JAIDS Journal of Acquired Immune Deficiency Syndromes:
Assessment of Birth Defects According to Maternal Therapy Among Infants in the Women and Infants Transmission Study
Watts, D Heather MD*; Li, Daner MS†; Handelsman, Ed MD‡; Tilson, Hugh MD, DrPh§; Paul, Mary MD∥; Foca, Marc MD¶; Vajaranant, Mark MD#; Diaz, Clemente MD**; Tuomala, Ruth MD††; Thompson, Bruce PhD†
From the *Pediatric, Adolescent, and Maternal AIDS Branch, National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD; †Clinical Trials and Surveys Corporation, Baltimore, MD; ‡State University of New York Downstate, Brooklyn, NY; §University of North Carolina, Chapel Hill, NC; ∥Baylor College of Medicine, Houston, TX; ¶Columbia University, New York, NY; #University of Illinois at Chicago, Chicago, IL; **University of Puerto Rico, San Juan, PR; and ††Brigham and Women's Hospital, Boston, MA.
Received for publication July 28, 2006; accepted November 6, 2006.
Please see the appendix for support information for individual investigators. Additional support provided by local clinical research centers as follows: Baylor College of Medicine, Houston, TX (NIH GCRC RR00188); Columbia University, New York, NY (NIH GCRC RR00645); and Children's Hospital, Boston, MA (NIH GCRC RR 00).
Reprints: D. Heather Watts, MD, Pediatric, Adolescent, and Maternal AIDS Branch, Center for Research on Mothers and Infants, NICHD, NIH, 6100 Executive Boulevard, Room 4B11, MSC 7510, Bethesda, MD 20892-7510 (for courier, use Rockville, MD 20852) (e-mail: firstname.lastname@example.org).
Background: To evaluate rate and types of birth defects according to timing of antiretroviral exposure among babies born to HIV-infected women.
Methods: Anomalies identified during the prenatal, neonatal, or follow-up period were classified using criteria of the Antiretroviral Pregnancy Registry. Antiretroviral use was classified as none, second or third trimester only, or first trimester.
Results: From January 1, 1990 through June 30, 2004, 2527 live births (LBs) occurred to 2353 women. Defects were identified in 90 babies for a rate of 3.56 defects per 100 LBs. The rate of defects was 3.19 per 100 LBs (24 of 752 LBs) with first-trimester antiretroviral exposure, 3.54 per 100 LBs (41 of 1158 LBs) with exposure later in pregnancy, and 4.05 of 100 LBs (25 of 617 LBs) with no antiretroviral use. Only genital abnormalities, specifically hypospadias, were significantly increased among babies born to women with first-trimester exposure to antiretrovirals (7 of 382 male LBs) compared with the 2 other groups (2 of 892 male LBs; P = 0.007). On logistic regression, use of zidovudine in the first trimester was associated with hypospadias (adjusted odds ratio = 10.68, 95% confidence interval: 2.11 to 54.13; P = 0.004).
Conclusions: In general, data were reassuring, although the frequency of exposure to newer agents was limited. The increased risk of hypospadias after first-trimester exposure must be explored, because this association has not been detected previously.
Women are, with increasing frequency, entering pregnancy while being treated with multiple antiretroviral agents,1 raising concerns about possible teratogenicity. Exposure to efavirenz has been associated with central nervous system defects in monkeys, and case reports of neural tube defects in human patients are concerning but inconclusive.2 Evaluating any antiretroviral exposure, one retrospective study found an increased risk of birth defects among 13 women with first-trimester exposure to antiretroviral therapy and folate antagonists (23% vs. 4% with neither exposure, odds ratio [OR] = 7.1, 95% confidence interval [CI]: 1.5 to 34.0) but not with exposure to antiretrovirals or folate antagonists alone.3 Studies in larger numbers of subjects, including the European Collaborative Study and a surveillance project from the United Kingdom and Ireland, have not detected an increased risk of birth defects after antiretroviral drug exposure.4,5
The largest source of data regarding antiretroviral exposure and birth defects is the Antiretroviral Pregnancy Registry (APR), a prospective registration cohort study.6,7 In the primary analysis, no increased risk of defects after first-trimester exposure to antiretrovirals has been noted, except an unexplained increase of overall defect reports after first-trimester exposure to didanosine, without increases in any individual defect.7,8 Among clinical trials cases reported to the APR, the risk of birth defects after first-trimester exposure was increased, primarily attributable to an excess of septal cardiac defects in 2 studies: the Pediatric AIDS Clinical Trials Group (PACTG) 185 study and a German multisite study. This difference could have been attributable to a severity bias, ascertainment bias, other unmeasured confounders or to an actual effect of zidovudine.9 Because it is impossible to determine all sources of bias and their potential effect on the findings, further assessment of the rate of birth defects among women exposed to antiretrovirals during pregnancy is required.
We evaluated the number and types of birth defects among babies in the Women and Infants Transmission Study (WITS), a cohort study enrolling women during pregnancy and providing long-term follow-up of their babies. Extensive data are available on antiretroviral drug exposures and maternal clinical characteristics during pregnancy, providing the opportunity to assess the possible impact of antiretroviral therapy on birth defects.
The WITS is a multicenter prospective observational study of pregnant women and their babies.10 Beginning in December 1989, pregnant HIV-1-infected women were recruited at centers in Chicago, Massachusetts (Boston and Worcester), New York City, and San Juan. Sites were added in Brooklyn in 1991 and in Houston in 1993. The study was approved by each site's institutional review board, and all women provided informed consent for enrollment of themselves and their newborns. Women were enrolled during pregnancy or within 7 days after delivery, and neonates were enrolled within 7 days of birth. The cohort for the current analyses includes pregnancies with an outcome through June 30, 2004.
For women monitored during pregnancy, study visits occurred at or before 20 weeks of gestation, at 25 ± 2 weeks, at 32 ± 2 weeks, and at delivery. At each visit, a detailed medical and behavioral questionnaire was administered and a physical examination and phlebotomy were performed. Additional data on women and babies were obtained from medical record abstraction. Newborn/infant visits occurred at <7 days; 1, 2, 4, 6, 9, 12, and 18 months; and every 6 months thereafter. Each visit included a medical history, a physical examination, and phlebotomy. Additional study testing other than routine pediatric evaluations and assessment of HIV-1 infection status included only age-appropriate neurodevelopment testing beginning at 4 months of age.
Antiretroviral treatment was not prescribed as part of the study. The start and stop dates for medications reported were recorded as the month and year of first or last use. Trimesters were defined as follows: first trimester, the first day of the last menstrual period through 13 completed weeks of gestation; second trimester, 14 through 26 completed weeks of gestation; and third trimester, beginning at 27 weeks of gestation until delivery. For a given woman who initiated multiple drugs at different times during pregnancy, each drug was assigned a starting trimester based on the date it was begun. A woman's exposure was categorized only once for each pregnancy, based on the earliest trimester of exposure, when assessing rates of birth defects. Data from 380 pregnancies, 6 (1.58%) with newborn birth defects, were excluded from the analysis because of unconfirmed medication histories. Women with unconfirmed medication histories were more likely to be enrolled before February 1994 (P < 0.001).
Maternal illicit drug use during pregnancy was considered positive if there was self-report or a positive urine toxicology test result for heroin or opiates, methadone, cocaine, or any injection drug use. Cigarette smoking and alcohol use were self-reported variables.
Abnormalities in the fetus/newborn/infant were determined from all available data, including prenatal ultrasound examinations, physical examinations in the newborn period and at each follow-up visit, and any ancillary testing ordered by the primary care provider. Birth defects were categorized based on the same criteria as used by the APR to provide consistency for comparisons.7,11 This categorization counts all major defects as listed in the Centers for Disease Control and Prevention Metropolitan Atlanta Congenital Defects Project (MACDP) but also counts as babies with defects those with 2 or more conditional, or minor, defects.7,12 Defects were included if they were confirmed in a liveborn baby or in a stillbirth or induced abortion at or after 20 weeks of gestation. A baby with multiple defects was counted as a single outcome. The denominator for calculation of birth defect rates was live births (LBs), consistent with the APR and MACDP. All babies from a multiple birth were included in the data set.
CD4+ lymphocyte counts were determined by flow cytometry at certified laboratories. Plasma HIV-1 RNA was measured in stored specimens using the Roche Amplicor HIV-1 Monitor Test (Roche Diagnostic Systems, Branchburg, NJ), as described.13
The rate of detection of birth defects per 100 LBs overall and for different exposure groups was calculated, and 95% CIs were calculated using a binomial approximation. A minimum of 200 LBs with a specific exposure was required to provide rates and 95% CIs for a specific drug, because 200 exposures allows detection of a doubling of the overall rate of birth defects.7 Birth defects were grouped according to an organ system classification11 to compare defect rates with various exposures. If any association with organ system defects was detected, further exploration of individual defects and risk factors was performed using univariate analyses. The χ2 or Fisher exact test was used to assess statistical significance. For logistic regression analysis, factors listed in Table 1 and antiretroviral drug exposures were evaluated in stepwise multivariate models with cohort time included in each model. Any variable with a significance level of 0.10 or less was retained in the stepwise model.
During the study period, 2527 LBs occurred among 2353 women with complete antiretroviral information, including 1817 with 1 LB (36 sets of twins), 261 with 2 deliveries (9 sets of twins, 1 set of triplets), 40 women with 3 deliveries (1 set of twins), and 5 women with 4 deliveries. An additional 230 women had a stillbirth, miscarriage, or abortion after enrollment. A comparison of enrollment characteristics by antiretroviral exposure is shown in Table 1. Significant differences were seen between the 3 groups in all characteristics evaluated. Women on no antiretroviral therapy were more likely to use cigarettes, drugs, or alcohol during pregnancy and to have CD4+ lymphocyte counts greater than 500 cells/μL at enrollment. Women receiving first-trimester therapy were more likely to have CD4+ cell counts less than 200 cells/μL and to be receiving opportunistic infection prophylaxis.
Among the study population, birth defects were detected among 90 babies, for a rate of 3.56 per 100 LBs (95% CI: 2.89 to 4.38). The rate of birth defects per 100 LBs among HIV-infected women with first-trimester antiretroviral exposure was 24 of 752 (3.19 per 100 LBs, 95% CI: 2.10 to 4.78); among those with only second- or third-trimester exposure, it was 41 of 1158 (3.54 per 100 LBs, 95% CI: 2.58 to 4.82); and among those with no antiretroviral exposure, it was 25 of 617 (4.05 of 100 LBs, 95% CI: 2.69 to 6.01). Specific antiretroviral drugs and trimester of first exposure are summarized in Table 2. For individual antiretroviral drugs, only zidovudine and lamivudine have adequate numbers to detect an overall 2-fold increased risk of birth defects, and the risk was not increased. Likewise, for exposure to any nucleoside reverse transcriptase inhibitor (NRTI), protease inhibitor (PI), or highly active antiretroviral therapy (HAART) in the first trimester, the risk was not increased.
The specific birth defects detected, grouped by organ system and exposure are listed in Table 3. Specific defects with 5 or more reported cases included hypospadias, polydactyly, club feet, and hydronephrosis. Cleft lip or palate, hip dislocation, and micrognathia each were diagnosed in 4 cases. Three cases of ventricular septal defect were diagnosed, 1 case after first-trimester exposure to antiretrovirals and 2 cases after later exposure. In addition, 1 case of atrioventricular canal occurred after first-trimester exposure.
Univariate analyses were performed for the outcome of any birth defect, for each organ system classification separately, and for the most frequent defects, evaluating drug exposure coded as first trimester, second or third trimester only, and none for any antiretroviral drug, zidovudine, other nucleoside agents, any nonnucleoside agent, and any PI. Among the organ system classes, only genital defects showed a significant association with the timing of antiretroviral exposure, with an increased risk associated with first-trimester zidovudine exposure (OR = 4.93, 95% CI: 1.37 to 17.73; P = 0.015). The only specific defect found to be associated with antiretroviral exposure was hypospadias in male babies, associated on univariate analysis (see Table 4) with any first-trimester antiretroviral exposure (P = 0.007), with any first-trimester zidovudine exposure (P = 0.014), and with first-trimester NRTI exposure other than zidovudine (P = 0.045). On logistic regression analysis of all factors listed in Table 4, only use of zidovudine in the first trimester was associated with hypospadias (OR = 10.68, 95% CI: 2.11 to 54.13; P = 0.004).
Of the 9 cases of hypospadias, the urethral opening was on the glans penis in 7 (first degree), and on the scrotum or perineum in 2 (third degree). Both cases with scrotal hypospadias occurred after first-trimester antiretroviral exposure: 1 to zidovudine and lamivudine and 1 to didanosine, stavudine, and nelfinavir. During the follow-up period, 4 (57%) of 7 babies with first-degree hypospadias underwent surgical correction of the defect, but the duration of follow-up varied.
In general, our data are reassuring that there is not an overall increase in the risk of birth defects with first-trimester antiretroviral exposure. Numbers of exposures are inadequate for many of the newer antiretroviral agents to detect even a tripling of risk, however. For specific defects, such as neural tube defects, that occur in the general population at a rate of 1 to 2 per 1000, more than 1000 first-trimester exposures would be required to detect a tripling in the rate.14 Thus, continued surveillance of pregnancies exposed to antiretroviral therapy is required, especially because therapy has become more complex and new agents have been introduced. Providers should reports cases of antiretroviral exposure in pregnancy to the APR (available at: www.APRegistry.com) as early in pregnancy as possible.
The overall rate of defects detected after first-trimester exposure was not significantly increased from the rate after exposure to antiretrovirals later in pregnancy or among HIV-infected women with no antiretroviral use. Although women not receiving antiretroviral were more likely to use illicit drugs or alcohol during pregnancy, which are exposures that may increase the risk of defects, these exposures were not associated with any of the classes of defects or individual defects examined. In contrast, women with first-trimester antiretroviral use were more likely to receive opportunistic infection prophylaxis, a factor associated with an increased risk of birth defects in a study.3 The rate of defects after first-trimester antiretroviral exposure is similar to the rate of 3.1 per 100 LBs reported in the MACDP surveillance project, which includes active surveillance for defects through the age of 6 years,15 and to the rate of 2.9 per 100 LBs after first-trimester antiretroviral exposure in cases reported to the APR.7 Detection of defects in the WITS would be expected to be higher than that in the APR, because the APR relies on reports from prenatal providers, who often have limited follow-up information.
The use of any first-trimester exposure as a risk factor for birth defects is somewhat artificial, because fetal development continues throughout pregnancy and some defects, such as club feet, may occur after the first trimester.16 The bulk of organogenesis occurs during the first trimester, however. Although women coded as taking antiretroviral therapy during the first trimester may have had only limited exposure, most were receiving therapy before conception and continued throughout the first trimester and beyond.
The risk of septal heart defects was not increased among those with antiretroviral exposure, which is consistent with the APR prospective cohort data and reassuring in view of the APR clinical studies data discussed previously.7
The only signal detected was hypospadias after first-trimester exposure to antiretrovirals, specifically zidovudine. Hypospadias is a displacement of the urethral opening from the tip of the penis to a more proximal location ranging from the glans to the penile shaft, scrotum, or perineum. Single-stage surgical correction during infancy is generally required. This finding must be interpreted with caution. The small number of cases, the potential for over- and underdiagnosis of hypospadias,17,18 and the range of rates reported in the literature19-23 all must be considered. A change of a single diagnosis (eg, shifting of 1 case of hypospadias from first trimester to later exposure) would change the probability value to a nonsignificant level. In addition, the inference was not adjusted for the multiple comparisons done as part of this study. The overall rate of detection of hypospadias of 3.29 per 1000 total LBs reported here is within the range of 2 to 3.97 per 1000 LBs from US reports.19-21,23 The rate (7 of 752 LBs [9.31 of 1000 total LBs]) after first-trimester exposure to antiretrovirals seems elevated, however. The proportion of cases in our series that were penile or scrotal (22%) is similar to the 19% to 28% reported in the literature, suggesting against overdiagnosis of mild cases.17,19 Both severe cases occurred after first-trimester antiretroviral exposure, yielding a rate of 26.6 per 10,000 LBs compared with rates of 1.1 to 5.5 per 10,000 LB in US surveillance systems.19-21,23 No increased risk of hypospadias specifically, or of male genital defects in general, has been observed in the larger number of exposed pregnancies reported to the APR or in animal studies.7,24 Thus, this finding must be verified in other studies. Given the clear benefits of antiretrovirals for maternal health and prevention of perinatal transmission of HIV,25 no change in prescribing practices for antiretrovirals for pregnant women24 is indicated based on these data.
The rate of hypospadias has been noted to be increasing over the past several decades in some but not all cohorts studied in Europe and the United States.18,19,21,23 US surveillance data demonstrated a doubling of the rate of hypospadias from 1970 to the early 1990s.19 More recent data have been less consistent, with a study of Washington State births showing no change in the rate of detection from 1987 through 2002,21 whereas a study of more than 4 million male births shows a continuing increase in congenital penile anomalies, primarily hypospadias, from 1988 through 2000.26 If the rate of hypospadias is continuing to increase overall, the association in the current study may represent a temporal trend that happened to coincide with changes in antiretroviral prescribing practices, spuriously implicating antiretrovirals.
Hypospadias is hypothesized to be part of an entity called testicular dysgenesis syndrome that encompasses a range of male genital abnormalities, including undescended testes, hypospadias, poor semen quality, and testicular cancer.27 This syndrome is thought to be increasingly related to increasing environmental exposure to endocrine disrupters. Animals exposed in utero to exogenous estrogens or antiandrogens have an increased rate of hypospadias.27 None of the antiretroviral agents are known to have estrogenic or antiandrogenic effects that should predispose to the development of hypospadias. We did not have complete data on other drug exposures that might have such effects during the first trimester. Women receiving first-trimester antiretrovirals were, however, more likely to be receiving drugs for prevention of opportunistic infections. Some antifungal agents may have estrogenic effects, and it is possible that the use of antiretrovirals, along with other drugs, may alter the metabolism of the other agents. Prochloraz, an imidazole fungicide, has been shown to cause hypospadias in rats in a dose-dependent manner.28
Overall, these data are reassuring regarding antiretroviral use and detection of birth defects in exposed fetuses/newborns/infants. The single notable finding, an increase in the risk of hypospadias after first-trimester antiretroviral exposure, requires confirmation, because numbers are small, it has not been noted in other studies, and there are plausible alternate explanations for the finding. The potential increased risk does not negate the overwhelming benefits of antiretroviral therapy in the maintenance of maternal health and prevention of perinatal transmission.25 We underscore the need for continued vigilance, particularly reporting to the APR, to permit surveillance of birth defects among babies born to women receiving antiretroviral agents during pregnancy.
The authors gratefully acknowledge the children and their families who have participated in the WITS and the efforts of the dedicated study personnel at all sites throughout the study who have made this analysis possible.
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Principal investigators, study coordinators, program officers, and funding include the following: Clemente Diaz and Edna Pacheco-Acosta (University of Puerto Rico, San Juan, PR; U01-AI-34858); Ruth Tuomala, Ellen Cooper, and Donna Mesthene (Boston/Worcester site, Boston, MA; U01-DA-15,054); Phil La Russa and Alice Higgins (Columbia-Presbyterian Hospital, New York, NY; U01-DA-15053); Sheldon Landesman, Edward Handelsman, and Ava Dennie (State University of New York, Brooklyn, NY; U01-HD-36117); Kenneth Rich and Delmyra Turpin (University of Illinois at Chicago, Chicago, IL; U01-AI-34841); William Shearer, Susan Pacheco, and Norma Cooper (Baylor College of Medicine, Houston, TX; U01-HD-41,983); Joana Rosario (National Institute of Allergy and Infectious Diseases, Bethesda, MD); Kevin Ryan, (National Institute of Child Health and Human Development, Bethesda, MD); Vincent Smeriglio and Katherine Davenny (National Institute on Drug Abuse, Bethesda, MD); and Bruce Thompson (Clinical Trials and Surveys Corporation, Baltimore, MD; N01-AI-85339). The scientific leadership core includes Kenneth Rich (Principal Investigator) and Delmyra Turpin (Study Coordinator) (1-U01-AI-50274-01). Cited Here...
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