Metropolitan Atlanta Congenital Defects Program Research Articles

First-trimester exposure to newer antiretroviral agents and congenital anomalies in a US cohort.

To characterize associations of exposure to newer antiretroviral medications in the first trimester with congenital anomalies among infants born to persons with HIV in the United States. Longitudinal cohort of infants born 2012-2022 to pregnant persons with HIV enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) study. First-trimester exposures to newer antiretrovirals (ARVs) were abstracted from maternal medical records. Trained site staff conducted physical exams and abstracted congenital anomalies from infant medical records. Investigators classified anomalies using the Metropolitan Atlanta Congenital Defects Program classification system. The prevalence of major congenital anomalies identified by age one year was estimated for infants exposed and unexposed to each ARV. Generalized estimating equation models were used to estimate the odds ratio (OR) of major congenital anomalies for each ARV exposure, adjusting for potential confounders. Of 2034 infants, major congenital anomalies were identified in 135 [6.6%; 95% confidence interval (CI): 5.6-7.8%]. Cardiovascular ( n = 43) and musculoskeletal ( n = 37) anomalies were the most common. Adjusted ORs (95% CI) of congenital anomalies were 1.03 (0.62-1.72) for darunavir, 0.91 (0.46-1.81) for raltegravir, 1.04 (0.58-1.85) for rilpivirine, 1.31 (0.71-2.41) for elvitegravir, 0.76 (0.37-1.57) for dolutegravir, and 0.34 (0.05-2.51) for bictegravir, compared to those unexposed to each specific ARV. Findings were similar after adjustment for nucleoside/nucleotide backbones. The odds of congenital anomalies among infants with first-trimester exposure to newer ARVs did not differ substantially from those unexposed to these specific ARVs, which is reassuring. Continued evaluation of these ARVs with larger studies will be needed to confirm these findings.

The Antiretroviral Pregnancy Registry: Three decades of prospective monitoring for birth defects.

Antiretrovirals (ARVs) are life-saving drugs used for the treatment and prevention of HIV infection and antiviral drugs (AVs) for the treatment of chronic HBV infection. ARVs have proven highly effective in reducing perinatal HIV transmission, however the risk of birth defects from prenatal exposure to ARVs/AVs is an ongoing concern. The Antiretroviral Pregnancy Registry (APR), an international, prospective exposure-registration cohort study, monitors ARV and AV use in pregnancy for early signals of teratogenicity. This communication reports results of 30-years' experience of ARV/AV exposure during pregnancy and lessons learned through continuous quality improvement. Birth defect prevalence is estimated and compared to internal and external groups. Statistical inference is based on exact methods for binomial proportions. Between 2006 and 2023, cumulative enrollment more than tripled from 6893 to 25 960 pregnancies and ARVs/AVs monitored increased from 29 to 222. Through January 2023, there were 21 636 live births and 631 outcomes with birth defects, for overall prevalence of 2.9/100 live births (95% CI 2.7, 3.2). The birth defect prevalence was 3.0% (95% CI 2.7%, 3.3%) among first trimester exposures and 2.8% (95% CI 2.5%, 3.2%) among second/third trimester exposures (prevalence ratio 1.04 [95% CI 0.89, 1.21]). Birth defect prevalence is not statistically significantly different between first trimester ARV/AV pregnancy exposures compared to second/third trimester exposures and is also not different from two population-based surveillance systems: 2.72/100 live births reported in the Metropolitan Atlanta Congenital Defects Program (MACDP); and 4.17/100 live births from the Texas Birth Defects Registry (TBDR).

Pregnancy and fetal outcomes following paternal exposure to glatiramer acetate

Objectives This study aimed to examine pregnancy and fetal outcomes following paternal exposure to glatiramer acetate (GA). Methods Pregnancy reports of paternal GA-exposure at time of conception from 2001 to 2022 were extracted from Teva Global Pharmacovigilance database. Pregnancy reports obtained prior to (prospective) or after (retrospective) knowledge of the pregnancy outcome were included. The primary endpoint was major congenital malformation (MCM) in the offspring according to the US Metropolitan Atlanta Congenital Defects Program (MACDP) and European Surveillance of Congenital Anomalies and Twins (EUROCAT) classification. Other pregnancy and fetal outcomes, including spontaneous abortion, pregnancy termination, fetal death, preterm birth, and low birth weight, were assessed. Results A total of 466 paternal GA-exposed pregnancies were retrieved, 232 prospective cases and 234 retrospective cases. Of 349 (74.9%) pregnancies with known outcomes, 316 (90.5%) were live births, 28 (8.0%) were spontaneous abortions, 3 (0.9%) were elective pregnancy terminations, and 2 (0.6%) were stillbirths. In prospective live birth cases, there were 7/111 (6.3%) preterm births and 5/115 (4.3%) neonates with a low birth weight. The prevalence of total MCM among prospective cases was 1.7% (2 cases of 116 live births and fetal death/stillbirth), which is slightly lower than the background rates from MACDP (3%) and EUROCAT (2.1%). Conclusions This study did not indicate an increase in the rate of adverse pregnancy and fetal outcomes after paternal exposure to GA. These results provide additional information regarding pregnancy outcomes following paternal exposure to GA for healthcare professionals, male patients and their female partners who are considering pregnancy while their male partner is using GA.

Analysis of Pregnancy Outcomes Following Exposure to Intramuscular Interferon Beta-1a: The AVONEX® Pregnancy Exposure Registry.

There is a lack of well-controlled US studies of intramuscular (IM) interferon beta (IFNβ)-1a use in pregnant women with multiple sclerosis; however, in the European Medicines Agency region, IFNβ formulations may be considered during pregnancy if clinically needed based on data from European Union cohort registries. The AVONEX Pregnancy Exposure Registry was established to prospectively study the effects of IM IFNβ-1a on the risk of birth defects and spontaneous pregnancy loss in a US population. Pregnant women with multiple sclerosis exposed to IM IFNβ-1a within ~ 1 week of conception or during the first trimester were included. Participants were followed until there was a pregnancy outcome, live-born infants were followed until age 8-12 weeks. Data were collected on IM IFNβ-1a exposure, demographics, patient characteristics, medical history, and pregnancy outcomes, including live births (with or without birth defect), spontaneous abortions/miscarriages and fetal death/stillbirth, elective abortions (with and without birth defect), and ectopic pregnancies. A population-based birth defect surveillance program, the Metropolitan Atlanta Congenital Defects Program (MACDP), served as the primary external control group for evaluating the risk of birth defects. Three-hundred and two patients with a median (range) age of 31.0 (16-48) years and a median (range) gestational age at the time of enrollment of 10.1 (4-39) weeks were evaluable. Most patients (n = 278/302; 92%) reported IM IFNβ-1a exposure in the week before conception and most (n = 293/302; 97%) discontinued treatment before the end of the first trimester. Of 306 pregnancy outcomes, there were 272 live births, 28 spontaneous abortions of 266 pregnancies enrolled before 22 weeks' gestation (rate 10.5%; 95% confidence interval 7.2-15.0), five elective abortions, and one stillbirth. There were 17 adjudicator-confirmed major birth defects of 272 live births (rate 6.3%; 95% confidence interval 3.8-10.0); the pattern of birth defects observed was not suggestive of a relationship to prenatal IM IFNβ-1a exposure. This large US registry study suggests IM IFNβ-1a exposure during early pregnancy was not clinically associated with adverse pregnancy outcomes in women with multiple sclerosis. These findings help inform clinicians and patients in weighing the risks and benefits of IM IFNβ-1a use during pregnancy. ClinicalTrials.gov: NCT00168714, 15 September, 2005.

Narrowing the Survival Gap: Trends in Survival of Individuals with Down Syndrome with and without Congenital Heart Defects Born 1979 to 2018

To evaluate the hypothesis that childhood survival for individuals with Down syndrome (DS) and congenital heart defects (CHDs) has improved in recent years, approaching the survival of those with DS without CHDs. Individuals with DS born from 1979 to 2018 were identified through the Metropolitan Atlanta Congenital Defects Program, a population-based birth defects surveillance system administered by the Centers for Disease Control and Prevention. Survival analysis was performed to evaluate predictors of mortality for those with DS. The cohort included 1671 individuals with DS; 764 had associated CHDs. The 5-year survival in those with DS with CHD improved steadily among individuals born in the 1980s through the 2010s (from 85% to 93%; P=.01), but remained stable (96% to 95%; P=.97) in those with DS without CHDs. The presence of a CHD was not associated with mortality through 5years of age for those born 2010 or later (hazard ratio, 2.63; 95% CI, 0.95-8.37). In multivariable analyses, atrioventricular septal defects were associated with early (<1year) and late (>5year) mortality, whereas ventricular septal defects were associated with intermediate (1-5years) mortality and atrial septal defects with late mortality, when adjusting for other risk factors. The gap in 5-year survival between children with DS with and without CHDs has improved over the last 4 decades. Survival after 5years remains lower for those with CHDs, although longer follow-up is needed to determine if this difference lessens for those born in the more recent years.

Final results from the ribavirin pregnancy registry, 2004-2020.

Significant teratogenic effects have been demonstrated for ribavirin in animal studies. Ribavirin is prescribed for chronic hepatitis C and is contraindicated in pregnant women and their male sexual partners. Both are advised to avoid pregnancy for 6months after exposure. The registry monitored pregnancy exposures to oral formulations of ribavirin for hepatitis C for signals of possible human teratogenicity from 2004 to 2020. Pregnant women were voluntarily enrolled following direct exposure (ribavirin use during pregnancy or the 6months prior) or indirect exposure (through sexual contact during pregnancy or 6months prior, with a man who has taken ribavirin within 6months). Women were followed until the end of pregnancy. Infants were followed until 1year of age. Birth defect rates were compared with the published rate of 2.67 per 100 live births from the Metropolitan Atlanta Congenital Defects Program (MACDP). The registry enrolled 280 pregnancies resulting in 186 live births: eight birth defect cases among 88 directly exposed [9.09% (8/88, 95% CI: 4.01, 17.13)], and six birth defect cases among 98 indirectly exposed [6.12% (6/98, 95% CI: 2.28, 12.85)]. The 95% CI around the birth defect rate among directly exposed pregnancies exceeds the MACDP rate; however, no patterns suggestive of a teratogenic mechanism or safety signal were detected. Based on the patterns of birth defects reported, the final results from this registry do not suggest a clear signal of human teratogenicity for ribavirin. The registry did not meet sample size requirements; therefore, caution should be exercised when interpreting the results.

Pharmacovigilance pregnancy data in a large population of patients with chronic inflammatory disease exposed to certolizumab pegol.

Introduction:Chronic inflammatory diseases (CIDs), including rheumatic diseases and other inflammatory conditions, often affect women of reproductive age. Tumor necrosis factor inhibitors (TNFi) are widely used to treat CID, but there is limited information on outcomes of TNFi-exposed pregnancies. We evaluated pregnancy outcomes from 1392 prospectively reported pregnancies exposed to certolizumab pegol (CZP), a PEGylated, Fc-free TNFi with no to minimal placental transfer.Methods:CZP-exposed pregnancies in patients with CID from the UCB Pharmacovigilance global safety database were reviewed from the start of CZP clinical development (July 2001) to 1 November 2020. To limit bias, the analysis focused on prospectively reported cases with known pregnancy outcomes.Results:In total, 1392 prospective pregnancies with maternal CZP exposure and known pregnancy outcomes (n = 1425) were reported; 1021 had at least first-trimester CZP exposure. Live birth was reported in 1259/1425 (88.4%) of all prospective outcomes. There were 150/1425 (10.5%) pregnancy losses before 20 weeks (miscarriage/induced abortion), 11/1425 (0.8%) stillbirths, and 5/1392 (0.4%) ectopic pregnancies. Congenital malformations were present in 30/1259 (2.4%) live-born infants, of which 26 (2.1%) were considered major according to the Metropolitan Atlanta Congenital Defects Program criteria. There was no pattern of congenital malformations.Discussion and conclusion:No signal for adverse pregnancy outcomes or congenital malformations was observed in CZP-exposed pregnancies. Although the limitations of data collected through this methodology (including underreporting, missing information, and absence of a comparator group) should be considered, these data provide reassurance for women with CID who require CZP treatment during pregnancy, and their treating physicians.

74. Maternal Dolutegravir (DTG) Use During Pregnancy and Birth Outcomes: The Antiretroviral Pregnancy Registry (APR)

BackgroundThe APR is prospective exposure-registration cohort study, monitoring for early warning signals of major teratogenic effects of antiretrovirals (ARV) used during pregnancy. This analysis aimed to assess maternal demographics, pregnancy and neonatal outcomes including birth defects among infants with periconception and prenatal exposure to DTG using APR data.MethodsDescriptive analysis with frequency tabulation of pregnancy and neonatal outcomes is reported. Periconception is defined as any exposure within two weeks prior to or through 28 days after conception. ResultsThere were 1010 prospectively reported pregnancies with exposure to DTG through 31January2021, with 526 periconception exposures, 105 exposed later during 1st trimester, 260 during 2nd trimester and 119 during 3rd trimester. Maternal median age at conception was 30 years and 77.0% of pregnancies were reported from the United States. At the time of reporting, 46.6% had CD4 count ≥500 cells/µL, 31.8% had 200-499 cells/µL, 12.5% had < 200 cells/µL and 9.1% unknown. The 1010 DTG exposed pregnancies resulted in 1036 outcomes: 956 (92.3%) live births (26 twin pairs), 12 (1.2%) stillbirths, 28 (2.7%) induced abortions, and 38 (3.7%) spontaneous abortions. Among live births, 39 (4.1%) reported birth defects. For 1st trimester exposures, overall defect prevalence was 3.3% (19/576, 95% CI:2.0-5.1) and for 2nd/3rd trimester exposures defect prevalence was 5.3% (20/380, 95% CI:3.2-8.0). One neural tube defect (NTD) case of anencephaly with periconception DTG exposure was reported. Among the 873 singleton, live births without birth defects, 92 (10.5%) were preterm (< 37 weeks of gestation); 103 (11.8%) had low birth weight (lbw) < 2500 grams including 22 (2.5%) < 1500 (very lbw) grams. ConclusionAPR data do not demonstrate an increased risk of overall birth defects with DTG use above the population expected rate of defects (2.72 to 4.17 per 100 live births from Metropolitan Atlanta Congenital Defects Program [MACDP] and Texas Birth Defects Registry [TBDR] respectively). The number of periconception exposure outcomes is not yet sufficient to evaluate potential association of DTG with NTD. The Registry continues to closely monitor birth defects, including NTDs in pregnancies exposed to DTG and other integrase inhibitors.Disclosures Vani Vannappagari, MBBS, MPH, PhD, ViiV Healthcare Limited (Employee) Jessica Albano, PhD, MPH, Syneos Health (Employee, Shareholder) Leigh Ragone, MS, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Taylor Cook, BS, Syneos Health (Employee) Angela Scheuerle, MD, ViiV (Independent Contractor) William R. Short, MD, Gilead Sciences (Individual(s) Involved: Self): Consultant; ViiV (Individual(s) Involved: Self): Consultant Claire Thorne, MSc, PhD, MSD (Grant/Research Support)ViiV Healthcare (Grant/Research Support, Other Financial or Material Support, Contributor to Think Tank)

Abstract 9959: Narrowing the Survival Gap: Trends in Survival in Individuals with Down Syndrome with and without Congenital Heart Defects Born 1979 - 2018

Introduction: Congenital heart defects (CHD) affect nearly 50% of children born with Down syndrome (DS) and have been shown to affect both early (&lt;1 year) and late mortality. In the non-DS population, survival with CHD has improved greatly over the last 40 years. We aim to evaluate if these changes have narrowed the survival gap between those with DS + CHD and those with DS alone over recent decades. Methods: Individuals with DS born in metropolitan Atlanta between 1979 and 2018 were identified through the Metropolitan Atlanta Congenital Defects Program, a population-based surveillance system maintained by the Centers for Disease Control and Prevention. Survival analysis was performed to evaluate predictors of mortality for those with DS + CHD and DS alone. Results: Cohort included 1,668 individuals with DS, 764 individuals of whom had a CHD. There were 150 deaths at a median age of 0.4 years (interquartile range (IQR) 0.1 - 4.5 years). In a multivariable model evaluating survival through 10 years, CHD, birthweight &lt;2500g, birth before 2000, and maternal Black race were associated with mortality. Ten-year survival in DS + CHD improved steadily from the 1980s to 2010s (82% to 93%, p=0.01) but remained stable (96% to 95%, p=0.97) in those with DS alone; presence of CHD was not significantly associated with mortality for those born in the most recent decade (HR 1.65 [95% CI 0.60 - 4.51], Figure). In multivariable analysis conditioning on surviving to 1 year, presence of CHD (HR 3.04 [95% CI 1.79-5.18]) remained significantly associated with long-term mortality. Conclusions: Early survival among children with DS + CHD has significantly improved over the last 4 decades, such that the survival gap between those with DS + CHD and those with DS alone has disappeared in the most recent decade. It remains to be seen whether these improvements will translate into improved long-term survival; CHD continues to be a risk factor for late mortality for those born in earlier decades.

POS0022 PHARMACOVIGILANCE PREGNANCY DATA IN A LARGE POPULATION OF PATIENTS WITH CHRONIC INFLAMMATORY DISEASE EXPOSED TO CERTOLIZUMAB PEGOL: PREGNANCY OUTCOMES AND CONFOUNDERS

Background:Chronic inflammatory diseases (CID) in women of reproductive age are increasingly being treated with tumour necrosis factor inhibitors (TNFi), in line with recent guidelines.1 However, data on TNFi-exposed pregnancy outcomes are still limited. Certolizumab pegol (CZP), a PEGylated, Fc-free TNFi, has no/minimal placental transfer from mother to infant during the third trimester.2Objectives:To assess pregnancy outcomes from the UCB Pharmacovigilance safety database from over 1,300 prospectively reported pregnancies with maternal CZP exposure.Methods:Details of CZP-exposed pregnancies from the UCB Pharmacovigilance safety database were reviewed up to November 1, 2020. Analysis was limited to prospectively reported cases with known pregnancy outcomes to avoid potential reporting bias. Confounders (specific CID, non-biologic medications and maternal infection) were evaluated using a multivariate stepwise regression model; results from the confounders analysis are reported as odds ratios (OR) with 95% confidence intervals (CI). Patients with missing information about presence or absence of confounders were excluded from the model.Results:1,392 prospective pregnancies (1,425 fetuses) with maternal CZP exposure and known outcomes were reported (Figure 1). Mean (SD) maternal age was 31.9 (5.1) years. Of these, 1,021/1,392 (73.3%) pregnancies had at least first-trimester CZP exposure and 547/1,392 (39.3%) were exposed during all trimesters. Overall, there were 1,259/1,425 (88.4%) live births, 150/1,425 (10.5%) abortions (miscarriages and terminations), 11/1,425 (0.8%) stillbirths, and 5/1,425 (0.4%) ectopic pregnancies. Congenital malformations were reported in 35/1,425 fetuses (2.5%) and in 30/1,259 live-born infants (2.4%); 26 (2.1%) congenital malformations were major according to the Metropolitan Atlanta Congenital Defects Program criteria. There was no pattern of specific congenital malformations. Preterm births occurred in 124/1,259 (9.8%) live births, and 101/1,259 (8.0%) of infants had low birth weight (&lt;2.5 kg). In the confounders analysis, reported corticosteroid use was independently associated with increased odds of preterm birth (OR [95% CI]: 2.1 [1.3–3.4]; p&lt;0.005) and low birth weight (OR [95% CI]: 1.7 [1.0–2.9]; p&lt;0.05), but decreased odds of abortion (OR [95% CI]: 0.5 [0.3–0.9]; p&lt;0.05). Reported NSAID use was associated with increased odds of abortion (OR [95% CI]: 2.2 [1.2–4.0]; p&lt;0.05), as was methotrexate/leflunomide use (OR [95% CI]: 3.2 [1.7–6.2]; p&lt;0.0005). Maternal infections were associated with increased odds of preterm birth (OR [95% CI]: 1.9 (1.1–3.5; p&lt;0.05). Finally, there was an association between a diagnosis of Crohn’s disease and odds of abortion (OR [95% CI]: 2.5 [1.5–4.1]; p=0.0005), and between rheumatoid arthritis and low birth weight (OR [95% CI]: 1.9 [1.1–3.3]; p&lt;0.05).Conclusion:This prospective analysis, including more than 1,000 pregnancies with CZP exposure in at least the first trimester, represents one of the largest cohorts of pregnancies with known outcomes in patients with CID. Our data confirm the impact of specific CID, concomitant drugs or comorbidities on pregnancy outcomes. In particular, additional use of corticosteroids was highlighted as a risk factor for preterm birth and low birth weight in our cohort of CZP-treated patients. No increase in adverse pregnancy outcomes or specific congenital malformations was observed in CZP-exposed pregnancies, compared to the general population,3,4 which offers further reassurance for women of childbearing age considering CZP treatment.

The Antiretroviral Pregnancy Registry: 30 Years of Monitoring for Congenital Anomalies [OP04-6D

INTRODUCTION: Antiretroviral (ARV) treatment saves lives and prevents vertical transmission of HIV. The Antiretroviral Pregnancy Registry (APR) began prospectively monitoring prenatal ARV use for potential teratogenicity in 1989 and depends on voluntary registration of ARV exposed pregnancies (www.APRegistry.com). METHODS: The APR is an IRB approved, prospective exposure-registration cohort study with data from 70 countries. Prevalence of congenital anomalies (CAs) are estimated and compared to internal and external comparison groups. Twenty-two ARVs have sufficient 1st trimester exposures to detect at least a 2-fold increase in risk of CAs overall, of which 11 can detect a 1.5-fold increase. RESULTS: Of the 20,759 pregnancies prospectively enrolled through 31 July 2019, reported outcomes include 19,642 live births (LB) with ARV exposure at any time during pregnancy and 554 CAs. Prevalence of CAs was 2.8% (95% CI 2.6-3.1) overall, 2.8% (95% CI 2.5-3.1) among 1st trimester exposures and 2.8% (95% CI 2.5-3.2) among 2nd/3rd trimester exposures to ARVs (prevalence ratio 1.00 [95% CI 0.85-1.18]). CONCLUSION: The APR has not detected a significant difference in overall CA prevalence compared to two population based surveillance systems: 2.72/100 LB (95% CI 2.68-2.76) Metropolitan Atlanta Congenital Defects Program (MACDP) and 4.17/100 LB (95% CI 4.15-4.19) Texas Birth Defects Registry (TBDR). Two ARVs, didanosine and nelfinavir, have modest statistically significant increased prevalence compared to MACDP but not TBDR. The APR independent Advisory Committee concludes, “The Registry finds no apparent increases in frequency of specific defects with first trimester exposures and no pattern to suggest a common cause; however, potential limitations of registries should be recognized.”

The Ribavirin Pregnancy Registry: An Interim Analysis of Potential Teratogenicity at the Mid-Point of Enrollment.

IntroductionSignificant teratogenic effects have been demonstrated in all animal species exposed to ribavirin. Ribavirin is prescribed for chronic hepatitis C and is contraindicated in women who are pregnant and in the male sexual partners of women who are pregnant. Both sexes are advised to avoid pregnancy for 6 months after exposure. The Ribavirin Pregnancy Registry was established in 2003 to monitor pregnancy exposures to ribavirin for signals of possible human teratogenicity.MethodsThis voluntary registry enrolls pregnant women with prenatal exposure to ribavirin. Exposure is classified as direct—women taking ribavirin during pregnancy or the 6 months prior to conception—or indirect—women exposed through sexual contact, 6 months prior to or during pregnancy, with a man who is taking or has taken ribavirin in the past 6 months. Women are followed until delivery and infants for 1 year. When enrollment is complete, birth defect rates will be compared with the Metropolitan Atlanta Congenital Defects Program’s published rate of 2.67. Using data collected since inception in 2003 through February 2016, preliminary rates were calculated.ResultsThe registry has enrolled 272 pregnant women, with 180 live births: there were seven birth defect cases among 85 directly exposed women [7/85 (8.2%) (95% confidence interval (CI) 3.4–16.2)] and four birth defect cases among 95 indirectly exposed women [4/95 (4.2%) (95% CI 1.2–10.4)]. Of the 11 infants, nine had structural defects and two had chromosomal anomalies. Patterns suggesting a common etiology or relationship with ribavirin exposure are not seen.ConclusionBased on the patterns of birth defects reported, preliminary findings do not suggest a clear signal of human teratogenicity for ribavirin. However, the current sample size is insufficient for definitive conclusions, and ribavirin exposure should be avoided during pregnancy and during the 6 months prior to pregnancy, in accordance with prescribing information.Clinical Trial RegistrationClinicalTrials.gov identifier: NCT00114712.

The Safety of Medications in Pregnant Women: An Opportunity to Use Database Studies.

* Abbreviations: FDA — : Food and Drug Administration NAAEDR — : North American Antiepileptic Drug Registry Information on the safety of medications that pregnant women may need is key to protecting the health of the woman and her fetus. When new drugs are first marketed, this information is scarce, because pregnant women are generally excluded from randomized clinical trials. Broader inclusion of pregnant women in clinical research is being discussed by regulatory authorities and funders.1 But even with greater inclusion of pregnant women in clinical trials, safety data from those trials would be limited by the combination of study size, low frequency of many key outcomes, and strict conditions for enrollment. Postapproval observational studies still would be needed to assess drug safety in routine health care. These assessments can be conducted as pregnancy exposure registries or by using existing health databases. Currently, because of our overreliance on pregnancy exposure registries and underuse of database studies, we are missing an opportunity to provide information that would help women and their physicians make better informed decisions about treatment in pregnancy. Pregnancy exposure registries, usually sponsored by a single pharmaceutical company, are a primary method requested by the US Food and Drug Administration (FDA) for postapproval safety studies in pregnant women.2 However, these registries often fail to enroll a sufficient number of exposed pregnancies, and when they do, it is often difficult to interpret results because they generally do not include an internal comparison cohort and rely on comparisons to external data sources, such as the Metropolitan Atlanta Congenital Defects Program.2 The pregnancy registries that have been most successful in enrolling … Address correspondence to Andrea V. Margulis, MD, ScD, RTI Health Solutions, Diagonal 605, 9-1, 08028 Barcelona, Spain. E-mail: amargulis{at}rti.org

Survival Disparities Associated with Congenital Diaphragmatic Hernia.

We assessed sociodemographic and clinical factors that are associated with survival among infants with congenital diaphragmatic hernia (CDH). Using data from the Metropolitan Atlanta Congenital Defects Program, we ascertained 150 infants born with CDH between 1979 and 2003 and followed via linkage with state vital records and the National Death Index. Kaplan-Meier survival probabilities and adjusted hazard ratios (HRs) were calculated for socioeconomic and clinical characteristics. Survival increased from 40 to 62% over the study period. White infants born before 1988 were 2.9 times less likely to survive than those born after 1988. Black infants' survival did not show significant improvement after 1988. White infants' survival was not significantly affected by poverty, whereas black infants born in higher levels of poverty were 2.7 times less likely to survive than black infants born in lower levels of neighborhood poverty. White infants with multiple major birth defects were 2.6 times less likely to survive than those with CDH alone. The presence of multiple defects was not significantly associated with survival among black infants. Survival among infants and children with CDH has improved over time among whites, but not among blacks. Poverty is associated with lower survival among blacks, but not among whites. The presence of multiple defects is associated with lower survival among whites, but not among blacks. The differential effects of poverty and race should be taken into account when studying disparities in health outcomes. Birth Defects Research 109:816-823, 2017. © 2017 Wiley Periodicals, Inc.

A systematic review of pregnancy exposure registries: examination of protocol-specified pregnancy outcomes, target sample size, and comparator selection.

Our study sought to systematically evaluate protocol-specified study methodology in prospective pregnancy exposure registries including pre-specified pregnancy outcomes, power calculations for sample size, and comparator group selection. U.S. pregnancy exposure registries designed to evaluate safety of drugs or biologics were identified from www.clinicaltrials.gov, the FDA's Office of Women's Health website, and the FDA's list of postmarketing studies. Protocols or similar documentation were obtained. We identified 35 U.S. registries for drugs or biologic use during pregnancy. All registries assessed risk for overall major congenital malformations. Pre-specified target enrollment was stated for 18 (51%) registries, and ranged from 150 to 500 exposed pregnancies (median 300). Thirty-two (91%) registries identified at least one comparison group, but only nine (26%) planned to use an internal comparator. The most common external comparator group (n = 24, 69%) was the Metropolitan Atlanta Congenital Defects Program (MACDP). No registries were designed to have sufficient power to assess specific malformations, despite the plausibility that most teratogens cause specific defects. Only half of the registries included a power analysis. Despite their common use, external comparators, including MACDP, have important limitations. In the absence of randomized controlled trial data in pregnant women, pregnancy registries remain an important tool as part of a comprehensive pregnancy surveillance program; however, pregnancy registries alone may not be sufficient to obtain adequate data regarding risks of specific malformations. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Evaluation of pregnancy outcomes from the Tysabri® (natalizumab) pregnancy exposure registry: a global, observational, follow-up study.

BackgroundPatients with multiple sclerosis (MS) or Crohn’s disease (CD) being treated with natalizumab (Tysabri®, Biogen) who are planning to become pregnant or discover they are pregnant after exposure to natalizumab are currently advised to balance the potential benefits and potential risks of exposure when considering treatment options. This study was undertaken to evaluate pregnancy outcomes of women with MS or CD who were exposed to natalizumab at any time within 3 months prior to conception or during pregnancy. A pregnancy registry was created to better understand the effect of natalizumab exposure on pregnancy outcomes.MethodsThe Tysabri Pregnancy Exposure Registry was a global, observational exposure registration and follow-up study. Evaluations included spontaneous abortions (<22 weeks gestational age), fetal losses (≥22 weeks gestational age), ectopic pregnancies, elective or therapeutic terminations, stillbirths, birth defects, and live births. Birth defects were reviewed and coded in accordance with the Metropolitan Atlanta Congenital Defects Program (MACDP) classification of birth defects.ResultsA total of 369 patients with MS and 7 patients with CD were enrolled prospectively, of whom 355 patients (99.4 %; 349 MS and 6 CD) had known pregnancy outcomes (including 8 twin sets). The spontaneous abortion rate was 9.0 % (n = 32; 95 % confidence interval [C. I.], 6.3–12.5 %). An independent advisory committee review determined the major birth defect rate to be 5.05 % (16 of 316 live births + 1 elective abortion; 95 % C. I., 2.9–8.1 %). The mean gestational age of the live-born infants was 38.3 weeks, and the mean birth weight was 3158.3 g.ConclusionsAlthough the overall rate of birth defects was higher than that observed by the MACDP, these registry outcomes showed no specific pattern of malformations that would suggest a drug effect, and the spontaneous abortion rate was consistent with that of the general population.Trial registrationClinicalTrials.gov NCT00472992 (11 May 2007).

Survival of Children With Hypoplastic Left Heart Syndrome.

To examine the survival of infants with hypoplastic left heart syndrome (HLHS) and potential influence of demographic and clinical characteristics on survival using population-based data. Infants with nonsyndromic HLHS (n = 212) born between 1979 and 2005 were identified through the Metropolitan Atlanta Congenital Defects Program. Vital status was ascertained through 2009 based on linkage with vital records. We estimated Kaplan-Meier survival probabilities stratified by select demographic and clinical characteristics. The overall survival probability to 2009 was 24% and significantly improved over time: from 0% in 1979-1984 to 42% in 1999-2005. Survival probability was 66% during the first week, 27% during the first year of life, and 24% during the first 10 years. Survival of very low and low birth weight or preterm infants and those born in high-poverty neighborhoods was significantly poorer. For children with information on surgical intervention (n = 88), the overall survival was 52%, and preterm infants had significantly poorer survival (31%) compared with term infants (56%). For children who survived to 1 year of age, long-term survival was ∼90%. Survival to adolescence of children with nonsyndromic HLHS born in metropolitan Atlanta has significantly improved in recent years, with those born full term, with normal birth weight, or in a low-poverty neighborhood having a higher survival probability. Survival beyond infancy to adolescence is high. A better understanding of the growing population of survivors with HLHS is needed to inform resource planning.

Stillbirth surveillance consortium

Stillbirths have an estimated prevalence of 6 per 1,000 live births and fetal deaths combined in the United States (U.S.), yet major risk factors for these adverse birth outcomes remain elusive [1,2]. Historically in the U.S., surveillance information about stillbirth has come from fetal death certificates maintained by the National Vital Statistics System. Data collection within the National Vital Statistics System is guided by the Model State Vital Statistics Act and Regulations (Model Law), which defines fetal loss as showing no signs of breath or cardiac activity after expulsion [3]. The Model Law also recommends reporting a fetal loss as a stillbirth if the fetus weighs 350 grams or greater, or if no birth weight is available, the fetus is at least 20 weeks in gestational age. Each state in the U.S. develops its own definition, reporting criteria, and fetal death certificate, which can produce variability in reporting across states [4]. Additionally, previous studies suggest that fetal death certificate data are limited in utility as a source for national stillbirth surveillance due to under- or over-reporting and the completeness and quality of recorded data [5]. An alternative approach to surveillance of stillbirths is the use of established birth defect surveillance systems to incorporate active case finding for stillbirths. This approach permits population-based identification of affected pregnancies and characterization of the epidemiology of these pregnancies. In 2005, the Centers for Disease Control and Prevention established projects for stillbirth surveillance using the established infrastructures of the Metropolitan Atlanta Congenital Defects Program and the Iowa Registry for Congenital and Inherited Disorders, two premier birth defect surveillance systems in the U.S. The goals of our Iowa project, the Iowa Stillbirth Surveillance Project (ISSP), were to: evaluate the feasibility of expanding the Iowa Registry for Congenital and Inherited Disorders to incorporate data from existing records on stillbirths; monitor and report, as feasible, on the occurrence of stillbirths in the state of Iowa; serve as a registry for etiologic studies of stillbirths; and serve as a resource for education and evaluation of prevention programs that aim to reduce the occurrence of stillbirths . Active case finding and record abstraction approaches, originally developed for birth defect surveillance in Iowa, were used by the ISSP for state-wide ascertainment of stillbirths. We ascertained 1,301 reportable stillbirths (≥20 weeks gestation or ≥350 grams delivery weight) delivered from January 1, 2005 through December 31, 2011. Surveillance data collected are being used to estimate population-based prevalence estimates for stillbirths in Iowa and to examine fetal and parental characteristics associated with stillbirths. Also, these data are being used to conduct individual-level geospatial surveillance of stillbirths. Knowledge of the spatial patterns of stillbirths may provide important insights into possible links to environmental exposures and the opportunity to plan detailed etiological investigations. We continue to monitor stillbirths among the approximately 40,000 deliveries in Iowa annually. In 2012, we also expanded active case finding and record abstraction for stillbirths to include birth defect surveillance systems in Colorado, Hawaii, and New York State. This Stillbirth Surveillance Consortium (SSC) uses similar surveillance methods and tools to provide a systematic approach to population-based surveillance of stillbirths and covers more than 120,000 deliveries annually with a diverse racial/ethnic composition. To date, the SSC has ascertained 784 reportable stillbirths delivered from January 1, 2010 through December 31, 2011. Surveillance data collected by the SSC will expand ongoing analyses by the ISSP for prevalence estimation, examination of fetal and parental characteristics, and individual-level geospatial surveillance. The methods developed by the SSC can serve as a model for other states to expand birth defect surveillance programs to include active case finding and record abstraction for stillbirths.

Congenital anomalies and in utero antiretroviral exposure in human immunodeficiency virus-exposed uninfected infants.

Most studies examining the association of prenatal antiretroviral (ARV) exposures with congenital anomalies (CAs) in children born to human immunodeficiency virus (HIV)-infected women have been reassuring, but some evidence suggests an increased risk with specific ARV agents. To evaluate the association of in utero ARV exposures with CAs in HIV-exposed uninfected children. Prospective cohort study design. The Pediatric HIV/AIDS Cohort Study's Surveillance Monitoring of ART Toxicities (SMARTT) Study was performed at 22 US medical centers among 2580 HIV-exposed uninfected children enrolled in the SMARTT Study between March 23, 2007, and June 18, 2012. First-trimester exposure to any ARV and to specific ARV medications. The primary end point was a CA based on physician review of infant physical examinations according to the Antiretroviral Pregnancy Registry modification of the Metropolitan Atlanta Congenital Defects Program. Rates of CAs were estimated overall and by birth year. Logistic regression models were used to evaluate the association of CAs with first-trimester ARV exposures, adjusting for demographic and maternal characteristics. Congenital anomalies occurred in 175 of 2580 children, yielding a prevalence of 6.78% (95% CI, 5.85%-7.82%); 242 major CAs were confirmed, including 72 musculoskeletal and 55 cardiovascular CAs. The prevalence of CAs increased significantly among successive birth cohorts (3.8% for children born before 2002 and up to 8.3% for those born 2008-2010). In adjusted models, no association of first-trimester exposures with CAs was found for any ARV, for combination ARV regimens, or for any drug class. No individual ARV in the reverse transcriptase inhibitor drug classes was associated with an increased risk of CAs. Among protease inhibitors, higher odds of CAs were observed for atazanavir sulfate (adjusted odds ratio [aOR], 1.95; 95% CI, 1.24-3.05) and for ritonavir used as a booster (aOR, 1.56; 95% CI, 1.11-2.20). With first-trimester atazanavir exposure, risks were highest for skin (aOR, 5.23) and musculoskeletal (aOR, 2.55) CAs. Few individual ARVs and no drug classes were associated with an increased risk of CAs in HIV-exposed infants after adjustment for calendar year and maternal characteristics. While the overall risk remained low, a relative increase was observed in successive years and with atazanavir exposure. Given the low absolute CA risk, the benefits of recommended ARV therapy use during pregnancy still outweigh such risks, although further studies are warranted.

Association between prenatal exposure to antiretroviral therapy and birth defects: an analysis of the French perinatal cohort study (ANRS CO1/CO11).

Antiretroviral therapy (ART) has major benefits during pregnancy, both for maternal health and to prevent mother-to-child transmission of HIV. Safety issues, including teratogenic risk, need to be evaluated. We estimated the prevalence of birth defects in children born to HIV-infected women receiving ART during pregnancy, and assessed the independent association of birth defects with each antiretroviral (ARV) drug used. The French Perinatal Cohort prospectively enrolls HIV-infected women delivering in 90 centers throughout France. Children are followed by pediatricians until 2 y of age according to national guidelines. We included 13,124 live births between 1994 and 2010, among which, 42% (n = 5,388) were exposed to ART in the first trimester of pregnancy. Birth defects were studied using both European Surveillance of Congenital Anomalies (EUROCAT) and Metropolitan Atlanta Congenital Defects Program (MACDP) classifications; associations with ART were evaluated using univariate and multivariate logistic regressions. Correction for multiple comparisons was not performed because the analyses were based on hypotheses emanating from previous findings in the literature and the robustness of the findings of the current study. The prevalence of birth defects was 4.4% (95% CI 4.0%-4.7%), according to the EUROCAT classification. In multivariate analysis adjusting for other ARV drugs, maternal age, geographical origin, intravenous drug use, and type of maternity center, a significant association was found between exposure to zidovudine in the first trimester and congenital heart defects: 2.3% (74/3,267), adjusted odds ratio (AOR) = 2.2 (95% CI 1.3-3.7), p = 0.003, absolute risk difference attributed to zidovudine +1.2% (95% CI +0.5; +1.9%). Didanosine and indinavir were associated with head and neck defects, respectively: 0.5%, AOR = 3.4 (95% CI 1.1-10.4), p = 0.04; 0.9%, AOR = 3.8 (95% CI 1.1-13.8), p = 0.04. We found a significant association between efavirenz and neurological defects (n = 4) using the MACDP classification: AOR = 3.0 (95% CI 1.1-8.5), p = 0.04, absolute risk +0.7% (95% CI +0.07%; +1.3%). But the association was not significant using the less inclusive EUROCAT classification: AOR = 2.1 (95% CI 0.7-5.9), p = 0.16. No association was found between birth defects and lopinavir or ritonavir with a power >85% for an odds ratio of 1.5, nor for nevirapine, tenofovir, stavudine, or abacavir with a power >70%. Limitations of the present study were the absence of data on termination of pregnancy, stillbirths, tobacco and alcohol intake, and concomitant medication. We found a specific association between in utero exposure to zidovudine and heart defects; the mechanisms need to be elucidated. The association between efavirenz and neurological defects must be interpreted with caution. For the other drugs not associated with birth defects, the results were reassuring. Finally, whatever the impact that some ARV drugs may have on birth defects, it is surpassed by the major role of ART in the successful prevention of mother-to-child transmission of HIV. Please see later in the article for the Editors' Summary.