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

PURPOSE: 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. METHODS AND RESULTS: 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]). CONCLUSIONS: 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).

A Prospective Cohort Study on Pregnancy Outcomes of Persons Immunized with a Seasonal Quadrivalent Inactivated Influenza Vaccine during Pregnancy.

This US-based, prospective observational cohort study evaluated the safety of a quadrivalent inactivated influenza vaccine (IIV4; Afluria Quadrivalent) in pregnant persons immunized over four influenza seasons between 2017 and 2021. Pregnancy outcomes included live birth, stillbirth, spontaneous abortion, and elective termination. Infant events of interest were major congenital malformations (MCMs), preterm birth (<37 weeks gestational age), and low birth weight (LBW). Data were descriptive; prevalence point estimates were reported with 95% confidence intervals (CI). A total of 483 pregnant persons were given IIV4 and evaluated; 477 (98.8%) reported a live birth, and there were 2 stillbirths, 4 spontaneous abortions, and no elective terminations or maternal deaths. The prevalence rates of infant events were as follows: preterm birth, 7.2% (upper 95% CI, 9.6%); LBW, 5.4% (upper 95% CI, 7.4%); and MCMs, 0.8% (upper 95% CI, 1.9%). Point estimates and upper 95% CIs of the observed prevalence rates were lower than or similar to background prevalence in the general US population. Our findings suggest no evidence of a safety concern with vaccinating this group at high risk of influenza complications and are consistent with published data from databases and surveillance systems that monitor the safety of influenza vaccines in pregnant persons.

Outcomes in Pregnant Persons Immunized with a Cell-Based Quadrivalent Inactivated Influenza Vaccine: A Prospective Observational Cohort Study.

Objective: To evaluate pregnancy and infant outcomes among persons immunized with a cell-based quadrivalent inactivated influenza vaccine (IIV4c) during routine pregnancy care. Design: Prospective observational cohort. Setting: US-based obstetrics/gynecology clinics. Population: Pregnant persons. This US-based, prospective observational cohort study evaluated the safety of quadrivalent inactivated influenza vaccine (IIV4c; Flucelvax® Quad) in pregnant persons immunized over 3 influenza seasons between 2017 and 2020. Pregnant persons were immunized with IIV4c as part of routine care, after which their health care provides HCPs with all observational data to a single coordinating center. Follow-up data were collected at the end of the second trimester and/or at the time of pregnancy outcome. A scientific advisory committee reviewed the data. Prevalence point estimates were reported with 95% confidence intervals (CIs). Pregnancy outcomes included: live birth, stillbirth, spontaneous abortion, elective termination, and maternal death. Infant outcomes included: preterm birth (<37 weeks gestational age), low birth weight (<2500 g), or major congenital malformations (MCMs). Of the 665 evaluable participants, 659 (99.1%) had a live birth. No stillbirths (0% [95% CI 0.0−0.6]), 4 spontaneous abortions (1.9% [0.5−4.8]), and 1 elective termination (0.5% [0.0−2.6]) were reported. Among 673 infants, 9.2% (upper 95% CI 11.5%) were born prematurely, 5.8% (upper 95% CI 7.6%) had low birth weight, and 1.9% (upper 95% CI 3.1%) were reported to have an MCM. No maternal deaths were reported. Of the 2 infants who died shortly after birth, one was adjudicated as not related to the vaccine; the other's cause could not be determined due to maternal loss to follow-up. The prevalence of adverse pregnancy outcomes or preterm birth, low birth weight, or MCMs in newborns was similar in persons vaccinated with IIV4c compared to the rates observed in US surveillance systems. The safety profile of IIV4c in pregnant persons is consistent with previously studied influenza vaccines.

The safety of asthma medications during pregnancy and lactation: Clinical management and research priorities.

Asthma is one of the most common underlying diseases in women of reproductive age that can lead to potentially serious medical problems during pregnancy and lactation. A group of key stakeholders across multiple relevant disciplines was invited to take part in an effort to prioritize, strategize, and mobilize action steps to fill important gaps in knowledge regarding asthma medication safety in pregnancy and lactation. The stakeholders identified substantial gaps in the literature on the safety of asthma medications used during pregnancy and lactation and prioritized strategies to fill those gaps. Short-term action steps included linking data from existing complementary study designs (US and international claims data, single drug pregnancy registries, case-control studies, and coordinated systematic data systems). Long-term action steps included creating an asthma disease registry, incorporating the disease registry into electronic health record systems, and coordinating care across disciplines. The stakeholders also prioritized establishing new infrastructures/collaborations to perform research in pregnant and lactating women and to include patient perspectives throughout the process. To address the evidence gaps, and aid in populating product labels with data that inform clinical decision making, the consortium developed a plan to systematically obtain necessary data in the most efficient and timely manner.

Levetiracetam Pregnancy Registry: Final results and a review of the impact of registry methodology and definitions on the prevalence of major congenital malformations.

BACKGROUND: To evaluate pregnancy outcomes among women participating in the antiepileptic drug (AED) Levetiracetam Registry (LEV-Registry), and to review the impact of using two other registries' outcome definitions on the number of major congenital malformations (MCMs). METHODS: This US-based prospective study (ClinicalTrials.gov NCT00345475) was overseen by an independent Expert Panel. Women exposed to levetiracetam at any time during pregnancy enrolled, directly, or via their healthcare provider. The primary outcome was prevalence of MCMs, defined according to a modified version of the Metropolitan Atlanta Congenital Defects Program criteria. RESULTS: Of 491 women enrolled, 465 (94.7%) had a documented outcome. Most (92.3%) received levetiracetam for epilepsy; 323 (69.4%) as monotherapy and 142 (30.5%) as polytherapy. With three twin pregnancies, there were 468 outcomes-444 livebirths, 3 stillbirths, 19 miscarriages, and 2 terminations. Based on the MCM definition used by LEV-Registry, 46 infants among 444 livebirths had MCMs resulting in 10.4% (95% CI 7.7, 13.6) for overall prevalence, 9.4% (95% CI 6.4, 13.2) with monotherapy, and 12.6% (95% CI 7.5, 19.4) with polytherapy. When MCM reports were reviewed independently by staff at EURAP (International Registry of AEDs) and North American AED Pregnancy Registry according to their respective criteria, only 22 and 7 infants of the 46, respectively, were classified as having MCMs. CONCLUSION: The LEV-Registry Expert Panel did not find evidence suggestive of teratogenic association with prenatal exposure to levetiracetam. The substantial differences in which physical findings were considered MCMs highlight the major impact of pregnancy registry methodology on MCM prevalence estimates.

Safety evaluation of adenovirus type 4 and type 7 vaccine live, oral in military recruits.

Before the widespread adoption of vaccination, adenovirus type 4 and type 7 were long associated with respiratory illnesses among military recruits. When supplies were depleted and vaccination was suspended in 1999 for approximately a decade, respiratory illnesses due to adenovirus infections resurged. In March 2011, a new live, oral adenovirus vaccine was licensed by the US Food and Drug Administration and was first universally administered to military recruits in October 2011, leading to rapid, dramatic elimination of the disease within a few months. As part of licensure, a postmarketing study (Sentinel Surveillance Plan) was performed to detect potential safety signals within 42days after immunization of military recruits. This study retrospectively evaluated possible adverse events related to vaccination using data from the Armed Forces Health Surveillance Branch Defense Medical Surveillance System (DMSS) database. Among 100,000 recruits who received the adenovirus vaccine, no statistically significant greater risk of prespecified medical events was observed within 42days after vaccination when compared with a historical cohort of 100,000 unvaccinated recruits. In an initial statistical analysis of International Classification of Disease, 9th Revision, Clinical Modification codes, a statistically significant higher risk for 19 other (not prespecified) medical events occurring in 5 or more recruits was observed among vaccinated compared with unvaccinated groups. After case record data abstraction for attribution and validation, two events (psoriasis [21 vs 7 cases] and serum reactions [12 vs 4 cases]) occurred more frequently in the vaccinated cohort. A causal relation of these rare events with adenovirus vaccination could not be established given confounding factors in the DMSS, such as coadministration of other vaccines and incomplete or inaccurate medical information, for some recruits. Prospective surveillance assessing these uncommon, but potentially relevant, immune-related symptoms may be beneficial in defining potential causal association with adenovirus vaccination.

Toward Earlier Inclusion of Pregnant and Postpartum Women in Tuberculosis Drug Trials: Consensus Statements From an International Expert Panel.

Tuberculosis is a major cause of morbidity and mortality in women of childbearing age (15-44 years). Despite increased tuberculosis risk during pregnancy, optimal clinical treatment remains unclear: safety, tolerability, and pharmacokinetic data for many tuberculosis drugs are lacking, and trials of promising new tuberculosis drugs exclude pregnant women. To advance inclusion of pregnant and postpartum women in tuberculosis drug trials, the US National Institutes of Health convened an international expert panel. Discussions generated consensus statements (>75% agreement among panelists) identifying high-priority research areas during pregnancy, including: (1) preventing progression of latent tuberculosis infection, especially in women coinfected with human immunodeficiency virus; (2) evaluating new agents/regimens for treatment of multidrug-resistant tuberculosis; and (3) evaluating safety, tolerability and pharmacokinetics of tuberculosis drugs already in use during pregnancy and postpartum. Incorporating pregnant women into clinical trials would extend evidence-based tuberculosis prevention and treatment standards to this special population.

Prenatal exposure to zidovudine and risk for ventricular septal defects and congenital heart defects: data from the Antiretroviral Pregnancy Registry.

OBJECTIVE: To assess the risk for ventricular septal defects and congenital heart defects following zidovudine exposure during pregnancy using data from the Antiretroviral Pregnancy Registry. STUDY DESIGN: Data on 16,304 prospectively reported pregnancies were analyzed to estimate the frequency and risk of ventricular septal defects and congenital heart defects, comparing exposure between zidovudine-containing regimens and non-zidovudine antiretroviral regimens. The numerator includes defect cases in outcomes at ≥ 20 weeks of gestational age. The denominator includes live birth outcomes. Infants with chromosomal anomalies were excluded. RESULTS: There were 15,451 live birth outcomes; 13,073 were prenatally exposed to zidovudine-containing regimens and 2378 to non-zidovudine containing regimens. There were 36 ventricular septal defect cases: 31 exposed to prenatal zidovudine and 5 unexposed. Nine of the zidovudine-exposed cases had earliest exposure in the first trimester; 22 had second/third trimester exposure. Of the 5 ventricular septal defect cases not exposed to zidovudine, 2 had earliest exposure to non-zidovudine antiretroviral regimens in the first trimester, and 3 had exposure in the second/third trimester. The prevalence of ventricular septal defect was 0.24% (95% confidence interval: 0.16, 0.34) for infants exposed to zidovudine-containing regimens and 0.21% (95% confidence interval: 0.07, 0.49) for non-zidovudine regimens. The relative risk comparing the 2 was 1.13 (95% confidence interval: 0.44, 2.90). There were a total of 90 congenital heart defect cases; 78 were exposed prenatally to zidovudine-containing regimens, and 12 were unexposed. Twenty-six of the zidovudine-exposed cases had earliest exposure in the first trimester and 52 had second/third trimester exposure. Six congenital heart defect cases with non-zidovudine antiretroviral regimens had earliest exposure in the first trimester and 6 had exposure in the second/third trimester. The prevalence of congenital heart defects was 0.60% (95% confidence interval: 0.47, 0.74) for infants exposed to zidovudine-containing regimens and 0.50% (95% confidence interval: 0.26, 0.88) for non-zidovudine regimens. The relative risk comparing the 2 was 1.18 (95% confidence interval: 0.64, 2.17). CONCLUSIONS: The prevalence and risk of ventricular septal defects and congenital heart defects among infants exposed to zidovudine-containing regimens is not significantly different from the prevalence and risk in infants exposed to non-zidovudine containing regimens. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01137981.

Influence of estrogen plus testosterone supplementation on breast cancer.

BACKGROUND: Concern that the use of exogenous testosterone may increase breast cancer risk coexists with rising use of this medication in the United States. We sought to examine the relationship between the use of estrogen plus testosterone (E + T) therapy (esterified estradiol plus methyltestosterone) and the occurrence of breast cancer. METHODS: A total of 31,842 postmenopausal participants in the Women's Health Initiative Observational Study were followed for a mean of 4.6 years. At the 3-year visit, E + T users were compared with non-hormone therapy users for time to incident invasive breast cancer. Cox proportional hazards estimates were adjusted for known predictors of breast cancer including prior hormone use and screening mammography. RESULTS: Thirty five women using E + T at visit 3 developed invasive breast cancer. Use of E + T had a nonsignificant impact on invasive breast cancer risk (adjusted hazard ratio, 1.42; 95% confidence interval, 0.95-2.11). The most commonly used E + T preparation, Estratest, was associated with a significant elevation in invasive breast cancer (adjusted hazard ratio, 1.78; 95% confidence interval, 1.05-3.01). However, rates of breast cancer were lower in longer-term E + T users than in shorter-term E + T users. CONCLUSION: Although our results have less strength than an initial report linking E + T to breast cancer, we found a modest, albeit nonsignificant, elevation in breast cancer risk associated with E + T use.

Cancer mortality in the United States by education level and race.

BACKGROUND: Although both race and socioeconomic status are well known to influence mortality patterns in the United States, few studies have examined the simultaneous influence of these factors on cancer incidence and mortality. We examined relationships among race, education level, and mortality from cancers of the lung, breast, prostate, colon and rectum, and all sites combined in contemporary US vital statistics. METHODS: Age-adjusted cancer death rates (with 95% confidence intervals [CIs]) were calculated for 137,708 deaths among 119,376,196 individuals aged 25-64 years, using race and education information from death certificates and population denominator data from the US Bureau of the Census, for 47 states and Washington, DC, in 2001. Relative risk (RR) estimates were used to compare cancer death rates in persons with 12 or fewer years of education with those in persons with more than 12 years of education. RESULTS: Educational attainment was strongly and inversely associated with mortality from all cancers combined in black and white men and in white women. The all-cancer death rates were nearly identical for black men and white men with 0-8 years of education (224.2 and 223.6 per 100,000, respectively). The estimated relative risk for all-cancer mortality comparing the three lowest (< or = 12 years) with the three highest (> 12 years) education categories was 2.38 (95% CI = 2.33 to 2.43) for black men, 2.24 (95% CI = 2.23 to 2.26) for white men, 1.43 (95% CI = 1.41 to 1.46) for black women, and 1.76 (95% CI = 1.75 to 1.78) for white women. For both men and women, the magnitude of the relative risks comparing the three lowest educational levels with the three highest within each race for all cancers combined and for lung and colorectal cancers was higher than the magnitude of the relative risks associated with race within each level of education, whereas for breast and prostate cancer the magnitude of the relative risks associated with race was higher than the magnitude of the relative risks associated with level of education within each racial group. Among the most important and novel findings were that black men who completed 12 or fewer years of education had a prostate cancer death rate that was more than double that of black men with more schooling (10.5 versus 4.8 per 100,000 men; RR = 2.17, 95% CI = 1.82 to 2.58) and that, in contrast with studies of mortality rates in earlier time periods, breast cancer mortality rates were higher among women with less education than among women with more education (37.0 and 31.1 per 100,000, respectively, for black women and 25.2 versus 18.6 per 100,000, respectively, for white women). CONCLUSION: Cancer death rates vary considerably by level of education. Identifying groups at high risk of death from cancer by level of education as well as by race may be useful in targeting interventions and tracking cancer disparities.