

3 things such as monetary payments, vocational

4 rehabilitation, adaptive housing allowances, and

5 education. How to provide those effectively and

6 well requires a significant amount of background

7 research and work with veteran organizations as

8 well.

9 Finally, I think it is generally

10 agreed that more research into reproductive

11 outcomes, particularly male-mediated ones, is

12 needed. Therefore, the Department of Veterans

13 Affairs has announced plans to establish the fourth

14 environmental hazards research center. This one

15 will concentrate on birth defects and reproductive

16 health. The request for proposals was issued in May

17 of 1996, and we anticipate selecting the site before

18 the end of the fiscal year.

19 This ends my prepared remarks. I'd

20 be happy to answer any questions.

21 MS. LASHOF: Thank you very much.

22 Questions from the Committee members?


2 MR. McDANIELS: All the outreach

3 efforts that I've seen from VA as far as

4 reproductive issues have simply been a listing of

5 research efforts underway. Is there anything else

6 that VA could tell Gulf War veterans? Understanding

7 that the evidence of increased birth defects is

8 inconclusive, is there anything else that you could

9 transmit to them in addition to just a listing of

10 research efforts about this matter?

11 MR. GARTHWAITE: Well, you know, I

12 came to this meeting Sunday night and sat through

13 all the testimony yesterday and today, and feel that

14 I've probably learned a fair amount, as I think

15 everyone here has. I'm not sure I could conclude a

16 lot, not being a geneticist, or someone really

17 expert in that, but someone with a background in

18 internal medicine and endocrinology.

19 I'm not sure what clear and helpful

20 piece of information I could give them other than

21 that there are still significant issues to be

22 resolved and that there are significant -- that

495 1 there are considerable attempts being made to try to

2 resolve those; perhaps put into perspective those

3 good studies that show that there's not a -- that

4 the risk of a birth defect is real in everyone who

5 has a child, but at least so far is not demonstrably

6 that much greater in studies, although I think you

7 still have to put those limitations on the studies

8 that are done.

9 I think it's common in science to

10 have to have imprecise science, and try to help

11 people make real-life "now" decisions. And I don't

12 know what we can do to help clarify the issue. I

13 mean, I come away from this with the sense that

14 there's not yet clarity, and --

15 MS. LASHOF: I think that's very

16 true. And the question, I think, to follow up on

17 Tom's question on that, is: how much information is

18 being given to the veterans to explain how much

19 unclarity there is, how frequent this is in the

20 general population, what the real risks are in the

21 general population, and how much greater the risk

22 would have to be for us to discover it, so that they

496 1 aren't looking for quick, easy answers.


3 MS. LASHOF: And the question is: is

4 that included in the kind of information you're

5 giving out, and how does it reach the veterans in

6 general, not just those who have signed up in a

7 registry who have a birth defect, but those who are

8 out there wondering what to do?

9 MR. GARTHWAITE: Well, I think

10 legitimate attempts have been made to do that, but I

11 think that we need to continue to reassess whether

12 they're being effective or not. And I think we'll

13 go back and we'll reassess that once again to see if

14 there are other things that we can think of in light

15 of what's been presented here that may be more

16 effective than the things that I listed already in

17 our outreach efforts.

18 MS. LASHOF: And your satellite

19 teleconference call, who -- video conference -- who

20 was that geared to?

21 MR. GARTHWAITE: It was to all the

22 Persian Gulf coordinators and all the


1 specially-trained registry physicians. In each

2 medical center a physician has been designated as a

3 registry physician, and they get additional

4 education and sensitization to the issues

5 surrounding the Persian Gulf War.

6 MS. LASHOF: Okay. So it was to the

7 professionals. It wasn't --

8 MR. GARTHWAITE: Correct.

9 MS. LASHOF: -- an effort to get a

10 video or media out to the veterans themselves.


12 MS. LASHOF: Because I will admit

13 that one of my concerns is that the media -- and I

14 hesitate to say this in front of the TV cameras --

15 do tend to sensationalize these issues, and not

16 always present the fairest picture, and I think that

17 does a disservice to the veterans. And so I think

18 it is important that they understand how complex

19 this is, how much work is going on, and will go on,

20 and that we won't be satisfied until we get the best

21 answer possible. But those answer may not all be

22 forthcoming very quickly.

498 1 MR. GARTHWAITE: Sure. Before I left

2 as Chief of Staff in Milwaukee VA, we had a

3 traveling show throughout the State of Wisconsin

4 where we brought in the best experts we could, and

5 held open forum meetings advertised in every media

6 that would listen. And we got pretty good

7 attendance, and I think, you know, some reasonable

8 interchange between the best experts we could find

9 on the subject and Persian Gulf veterans. I think

10 we have to continue all those kinds of efforts

11 because no one way is good. We have a large number

12 of people who sign on to our Web site, but that's no

13 good for a whole bunch of people without computers.

14 Television advertisements aren't good

15 for people that don't watch a lot of TV. And I it's

16 just we have to use multiple media to try to reach

17 as many as possible.

18 MS. LASHOF: Did you have other

19 questions about the outreach, Tom?


21 MS. LASHOF: I didn't mean to

22 interrupt you.

499 1 Marguerite?

2 MS. KNOX: Yeah, I just wanted to ask

3 your opinion, Dr. Garthwaite. Yesterday you said

4 you stayed and you listened to testimony. What were

5 your feelings on that, knowing some of the comments

6 made about the VA system?

7 MR. GARTHWAITE: You mean with regard

8 to the patients who testified early in the morning?

9 MS. KNOX: Yeah. Early in the

10 morning. Were you surprised?

11 MR. GARTHWAITE: Well, for someone

12 who has been in the VA for twenty-two years, and who

13 has treated hundreds of veterans, and whose office

14 was down the hall from the patient representative, I

15 wasn't surprised. But I would also say that, you

16 know, any time that a veteran comes to the VA and is

17 less than 100 percent satisfied with their visit, I

18 feel badly. We see -- we have probably 25 million

19 outpatient contacts, visits, a year.

20 MS. KNOX: Uh-huh.

21 MR. GARTHWAITE: It's not going to be

22 possible to make all those visits perfect, but we

500 1 have to strive to do that. In listening to the

2 various comments, I think -- I was struck by the

3 fact that we need to try to help the individuals who

4 made those comments in any way possible. They all,

5 too me, seemed to have real issues and real

6 problems. The hard part is to know which of those

7 real issues and real problems are a direct result of

8 service in the Persian Gulf or not. But clearly

9 they all have very real legitimate problems, and

10 need to be addressed.

11 Not every time a physician or someone

12 who evaluates a patient, and they come up with a

13 conclusion, is that conclusion going to be what the

14 patient wants to hear. One of the most flagrant

15 cases in my own personal experience is when I

16 suggested to someone that a lot of his problems were

17 related to his smoking. And he didn't -- you know,

18 he got very indignant, and said, "I came here for

19 help, not to be told that I was smoking." But

20 legitimately, I was trying to be very kind. I was

21 not being difficult. But I think that sometimes the

22 answer isn't what we want to hear. It doesn't make

501 1 it necessarily wrong. So I think we have to be

2 careful.

3 And at the same time, we have to look

4 at our own system and make sure that the accuracy of

5 the diagnoses we give are correct, so that if you're

6 getting an answer you don't want to hear, we want to

7 make sure that it's as accurate an answer as

8 possible. And that has to do with professional

9 recruitment and training, and quality assurance, and

10 those sort of things, which we're aggressively

11 pursuing throughout the VA system. I'm sure you

12 know.

13 MS. KNOX: Yeah. It's disturbing at

14 times.

15 MS. LASHOF: Let me ask you a

16 question about the Agent Orange legislation that

17 you're struggling with. And I can imagine that

18 there are a lot of issues that have to be addressed.

19 And the decision to go ahead and reimburse for -- or

20 consider it related to service, was made on the

21 basis of the IOM report which suggested a limited --

22 a limited or suggestive category, and further


1 research will go on. I'm not familiar enough with

2 all of the research going on. It's hard to keep on

3 top of all of this, but to keep on top of all of the

4 Agent Orange research -- but are there further

5 studies going on to try to determine whether that

6 category will move from limited/suggestive to

7 definite, or move from limited/suggestive to

8 negative, unrelated, and -- well, that would be the

9 first question. Are such studies going on to try to

10 refine that category?

11 MR. GARTHWAITE: I understand there

12 are, but I would -- you know, I would really need to

13 ask someone specifically the nature of those studies

14 to be able to provide that information to you. But

15 it's my understanding --

16 MS. LASHOF: Well, the more important

17 -- not the more important, but the logical follow-up

18 to that become the question of how you will deal in

19 the legislation with the issue that if there are

20 further studies and those further studies show no

21 relationship, how do you make the decision about

22 what you do about further treatment, compensation,

503 1 whatever, under those circumstances?

2 MR. GARTHWAITE: I think that gets

3 into the very difficult issue of legislation,

4 legislative intent and interpretation, and where we

5 can go from there. You know, a lot of times we're

6 left to try to carry out legislation and direction

7 that we're given, whether or not it's all based on

8 what would be true scientific facts. It really is

9 based on what the best information in

10 decision-making is available to the legislators at

11 the time that they make those decisions. So there

12 clearly appear to be some times when legislative

13 decision-making and the scientific evidence are not

14 totally coincident.

15 MS. LASHOF: You know, I was just

16 curious as to whether you were going to try to make

17 any effort, or whether it's probably unnecessary to

18 try to make the effort within the legislation to

19 look ahead and deal with that, or whether the

20 legislation will say, "Based on this, we're going to

21 go ahead, and if something else happens later, we'll

22 face that later and figure out what to do about it

504 1 then, or decide we'll ignore it." I mean, you know,

2 there are policy issues that are separate from

3 science.


5 MS. LASHOF: You've been around both

6 government and science long enough to be well aware

7 of that, and it's always a dilemma how you deal with

8 it. And I was just wondering whether, in your

9 consideration in writing the legislation, you're

10 going to try to deal with it in this legislation, or

11 not deal with it.

12 MR. GARTHWAITE: Right. My limited

13 experience is that this is a complex effort that

14 involves a lot of people and a lot of different

15 considerations. And the administration will propose

16 legislation, and then -- and it certainly is subject

17 to additional modification later. And so my own

18 personal opinion would be that it might be wise to

19 anticipate that, because of the difficulty in

20 getting legislation through the Congress, and the

21 time lag, and so forth, and considerations. So

22 dealing with any anticipated changes, and dealing

505 1 with it once, and bringing everybody that needs to

2 vote on the legislation up to speed, has some

3 appeal. I appreciate those comments.

4 MS. LASHOF: Good luck.

5 MS. GWIN: Well, my questions lie

6 sort of along the same lines. You stated at the

7 beginning of your testimony that you're prohibited

8 by law from offering services to families of

9 veterans. So we have a situation that, even if we

10 did determine a link between Gulf War service and

11 families' illnesses, your hands are tied until

12 there's an act of Congress. Is that correct?

13 MR. GARTHWAITE: At the current time

14 that's my understanding of the interpretation of the

15 statutes.

16 MS. GWIN: So when you were

17 considering this spina bifida legislation did you

18 give any consideration to going more generic with

19 your request to Congress so that you would be more

20 empowered to help families if there turned out to be

21 a need to?

22 MR. GARTHWAITE: We've been pushing

506 1 for -- just for veterans, been pushing for an

2 improvement in the eligibility legislation which is,

3 today, very complex and convoluted, very difficult

4 to explain either to employees or to veterans, and

5 have been having a great deal of difficulty because

6 it has been scored as costing money to the

7 government, and there's hesitancy in worsening the

8 federal deficit. And so we've not been able, so

9 far, to get eligibility for them through, in that

10 we've not approached the issue of providing care in

11 VA medical centers to veterans' -- and there seems

12 to be no compelling interest so far in Congress to

13 providing additional benefits to families of

14 veterans.

15 The ability for us to provide care in

16 VA hospitals to non-veterans has been a politically

17 controversial issue for many years. There was a

18 pilot study a few years ago in which, in rural areas

19 that were having trouble supporting either a VA in

20 terms of workload, or a non-VA medical center,

21 whether we could combine patient and, together,

22 would have a viable institution to provide that

507 1 service. And at that time, that was not politically

2 doable, and so we were unable to get that pilot --

3 those pilots done.

4 So I guess what I'm getting around to

5 is saying that although I think there's evolution of

6 the thinking in terms of the politics of getting

7 non-veterans into VA hospitals, there still would be

8 a fair amount of work to do to do that. If you step

9 back and you say, "If legislation is there to pay

10 for case in a non-VA setting, could we do that,"

11 then I think that would be a different matter, and

12 that would be a more -- would be an easier

13 legislative initiative because it doesn't imply any

14 displacement of veterans from VA hospitals. And so

15 that would just be a, "Does the United States have

16 an obligation to provide for care for non-veterans

17 in those circumstances?"

18 And I think where we had the science

19 to back it up, we're going forward. I mean, you

20 know, here I think it's right now a more difficult

21 issue in terms of, "Do we have the science to push

22 that agenda?"


1 MS. LASHOF: Joe?

2 MR. CASSELLS: I understand the

3 problems with providing care to family members under

4 the current legislation, but male veterans have

5 reproductive concerns also. What kind of capability

6 within the VA system is there for dealing with

7 those?

8 MR. GARTHWAITE: I think we do a

9 fairly reasonable job there, simply because much of

10 that care is provided by urologists, and because we

11 have a significant number of well-trained urologists

12 within the system. We also have affiliations with

13 109 medical schools, so that we have

14 highly-qualified urologists coming into our medical

15 centers to provide consultation. So I think overall

16 our ability to provide at least some care to male

17 veterans is a bit better in terms of potential

18 fertility issues.

19 MR. CASSELLS: How about genetic

20 counseling?

21 MR. GARTHWAITE: I would say that my

22 sense is, with genetic counseling, that's a

509 1 relatively variable piece of the health spectrum for

2 the United States as a whole, and I would suspect at

3 the VA it's also somewhat variable. I mean, I think

4 you could find some urologists who are good at that,

5 but I suspect that also the predominant reservoir of

6 knowledge in genetic counseling probably revolves

7 around very active obstetric practices and

8 infertility clinics, and around neonatal intensive

9 care units, and less around urologists who

10 concentrate more in prostatic disease, and kidney

11 stones, and a variety of other things.

12 So I'm just saying I think that it's

13 not a -- not everyone -- as has been previously

14 testified, not everyone comes to the table with the

15 same amount of knowledge. You can hire someone to

16 examine newborns for genetic abnormalities; it

17 doesn't imply that they have the kind of knowledge

18 that you need. So what I'm kind of getting around

19 to is saying that my suspicion is that this is a

20 very specialized area, and that to provide that kind

21 of specialized care requires some effort. To my

22 knowledge, we've not probably made enough efforts in

510 1 making sure that's available, although I'm going to

2 have to go back and ask that question. So --

3 MR. CASSELLS: I was thinking about

4 the university affiliations --


6 MR. CASSELLS: -- that perhaps it

7 could be available to --

8 MR. GARTHWAITE: Right. I think

9 there's a lot we can do with that, but the question

10 is, if someone comes in and asks the Persian Gulf

11 registered veteran, have we made it easy for them to

12 then get the counseling by the individuals who

13 actually have that knowledge? And it's one thing to

14 provide a small amount of knowledge to a lot of

15 people, the generalist, but who needs the

16 specialized knowledge, and how is that handled?

17 From other testimony I was impressed that experts in

18 the field don't think that that always happens as

19 well as it might throughout the health case

20 spectrum. So I think we'll take a look at that. I

21 appreciate your question.

22 MS. LASHOF: Tom?

511 1 MR. McDANIELS: Just one more

2 outreach follow-up question about genetic

3 counseling. Is that something that -- in future

4 outreach, is that something you would feel

5 comfortable in placing in the outreach as a

6 recommendation to get genetic counseling, even if VA

7 couldn't provide those services to spouses?

8 MR. GARTHWAITE: This all gets

9 relatively complex because of some of the

10 prohibitions in law about what we can and cannot get

11 involved in. So I think we're going to have to take

12 a -- you know, I don't want to sound bureaucratic,

13 but I think the reality is, there are some issues

14 that need to be addressed. But clearly, I think

15 what we need to do is have a clear, and reasonable,

16 and fairly straight-forward approach that's clear

17 from the veteran's standpoint. Yes. "If you have a

18 concern about having children, here's how you get

19 help." I think that needs to be simple and clear.

20 MS. LASHOF: Thank you very much, Dr.

21 Garthwaite. We appreciate your coming.

22 Next is Diana Tabler. I guess we

512 1 have a panel coming up: Diana Tabler, Captain

2 Donald Johnson, and Colonel Robert Jarrett. And

3 some of the questions we've just asked will really

4 be addressed by this panel, who are going to talk

5 about genetic services, referral, and outreach.

6 And Diana Tabler, are you kicking it

7 off?

8 MS. TABLER: I'll begin. Thank you

9 very much.

10 MS. LASHOF: All right. Thank you.




14 MS. TABLER: Thank you. I'm here

15 today at the Committee's request specifically to

16 discuss health care benefits available for the

17 Military Health Services System beneficiaries who

18 experience reproductive problems including birth

19 defects and decreased fertility, and who seek care

20 under the Civilian Health and Medical Program of the

21 Uniformed Services, which is, in fact, my specific

22 area of responsibility.


1 To date, investigations by state and

2 national health agencies as well as the DOD have

3 not, as you know, identified elevated or unusual

4 patterns of problems, including birth defects, among

5 Persian Gulf War veterans. The Department of

6 Defense clearly understands the importance of these

7 issues to family members, and is working with other

8 agencies to continue to search for any undiscovered

9 correlations.

10 The benefits I'll describe today are

11 part of DOD's comprehensive care for our families

12 and our children with special needs. They are based

13 on eligibility for DOD-sponsored care and provided

14 without regard to the possible cause of those needs.

15 The heart of the military health care

16 system is the direct care system of about 116

17 hospitals and more than 500 clinics throughout the

18 world in which we provide a comprehensive range of

19 acute care services from primary to tertiary care to

20 our eligible beneficiaries, depending, of course, on

21 the size of the facility. Active duty members

22 receive virtually all of their care from our

514 1 military hospitals, and nearly two-thirds of all the

2 care delivered by DOD to our beneficiaries is

3 provided in our system of direct care military

4 hospitals.

5 When that direct care system is short

6 on space or staff, then family members of active

7 duty personnel, and retirees and their family

8 members who are under the age of sixty-five, may

9 seek care under the Civilian Health and Medical

10 Program of the Uniformed Services, known as CHAMPUS.

11 TRICARE, the Department's comprehensive managed care

12 initiative, is now replacing CHAMPUS to more

13 effectively integrate our military and civilian

14 health care resources, establish uniform benefits,

15 and introduce managed care improvements throughout

16 the system.

17 TRICARE provides cost sharing for

18 medically-necessary health care purchase from

19 civilian sources when MTF care or military treatment

20 facility care is not available. Coverage is

21 provided without regard to pre-existing conditions.

22 A key facet of TRICARE is the beneficiaries'

515 1 voluntary enrollment, selection of a primary care

2 manager who either provides or arranges for a

3 family's health care. Because of the relative youth

4 of our active duty population, family planning and

5 reproductive health are important components of the

6 care we provide.

7 Beneficiaries who experience

8 fertility problems can use their TRICARE benefit to

9 obtain a variety of reproductive health services

10 including infertility testing and treatment.

11 Covered services include diagnostic testing,

12 surgical intervention, hormone therapy, and other

13 procedures performed to correct or monitor progress

14 in overcoming the causes of infertility. Chromosome

15 analysis in cases of habitual spontaneous abortion

16 is also a covered benefit. Like many other health

17 care plans, TRICARE does not cover non-coital

18 reproductive technologies such as artificial

19 insemination and in vitro fertilization, but some of

20 these fertility programs are offered to a limited

21 extent in certain military hospitals, primarily

22 tertiary teaching hospitals.

516 1 When an eligible beneficiary becomes

2 pregnant a primary care manager or obstetrician

3 oversees the course of her antenatal postpartum

4 care. If a patient has questions or concerns about

5 the health of the fetus, genetic counseling and

6 testing such as amniocentesis, chorionic villus

7 sampling may be covered. High-risk pregnancies are

8 managed in accordance with accepted practice

9 guidelines. Under the Civilian Health Care Program,

10 ultrasound testing is a covered benefit in a

11 high-risk pregnancy situation.

12 For fetal testing, the general

13 guidelines for sharing the costs of care purchase

14 from civilian sources, if a pregnant woman is

15 thirty-five years or older, if the parents of the

16 fetus have had a previous child or personal or

17 family history with a congenital abnormality, if the

18 pregnant woman contacted rubella during the first

19 trimester of the pregnancy, or if medically

20 necessary for any other reason. The determination

21 of medical necessity is made on a case-by-case

22 basis. The obstetrician fully evaluates each

517 1 patient in determining the appropriateness of

2 providing the test. If these tests detect a fetal

3 abnormality, then the obstetrician will provide

4 genetic counseling, or refer the beneficiary to an

5 authorized provider for genetic counseling.

6 The Department of Defense is

7 Congressionally prohibited by Title 10 U.S. Code,

8 Section 1093, from providing payment for abortions

9 in either the direct care system or for care

10 purchased from civilian sources in all cases, except

11 where the life of the mother would be endangered if

12 the fetus were carried to term.

13 Once born, a child with special

14 health care needs will receive a full range of

15 medical and related health care benefits from the

16 Department of Defense to the full extent of his or

17 her eligibility. In addition, the child with a

18 disability and incapable of self-support remains

19 eligible for care in the medical health services

20 systems as a family member of an active duty member

21 or retiree even after the child reaches the age of

22 majority. The TRICARE program is the child's

518 1 primary source for medical care.

2 Based on two recent studies, both of

3 which I've provided to the Committee, we believe

4 TRICARE has had a positive impact on access to

5 pediatric health for all of our beneficiaries.

6 In addition to the coverage of

7 medical needs under TRICARE, the Department also

8 provides or arranges for special services in other

9 ways. For example, the Exceptional Family Member

10 Program provides for the screening of children with

11 potential special health care needs and the

12 coordination of duty assignments for the active duty

13 sponsor to insure that all services of the

14 exceptional family member can be met at the gaining

15 duty station. This program is designed so that the

16 active duty member who moves an average of once

17 every three years will locate to a duty assignment

18 that has the appropriate medical and non-medical

19 support structure available. For children with

20 special health care needs, this means access to care

21 either in the direct system, such as to a base or

22 medical center, or in the civilian community with


1 civilian medical care costs shared through the

2 TRICARE program.

3 Case workers also work with the

4 families of children with birth defects to

5 coordinate the delivery of services which are

6 provided under TRICARE. When a child with special

7 health care needs requires care, equipment, or

8 services that are not covered for any reason, case

9 managers will look to the next available source of

10 care. If available locally, they are generally

11 available through state-administered Title 5

12 programs, federal grants to states, programs for

13 child and maternal health, including comprehensive

14 health and rehabilitation.

15 For those who are eligible for DOD

16 care, our case management program will permit

17 waivers to our current TRICARE benefit for services,

18 supplies, and care in lieu of hospitalization where

19 it's clinically appropriate and cost effective.

20 Case managers will be able to authorize on a

21 case-by-case basis supplies or services that would

22 not otherwise be covered.

520 1 The DOD Program for Persons with

2 Disabilities is a safety net, another program, for

3 children of active duty families to insure that all

4 their health care needs are met, and to protect

5 those excluded from state programs due to residency

6 laws. After considering the availability of other

7 resources, the program allows for moderately or

8 severely disabled persons to receive cash payments

9 or benefit payments for special institutionalized

10 care, training, rehabilitation, and equipment not

11 otherwise covered. It provides up to $1,000 a month

12 to families for financial assistance, the families

13 making a copayment based on a sliding scale

14 according to rank and income from 25 to $250 per

15 month.

16 Men and women who leave active duty

17 have some provisions for health care coverage as

18 they transition to civilian life. The first is the

19 right to transitional health care in our direct care

20 and TRICARE systems of either 30, 60, or 120 days,

21 depending on their length of service.

22 We've also established a continued

521 1 health care benefit program of temporary continued

2 health benefits for all who no longer have the

3 entitlement to military health care following

4 separation from active service. This program is

5 premium-based. Former active duty members and their

6 families may purchase coverage for a total of

7 eighteen months. It generally provides the same

8 coverage as available under TRICARE, and coverage is

9 available regardless of the existence of any

10 pre-existing conditions.

11 The Department of Defense is engaged

12 in a variety of outreach programs which have

13 detailed in great detail to you and outlined in your

14 interim report, including, of course, the two

15 hotline numbers, the Web site, and other print and

16 broadcast outreach programs.

17 In response to the Committee's

18 concern about civilian health care provided to our

19 beneficiaries, I recently directed that information

20 on the DOD incident reporting line, and the

21 evaluation program, and the Internet access for the

22 Web site devoted to Gulf War issues be disseminated

522 1 to health benefit advisors and TRICARE participating

2 physicians throughout the world to encourage them to

3 call when they believe they have -- they or their

4 patients have information, medical information,

5 about the causes of health problems suffered by Gulf

6 War veterans. And our guidance includes a specific

7 reference to reproductive health problems.

8 Individuals and families eligible for

9 DOD health care can obtain medically-necessary

10 reproductive health benefits through the direct care

11 system and TRICARE. The Department has also

12 accepted responsibility to coordinate various

13 available local, state, and federal programs. And

14 when these programs cannot provide the needed care,

15 we have a backup program called the Program for

16 Persons with Disabilities.

17 We are acutely aware of the concerns

18 expressed by Persian Gulf veterans and their

19 families regarding potential reproductive health

20 risks, and recognize the profound impact it has on a

21 family. No connection has been demonstrated, but we

22 are keeping the book open with continued research.

523 1 We'll continue to provide the highest quality care

2 and support possible to eligible service members and

3 their families. Thank you.

4 MS. LASHOF: Thank you very much. I

5 think we'll hear from the whole panel, and then

6 we'll have questions at the end.

7 You're next, Dr. Johnson.




11 MR. JOHNSON: Good morning. I

12 understand that I am the second Don Johnson to speak

13 to your committee. I can assure you I do not act.

14 I have been asked to brief your

15 Committee concerning the U.S. Navy's policy

16 regarding evaluation and care of high-risk

17 pregnancy, prenatal diagnosis, and neonatal and

18 follow-up care for children born with congenital

19 anomalies. This briefing will consists of two

20 parts. The first part will be a discussion of

21 normal procedures for high-risk pregnancy or infants

22 with congenital anomalies, and the second will be


1 specific to Gulf War veterans.

2 With a high-risk pregnancy, each

3 woman at her first prenatal visit will receive a

4 packet of questionnaires that deal with a variety of

5 issues including general information about the

6 patient, past medical history, past obstetrical

7 history, nutritional assessment, social history,

8 genetic and infectious screens, as well as

9 occupational health screens. Physical examinations,

10 standard laboratory screening, and ultrasonic

11 examinations are done.

12 All assessments, laboratory tests,

13 and ultrasonic examinations fall within the

14 guidelines set by the American College of

15 Obstetricians and Gynecologists.

16 If, based on these screens and/or

17 physical examination, the pregnancy is felt to be

18 high-risk, the patient will be followed by -- in a

19 complicated OB clinic at the local medical treatment

20 facility, or referred to a perinatology group in or

21 outside the local medical treatment facility. If,

22 during ongoing prenatal checks, the mother's or

525 1 fetus's condition changes, referral of the pregnant

2 woman to the appropriate complicated OB clinic or

3 perinatology group will be made.

4 Perinatology groups consist of a

5 perinatologist, geneticist, morphologist,

6 nutritionist, and various social support personnel.

7 All known dysmorphic fetuses are referred to the

8 perinatology groups.

9 After delivery, if the neonate is

10 found to have dysmorphic features or congenital

11 anomalies and require immediate medical

12 intervention, that neonate will be referred to a

13 neonatal intensive care unit. If the neonate is

14 medically stable, the infant will be referred to a

15 geneticist, dysmorphologist, for outpatient

16 evaluation.

17 Infants and children outside of the

18 neonatal period who have congenital anomalies are

19 referred to a dysmorphologist and/of developmental

20 pediatrician for ongoing subspecialty care. General

21 pediatric care is provided by the patient's primary

22 care provider.

526 1 Gulf War veterans. Gulf War veterans

2 represent a special subpopulation of potential

3 occupational health risk. The Department of Defense

4 has developed a specific program, the Comprehensive

5 Clinical Evaluation Program, to evaluate and treat

6 medical problems that may have arisen from exposure

7 in the Gulf War. This program is well delineated,

8 starting with initial screening at the local medical

9 treatment facility, and referral to a regional

10 medical center when appropriate. Entry into this

11 program is voluntary and may be determined -- excuse

12 me -- may be terminated by the veteran at any time.

13 If a pregnant woman who is a Gulf War

14 veteran, or whose partner is a Gulf War veteran,

15 expresses concern that their health or the health of

16 their fetus may be adversely affected because of the

17 Gulf War, the appropriate person or persons will be

18 referred to the local medical treatment facility

19 administrative head for the CCEP program for

20 enrollment. If a patient has a concern that their

21 child is suffering from a condition that was caused

22 by the parents' exposure in the Gulf War, this

527 1 family will also be enrolled.

2 Evaluation, or Phase 1, will consist

3 of answering a standardized questionnaire assessing

4 health risk, occupational exposure, and reproductive

5 history. An in-depth medical system-directed

6 evaluation and complete physical exam will be done

7 by an internist or family practitioner. Basic

8 screening laboratory tests are drawn. If no

9 unexplainable findings are found, then Phase 1

10 evaluation is complete.

11 However, if the physician feels that

12 subspecialty evaluation is indicated, then the

13 patient is referred to the regional medical center

14 for entry into Phase 2. In the case of a pediatric

15 patient, evaluation of that patient would be done by

16 a pediatrician or a family practice physician.

17 I hope that this brief review has

18 clarified the U.S. Navy's policies on children with

19 congenital anomalies. Thank you for this

20 opportunity to meet with your committee.

21 MS. LASHOF: Thank you very much.

22 The last speaker is Colonel Jarrett.




4 MR. JARRETT: My comments in large

5 part will reiterate much of what has already been

6 said, and I think that is due to the nature of the

7 -- the integrated nature of military medicine. It

8 has become much more of a tri-service effort. Our

9 community hospitals and regional referral centers

10 are often intermixed. For example, Captain

11 Johnson's hospital at Bremerton is a community

12 hospital, and Madigan Army Medical Center, from

13 whence I come, is a referral medical center, and we

14 collaborate frequently on patients. And then, of

15 course, the CHAMPUS and TRICARE system is an

16 extension of both of our systems.

17 The U.S. Army provides a full

18 spectrum of obstetrical, neonatal, and pediatric

19 services to active duty members, their dependents,

20 and dependents of retired active duty personnel.

21 The organization of these services is very similar

22 to civilian practice. Obstetricians, pediatricians,

529 1 and family practitioners provide routine evaluation

2 and treatment of uncomplicated patients in community

3 hospitals. These community hospitals are located on

4 U.S. Army installations throughout the United

5 States, in Korea, and in Europe. Examples of those

6 installations would be Fort Hood in Texas, Fort

7 Benning, and Fort Bragg on the East Coast, Fort

8 Riley in Kansas, and Fort Knox in Kentucky.

9 Complicated patients are referred to

10 tertiary care military regional medical centers

11 staffed with perinatologists, neonatologists, and a

12 broad spectrum of pediatric subspecialists.

13 Subspecialist physicians who staff these hospitals

14 are trained in graduate medical education,

15 residency, and fellowship programs in both the

16 military and the civilian sector. And these

17 physicians are either board-eligible or

18 board-certified in their area of expertise, and are

19 subject to the same certification requirements as

20 their civilian counterparts.

21 When appropriate subspecialty

22 referral care is not available in the military


1 medical center, patients are referred to appropriate

2 civilian tertiary care facilities, often university

3 medical centers.

4 Women with uncomplicated pregnancies

5 are followed by family practitioners and

6 obstetricians. The care they receive follows ACOG

7 guidelines for health assessment screening,

8 diagnosis, and treatment. When obstetrical history,

9 laboratory, physical finding, or imaging criteria --

10 for example, ultrasound -- identify a high-risk

11 pregnancy, patients are referred to subspecialists

12 in perinatology. Those consultations may also

13 include consultation with neonatologists,

14 geneticists, pediatric dysmorphologists, pediatric

15 surgeons, or other subspecialists, depending on the

16 problems identified in that pregnancy.

17 For example, if a prenatal ultrasound

18 identifies a fetus to have an abnormal heart rhythm,

19 a pediatric cardiologist will assist the

20 perinatologist in evaluation of the fetus prior to

21 delivery. If an ultrasound would show an abdominal

22 wall defect, a pediatric surgeon would be consulted.

531 1 When prenatal evaluation detects a

2 fetus that will need specialized neonatal care, the

3 mother is transferred to a Level 3 regional medical

4 facility with a newborn intensive care unit prior to

5 delivery. When the Army community hospital is

6 located proximate to a regional military medical

7 center, the mother is transferred to the military

8 center, providing the expertise is present in that

9 center. If not, the mother is transferred to the

10 closest civilian facility with the appropriate

11 expertise. Infants with congenital anomalies that

12 are not identified prenatally are transferred to

13 regional medical centers after birth, using the same

14 logic.

15 Military regional medical center

16 newborn intensive care units are staffed by

17 fellowship-trained board-eligible or certified

18 neonatologists. They are assisted by a full range

19 of pediatric and surgical subspecialists in the

20 evaluation of therapy of infants with congenital

21 anomalies. Chromosome analysis, dysmorphology

22 evaluation, and genetics counseling are utilized as

532 1 medically indicated for these infants. When

2 in-house resources are not available, patients are

3 referred to civilian experts, usually at university

4 medical centers. Infants with no clearly

5 identifiable syndrome are presented as case reports

6 and discussions at national meetings.

7 Many children with congenital

8 anomalies continue to have special health care needs

9 beyond the neonatal period. When these children's

10 needs are identified, the Army's Exceptional Family

11 Member Program coordinates the assignment of

12 soldiers to locations where their children's medical

13 needs can be addressed.

14 Thank you.

15 MS. LASHOF: Thank you very much.

16 Questions? Marguerite?


18 MS. KNOX: Yeah. I just have one.

19 Are you collecting any data on the number of

20 abnormalities, and maybe what they are, that you've

21 seen?

22 MR. JARRETT: The Army, as such, has

533 1 no unified approach to the collection of data on

2 children with birth defects. All of our newborns,

3 whether they're routine newborn or are in a newborn

4 intensive care unit, they all have charts, and the

5 charts have discharge diagnoses which go into a

6 central database. But that's a database that's not

7 -- that's a database that looks at all diagnoses

8 across the board, and it's not subject to easy

9 queries. So in answer to your question, at the

10 present time we don't have a unified system for

11 looking at birth defects.

12 MS. LASHOF: Tom?

13 MR. McDANIELS: For the panel: for

14 active duty personnel who have reproductive concerns

15 because of Gulf War service, what could the medical

16 corps do? What type of information could be

17 disseminated, general information about birth

18 defects, to counteract, I guess, the negative spin,

19 or maybe some of the misinformation that's out there

20 about the incidence of birth defects to offspring of

21 Gulf War veterans?

22 MR. JOHNSON: I think the answer to

534 1 that is that you give them the best available

2 information, which is usually research-driven

3 information, as we do with any risk assessment, be

4 it immunizations, or otherwise. And you try to

5 educate them accordingly.

6 MR. McDANIELS: And that would be,

7 like, specifically through message traffic, through

8 liaisons with the commanding officers? How,

9 specifically, would that information be disseminated

10 to the troops? Do you have any recommendations?

11 MR. JOHNSON: It may come as message

12 traffic from the appropriate surgeon generals on

13 down. It may come from civilian literature, The

14 American Academy of Pediatrics, the American College

15 of Obstetrics and Gynecology, and their civilian

16 counterparts.

17 MR. McDANIELS: And do you think that

18 type of an outreach campaign would be effective, or

19 do you think it's necessary?

20 MR. JARRETT: I'll stick my neck out

21 on that one. I think the concern of the Gulf War

22 veterans illness and the publicity that it's


1 received has created a lot of concern, as we all

2 know. Otherwise, we wouldn't be here today. I

3 think, to allay people's anxieties with at least the

4 initial information that is present that if there is

5 a risk, it's probably a low risk of congenital

6 malformations, it's probably going to have to come

7 from the same type of public information.

8 Individual centers to get that type of information

9 out, I think would be very, very difficult. And I

10 say that because of other initiatives that we try to

11 get local information out about our practices, and

12 the success that we receive on that. I think we're

13 talking a big problem. So I really think the

14 Committee's findings, when those are made public,

15 when the results of ongoing studies are made public,

16 that's going to be how we get to the people.

17 MS. LASHOF: Joe?

18 MR. CASSELLS: Ms. Tabler, I have two

19 questions for you. First, do you have any idea --

20 I'm sure you do -- how much of the CHAMPUS budget is

21 devoted to reproductive problems and disabilities?

22 MS. TABLER: Well, actually we didn't

536 1 do a specific study on that. I can give you a few

2 numbers. And one reason -- current FY, I guess '95,

3 we spent about $900,000 on fetal testing in that

4 particular year. And again, it's hard to kind of

5 tease this out, but I think we could if we were to

6 do a special study on particular codes.

7 The Program for Persons with

8 Disabilities which I've described, we spend about $8

9 million a year. OB care, in general, is about 218

10 million a year, and then neonatal care is somewhat

11 -- about 47 million a year.

12 So those are very broad numbers. I

13 think it would be possible to dissect that further

14 with specific codes, but other than the program for

15 the disabilities, and neonatal, and fetal testing --

16 that's the ones that I have here today.

17 MR. CASSELLS: Okay. And one other

18 question. I commend your providing the information

19 about the Gulflink Web site, and the DOD incident

20 reporting line to your benefit advisors and the

21 TRICARE participating physicians. You said the

22 guidance includes a specific reference to

537 1 reproductive health problems. What's the nature of

2 that reference?

3 MS. TABLER: The nature is simply a

4 concern that it may be a concern among beneficiaries

5 seeking care or having questions. And actually I'd

6 be happy to provide to the Committee the actual

7 wording of our -- of our message to our contractors.

8 And I should also note that in every

9 TRICARE region --

10 MR. CASSELLS: We'd appreciate that.

11 MS. TABLER: Okay. I'll be happy to

12 do so. In every TRICARE region, 800 numbers for

13 help in TRICARE are being established, so I hope

14 that will build even more bridges between eligible

15 beneficiaries and the opportunity to have their

16 questions answered and evaluated.

17 MR. CASSELLS: Thank you.

18 MS. LASHOF: Granted that we're

19 knowledgeable that you cannot fund abortions, if

20 there are -- but you do do ultrasound and chorionic

21 villus sampling. And if the parent decides that she

22 wishes an abortion because of a severe congenital

538 1 defect, how available is it to them if they're

2 overseas, and do you have any data on the number who

3 will seek private abortions?

4 MS. TABLER: Let's see -- I do not

5 have that data available. I believe that the

6 restriction is very strict, and applies throughout

7 the world. It's not my specific area of

8 responsibility, but I'll be happy to provide that

9 information to you.

10 MS. LASHOF: Kathi?

11 MS. HANNA: This is a question I

12 guess directed to the panel, but perhaps, Diana, you

13 can take the first crack at it.

14 I'm sure you're all aware that a

15 family with a child with a disability of some type

16 faces extraordinary problems when it comes to health

17 -- having their health care paid for, whether

18 they're in the civilian sector or the military

19 sector. And in the military sector, I think

20 sometimes people stay in their job if they have

21 coverage for their child, just as they do in the

22 civilian sector.

539 1 What happens to the family who is

2 active duty, and has a child who's getting care

3 through the military hospital, when they separate

4 from the military? What happens -- you described a

5 transition period. You described a system where

6 possibly there's an extension of benefits for a

7 period of time. Can you describe what the options

8 are for that family before they're forced into a

9 civilian health insurance plan?

10 MS. TABLER: Well, during the period

11 of transition, which I said can be up to 120 days, I

12 think, depending on the amount of active service, or

13 longer if the family elects to pay premiums in what

14 is called the Continued Health Care Benefit Program.

15 Any medically-necessary health care related to birth

16 defects or congenital abnormalities, any of those

17 things, are still available as part of their basic

18 benefit. And included in that would be the services

19 under our Program for Case Management. And the

20 purpose of that program is really to find the best

21 array of family-centered services for that person.

22 And it is my belief that as a --

540 1 anyway, that as a family approaches the transition,

2 the point at which they will no longer be among --

3 be eligible for care in our system, that our case

4 managers will be working with them. For example,

5 they will have established, presumably, a state of

6 permanent residence, and that's where I think the

7 case managers can be very helpful in identifying

8 possible sources of care in the community following

9 that separation.

10 The next issue, about the subsequent

11 employment or alternative insurance is really an

12 issue that each family faces. No question.

13 Anyone else like to --

14 MR. JOHNSON: Each family that has a

15 severely handicapped child does a lot of

16 soul-searching before they decide to leave the

17 military, if they have that option. And as a

18 primary care pediatrician, we certainly would advise

19 them to think very seriously about leaving the

20 military and the economic impact that has on them.

21 Be that as it may, some people choose, and the

22 military chooses, sometimes, to separate these


1 families.

2 And I think I'd like to second that

3 most of these families actually are pretty savvy,

4 and have already looked at various state and local

5 types of programs where they're going to relocate

6 themselves. And a lot of these children do fall

7 under crippled children's or some other type of

8 benefit.

9 MS. LASHOF: I'd like to follow that

10 -- just one more item in that regard. As you

11 indicated, they are very cautious about leaving the

12 military because of those benefits. And retirees

13 continue to have benefits.

14 MS. TABLER: That's correct.

15 MS. LASHOF: Where does the category

16 of the medically discharged -- when the military

17 chooses to discharge someone because of medical

18 inability to continue to serve, do they fall under

19 the category of a retiree, or does it depend on how

20 long in the service, or are they entitled to further

21 benefits, or not?

22 MS. TABLER: I'm not sure.

542 1 MR. JARRETT: I'm sorry; as a

2 pediatrician, I don't know the answer to that.

3 MR. JOHNSON: As I understand it, if

4 they're medically retired, depending on their

5 disability, their family may be eligible for

6 continued care. It depends on the system, and I --

7 also as a pediatrician, I really don't know.

8 MR. CASSELLS: It's based on the

9 percent of disability --

10 MS. LASHOF: The percent of

11 disability --

12 MR. CASSELLS: -- and the family --

13 MS. LASHOF: -- determines whether

14 the family gets care?

15 MR. CASSELLS: The family continues

16 to get care.

17 MS. LASHOF: Okay. It's complicated.

18 MR. JOHNSON: And there are also some

19 other categories: designees of the Secretary of

20 Navy, Air Force, Army that could get care, even

21 though they're not now on active duty.

22 MS. TABLER: Dr. Lashof, if I may

543 1 make sure -- I didn't answer 'cause I wasn't sure,

2 but if a person is medically retired from the

3 service, then they remain eligible for CHAMPUS as a

4 retiree. I believe that's correct.

5 MS. LASHOF: Okay. Thank you. I

6 gather we're going to have a separate briefing on

7 compensation --

8 MR. CASSELLS: We are.

9 MS. LASHOF: -- so maybe we won't

10 push you any more.

11 MS. TABLER: Okay.

12 MR. CASSELLS: But I do want to

13 follow up on that eligibility question. What about

14 the instance of administrative separations, either

15 for disciplinary action or other reasons? Are those

16 transition --

17 MS. TABLER: I don't know the answer.

18 MR. CASSELLS: And those transition

19 programs are available to the families?

20 MS. TABLER: I believe so. Yes.

21 MR. CASSELLS: In most instances, in

22 those circumstances --

544 1 MS. TABLER: Yes, they are.

2 MR. CASSELLS: -- everything is lost.

3 MS. TABLER: Voluntary -- I believe

4 the transitional benefits are available to voluntary

5 and involuntarily separated persons. I'll confirm

6 that and get it back to you.

7 MR. CASSELLS: Thank you.

8 MS. LASHOF: Okay. Any other

9 questions? If not, thank you very much.

10 That completes our formal testimony,

11 and it's a question whether the Committee has any

12 other issues that they want to bring up to discuss

13 before we adjourn.

14 Do you have any, Holly?

15 MS. GWIN: No.

16 MS. LASHOF: No. I'll remind you

17 that our next meeting is July 8th and 9th in

18 Chicago, and the subject is --

19 MS. GWIN: We're going to get

20 different briefings, and then we'll also go over

21 staff memos on risk factors.

22 MS. LASHOF: Okay. So we'll see you

545 1 all then. And if there are no other questions --

2 Robyn, any last-minute words of wisdom?


4 MS. LASHOF: No? Okay. Thank you

5 all very much. Thank you, all of our participants.

6 And the meeting stands adjourned.

7 (Whereupon, at 12:15 p.m. the meeting

8 was adjourned.)