Understanding willingness and barriers to participate in clinical trials during pregnancy and lactation: findings from a US study.

BACKGROUND: Due to the exclusion of pregnant and lactating people from most clinical trials, there is an incomplete understanding of the risks and benefits of medication use in these populations and therapeutic decision-making is often conducted without adequate evidence. To change this paradigm, it is imperative to understand the perspectives of pregnant and lactating individuals concerning their participation in clinical trials. OBJECTIVES: To describe attitudes, perceptions, barriers, and preferences of pregnant and postpartum people in the United States (US) regarding participation in clinical trials and to identify factors influencing participation. METHODS: In November 2022, individuals aged ≥ 18 residing in the US who self-identified as pregnant or pregnant within the last 12 months were invited to complete an online survey about their perspectives regarding clinical trial participation. The survey included questions about demographic characteristics, health history, behaviors, and willingness to participate in clinical trials while pregnant and/or lactating. Multivariable logistic regression models were fit to identify predictors of clinical trial participation. RESULTS: Among the 654 respondents, 34.8% and 40.9% reported being likely or extremely likely to participate in a clinical trial for a new medication while pregnant or lactating, respectively; and 24.5% and 41.7% for a new vaccine while pregnant or lactating, respectively. Higher educational attainment (≥ Bachelor's degree) was associated with greater likelihood of clinical trial participation in pregnancy (odds ratio (OR) = 1.50, 95% Confidence Interval (CI): 1.01, 2.25 for medications; OR = 2.00, 95% CI: 1.28, 3.12 for vaccines). Chronic medical conditions were associated with a greater likelihood of participation in clinical trials for vaccines during lactation (OR = 1.59, 95% CI: 1.07, 2.36). The most cited motivator for participation in a clinical trial while pregnant or lactating was anticipated personal medical benefit (85.8% and 75.6%, respectively), while the primary deterrent was possible risk to the fetus or baby (97.9% and 97.2%, respectively). CONCLUSIONS: Willingness of a US sample to participate in clinical trials while pregnant or lactating varied by demographics and health status, with safety to the fetus being a nearly universal concern. These findings have implications for enhancing inclusion of pregnant and lactating people in clinical research and developing effective and equitable recruitment strategies.

Use of Sotrovimab in Pregnancy: Experiences from the COVID-19 International Drug Pregnancy Registry.

INTRODUCTION: Available data regarding the safety and efficacy of sotrovimab in pregnant patients remain limited due to their exclusion from clinical trials. METHODS: The COVID-19 International Drug Pregnancy Registry (COVID-PR) was established to gather comprehensive safety data from pregnant women who have received monoclonal antibody (mAb) or antiviral treatments for mild, moderate, or severe coronavirus disease 2019 (COVID-19) during pregnancy. Participants actively contributed self-reported data concerning their COVID-19 symptoms, in addition to sociodemographic and health-related characteristics. Obstetric, neonatal, and infant outcomes were also documented, with follow-up extending up to 12 months after childbirth. RESULTS: As of 30 November 2023, sotrovimab was administered to 39 participants enrolled in the COVID-PR. At the time of this report, 26 participants had given birth, with nine deliveries performed via cesarean section. The infants' birthweight ranged from 2381 g to 4762 g, with a mean of 3439.91 g. Twenty-five infants were born at ≥37 weeks. A total of 31 adverse events (AEs) were reported by 12 participants. The most frequently reported AE was gestational hypertension, observed in three participants. COVID-19 re-infection, fatigue, gestational diabetes, headache, and morning sickness were each reported by two participants. Of the reported AEs, eight (in five participants) were classified as serious, including four AEs (prolonged labor, pre-eclampsia, polyhydramnios, premature labor) that affected pregnancy. Seven of these eight serious AEs (SAEs) were found to be unrelated to sotrovimab, with one event (urinary retention) not assessable. A total of 44 AEs were reported in 19 delivered infants or in utero fetuses. The most common were COVID-19 (n = 6 events), ear infection (n = 5 events), neonatal dyspnea (n = 3 events), and respiratory syncytial virus infection (n = 3 events). Sixteen AEs (in 11 infants/fetuses) were classified as serious, including one report each of fetal cardiac disorder, congenital ankyloglossia, persistent right umbilical vein, and congenital hydronephrosis; the latter was considered a major congenital malformation. For all assessable SAEs, causality of sotrovimab treatment was ruled out based on lack of a temporal relationship alone or in combination with absence of a plausible mechanism. CONCLUSION: A sizable proportion of sotrovimab-treated participants in the COVID-PR had underlying medical conditions associated with an increased risk of severe COVID-19. None of the assessable SAEs were considered to be related to sotrovimab treatment.

The COVID-19 International Drug Pregnancy Registry (COVID-PR): Protocol Considerations.

BACKGROUND AND OBJECTIVE: Over the past 2 years, several drugs have been approved for coronavirus disease 2019 (COVID-19) treatment, but their safety during pregnancy remains poorly understood. This study aims to assess the relative risk of obstetric, neonatal, and infant outcomes associated with the use of drugs specifically indicated for the treatment of COVID-19 compared with other drug treatment strategies. The purpose of this article is to present elements of the study protocol. METHODS: The COVID-19 International Drug Pregnancy Registry (COVID-PR) is a noninterventional, postmarketing cohort study. Pregnant women receiving treatment with monoclonal antibodies (mAbs) or antiviral drugs for mild, moderate, or severe COVID-19 are matched 1:1 with pregnant women not receiving these study-specific drugs, based on calendar time, country, gestational age at enrollment, and COVID-19 severity. Participants complete online questionnaires at enrollment, during pregnancy, and for 12 months after delivery of liveborn infants. The study began enrolling participants on 1 December 2021 and is set to span 5 years for each drug of interest. DISCUSSION: The COVID-PR is designed to evaluate the safety profile of each studied drug. Additionally, it may allow for an analysis of the effects of COVID-19 drug exposure during relevant gestational periods on specific neonatal outcomes. Although the sample size will be too small to detect associations with rare outcomes, the study has the potential to generate hypotheses for future research. Ultimately, these data can provide valuable insights for evidence-based decisions about COVID-19 treatment during pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05013632. EU PAS EUPAS42517.

mRNA COVID-19 vaccination early in pregnancy and the risk of spontaneous abortion in an international pregnancy registry.

PURPOSE: mRNA COVID-19 vaccines are used in pregnant populations whether advertently or inadvertently. However, evidence on the safety of these vaccines during pregnancy is limited. The objective of this study is to evaluate the effect of BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccination during the first 20 weeks of gestation on the risk of spontaneous abortion (SAB). METHODS: All pregnant women who received at least one dose of BNT162b2 or mRNA-1273 and enrolled in the COVID-19 Vaccines International Pregnancy Exposure Registry (C-VIPER) were prospectively followed from enrollment until 20 weeks of gestation, SAB, or loss to follow-up. Baseline demographics, vaccination information, and pregnancy outcomes were collected via monthly online self-administered questionnaires, vaccination certificates, and medical records. Life tables were used to calculate the cumulative risk of SAB. Cox regression was used to estimate the hazard ratio (HR) comparing the two vaccines groups stratified by country of residence and gestational age at enrollment. RESULTS: Among 6840 participants who received at least one dose of BNT162b2 or mRNA-1273 at any time in pregnancy between Jan-Sep, 2021, 2129 met the inclusion criteria (1576 received BNT162b2 and 553 mRNA-1273). The two groups were balanced in terms of baseline characteristics. There were 37 SABs, with an overall 13.4% estimated cumulative risk by 20 weeks of gestation, which is similar to the expected risk in the population. The HR of SAB comparing mRNA-1273 to BNT162b2 was 1.46 (95% CI: 0.66, 3.22). CONCLUSION: The C-VIPER data show no evidence that mRNA COVID-19 vaccines increase the risk of SAB.

The COVID-19 Vaccines International Pregnancy Exposure Registry (C-VIPER): Protocol and Methodological Considerations.

INTRODUCTION: The advent of the coronavirus disease 2019 (COVID-19) pandemic has led to the development of vaccines against severe acute respiratory syndrome coronavirus 2. Prospective evidence regarding safety for pregnant people and their developing fetuses is lacking. The aim of the COVID-19 Vaccines International Pregnancy Exposure Registry (C-VIPER) is to estimate the relative risk of obstetric, neonatal, and infant outcomes by comparing participants vaccinated against COVID-19 during pregnancy to a reference group of people enrolled in the Pregistry International Pregnancy Exposure Registry (PIPER) who remained unvaccinated during pregnancy. METHODS: The C-VIPER and the PIPER are international, non-interventional, real-world cohort studies. Participants receiving a COVID-19 vaccine during pregnancy will be matched in the analyses by country and gestational age at enrollment to unvaccinated individuals. Self-enrolled and self-consented participants complete online questionnaires at enrollment, during pregnancy, and for 12 months after the delivery of a live infant. Where possible, outcomes are verified by medical records. The study aims to recruit at least 500 pregnancies for each approved or authorized vaccine and will last for 5 years for each product. CONCLUSIONS: By collecting data for each vaccine brand, the C-VIPER will be able to determine individual safety profiles. The study design allows for analysis of the effects of exposure to COVID-19 vaccines during specific etiologically relevant periods of gestation. Although the sample size may be too small to detect associations with rare outcomes, the study will be used to generate hypotheses for future research. Ultimately, the C-VIPER should provide data that will allow pregnant people and their healthcare providers to make informed decisions about COVID-19 vaccination. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT04705116. Registered on 12 January, 2021. EU PAS EUPAS39096. Registered on 20 January, 2021.

Social determinants of health associated with COVID-19 severity during pregnancy: a multinational cohort study (in the International Registry of Coronavirus Exposure in Pregnancy).

BACKGROUND: The COVID-19 pandemic has caused morbidity and mortality, particularly among vulnerable populations. We aimed to assess social and demographic characteristics associated with COVID-19 severity among symptomatic participants during pregnancy. METHODS: The International Registry of Coronavirus Exposure in Pregnancy is a multinational, longitudinal observational cohort study of adult participants tested for SARS-CoV-2 or who received clinical diagnosis of COVID-19 during pregnancy (NCT04366986). Disease severity status of mild, moderate, or severe was determined based on symptoms and healthcare utilization. Stratified by current versus recent pregnancy at enrollment, univariate mixed-effects logistic regression modeling was used to characterize association between social and demographic characteristics with COVID-19 severity, using a cumulative mixed effect model with country as a random effect. RESULTS: The odds of developing more severe COVID-19 (odds ratio [95% confidence interval]) were higher among participants with lower socioeconomic status (poor: 2.72 [2.01,3.69]; lower-middle class: 2.07 [1.62,2.65] vs wealthy), among participants with lower educational attainment (high school: 1.68 [1.39,2.03]; < high school (1.77 [1.25,2.51] vs graduate education). Participants over 25 years of age had lower odds of severe COVID-19 versus participants < 25 years (25-34: 0.69 [0.56,0.85]; 35-50: 0.62 [0.48,0.80]). Employment in food services was also associated with increased odds of more severe COVID-19, whereas employment in healthcare and within home, and primiparity were associated with lower severity. CONCLUSIONS: Findings suggest that employment setting and economic status have strong associations with COVID-19 severity, which warrants considering social determinants of health in the context of assessing risk factors of more severe COVID-19 during pregnancy. TRIAL REGISTRATION: IRCEP was registered with the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) [EUPAS37360] and clinicaltrials.gov [NCT04366986].

Timing and severity of COVID-19 during pregnancy and risk of preterm birth in the International Registry of Coronavirus Exposure in Pregnancy.

BACKGROUND: Studies of preterm delivery after COVID-19 are often subject to selection bias and do not distinguish between early vs. late infection in pregnancy, nor between spontaneous vs. medically indicated preterm delivery. This study aimed to estimate the risk of preterm birth (overall, spontaneous, and indicated) after COVID-19 during pregnancy, while considering different levels of disease severity and timing. METHODS: Pregnant and recently pregnant people who were tested for or clinically diagnosed with COVID-19 during pregnancy enrolled in an international internet-based cohort study between June 2020 and July 2021. We used several analytic approaches to minimize confounding and immortal time bias, including multivariable regression, time-to-delivery models, and a case-time-control design. RESULTS: Among 14,264 eligible participants from 70 countries who did not report a pregnancy loss before 20 gestational weeks, 5893 had completed their pregnancies and reported delivery information; others were censored at time of their last follow-up. Participants with symptomatic COVID-19 before 20 weeks' gestation had no increased risk of preterm delivery compared to those testing negative, with adjusted risks of 10.0% (95% CI 7.8, 12.0) vs. 9.8% (9.1, 10.5). Mild COVID-19 later in pregnancy was not clearly associated with preterm delivery. In contrast, severe COVID-19 after 20 weeks' gestation led to an increase in preterm delivery compared to milder disease. For example, the risk ratio for preterm delivery comparing severe to mild/moderate COVID-19 at 35 weeks was 2.8 (2.0, 4.0); corresponding risk ratios for indicated and spontaneous preterm delivery were 3.7 (2.0, 7.0) and 2.3 (1.2, 3.9), respectively. CONCLUSIONS: Severe COVID-19 late in pregnancy sharply increased the risk of preterm delivery compared to no COVID-19. This elevated risk was primarily due to an increase in medically indicated preterm deliveries, included preterm cesarean sections, although an increase in spontaneous preterm delivery was also observed. In contrast, mild or moderate COVID-19 conferred minimal risk, as did severe disease early in pregnancy.

Association between SARS-CoV-2 infection during pregnancy and postpartum depressive and anxiety symptoms: finding from the International Registry of Coronavirus Exposure in Pregnancy (IRCEP) study.

While there has been concern over the perinatal mental health implications of the COVID-19 outbreak, evidence on the risk of postpartum depression and anxiety following SARS-CoV-2 infection is limited. We studied this question using the International Registry of Coronavirus Exposure in Pregnancy, which included both a prospective and retrospective cohort. Study participants were required to have been tested for SARS-CoV-2 between the date of last menstrual period and delivery. The exposure of interest was SARS-CoV-2 infection during pregnancy, as well as COVID-19 severity (severe, moderate, mild, and asymptomatic). The outcome was postpartum depression and anxiety symptoms, assessed by the 4-item Patient Health Questionnaire. The final analytic cohort consisted of 3819 participants (COVID-19 positive: 771; COVID-19 negative: 3048). After adjusting for confounding by socio-demographics, prior obstetric and maternal health comorbidities, mothers with severe COVID-19 had an increased risk of depressive (aRR: 1.72; 95%CI: 1.18-2.52) and anxiety (aRR: 1.40; 0.98-2.00) symptoms. The strength of the association was attenuated for women with moderate COVID-19 (aRR = 1.12; 0.86-1.44 for depressive symptoms; aRR = 1.18; 0.96-1.44 for anxiety symptoms). No increased risk was observed for mild or asymptomatic illness. The findings can inform targeted interventions to minimize the risk of adverse COVID-19-related mental health outcomes for pregnant women.

First trimester COVID-19 and the risk of major congenital malformations-International Registry of Coronavirus Exposure in Pregnancy.

There is limited information about the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the first trimester of pregnancy on the risk of major congenital malformations (MCMs). The International Registry of Coronavirus Exposure in Pregnancy (IRCEP) was designed to estimate the relative risk of adverse perinatal outcomes among women with Coronavirus Disease 2019 (COVID-19) at specific times during gestation. Adult women were eligible to enroll if they had a SARS-CoV-2 test, regardless of the results, or clinically confirmed COVID-19 during pregnancy. Self-administered questionnaires collected data on SARS-CoV-2 infection, pregnancy outcomes (including detailed questions on MCMs), and potential confounders. The analysis of MCMs includes women with either a positive SARS-CoV-2 PCR test or a clinical diagnosis of COVID-19 during the first trimester (exposed group) or a negative SARS-CoV-2 test (reference) that enrolled while pregnant. Sensitivity analyses were restricted to participants who enrolled before the availability of informative prenatal screening tests and extended to those enrolled after end of pregnancy. Generalized linear models were used to estimate relative risks (RR) and 95% confidence intervals (CI). Of 17,163 participants enrolled between June 2020 and July 2021, 1727 had a SARS-CoV-2 infection during the first trimester, of whom 1,675 enrolled during pregnancy. Of 10,235 controls with a negative test during pregnancy, 4,172 enrolled during pregnancy. Restriction to participants with complete follow-up reduced the sample size to 92 exposed and 292 unexposed reference pregnancies. MCMs were reported in 3 (3.3%) exposed and 8 (2.7%) unexposed (RR 1.2; 95% CI 0.32-4.2) newborns. The RR was 2.5 (95%CI 0.23-27) among those enrolled before prenatal screening, and 2.2 (95%CI 0.89-5.3) in the overall study population including those enrolled post-pregnancy. No specific pattern of malformations was observed. Although results are compatible with no major teratogenic effects associated with maternal SARS-CoV-2 infection, RR estimates were imprecise and larger studies are warranted.

COVID-19 pharmacotherapy utilization patterns during pregnancy: International Registry of Coronavirus Exposure in Pregnancy.

PURPOSE: Women infected with SARS-CoV-2 during pregnancy are at increased risk of developing severe illness and experience a higher rate of preterm births than pregnant women who are not infected. The use of innovative or repurposed therapies to treat COVID-19 patients is widespread; however, there are very limited data regarding the patterns of use and safety profile of most of these therapeutics in pregnant women. We assessed the patterns of use of COVID-19 therapeutics during pregnancy using data from the International Registry of Coronavirus in Pregnancy (IRCEP). METHODS: The IRCEP is an international observational cohort study intended to assess the risk of major obstetric and neonatal outcomes among pregnant women with COVID-19. Women enrolled while pregnant or within 6 months after end of pregnancy. Follow-up for women enrolled while pregnant includes monthly online questionnaires throughout the pregnancy and, for live births, through the infant's first 90 days of life. Participants provide information on demographic characteristics, health history, COVID-19 tests and symptoms, medications, and obstetric and neonatal outcomes. RESULTS: A total of 5780 women with COVID-19 during pregnancy were identified from the IRCEP. Severity of COVID-19 was classified in 372 of them as severe, 3053 moderate, and 2355 mild. The most frequently reported COVID-19 therapies, other than analgesics, included azithromycin (12.8%), steroids (3.5%), interferon (2.4%), oseltamivir (2.1%), chloroquine/hydroxychloroquine (1.7%), anticoagulants (2.0%), antibodies (0.9%), and remdesivir (0.3%). Most drugs were preferentially used for severe cases. Patterns of use varied by country. CONCLUSIONS: IRCEP participants reported use of therapeutics for COVID-19 during pregnancy for which there is little safety information. Findings on COVID-19 pharmacotherapy utilization patterns can guide future studies examining the safety of COVID-19 therapies during pregnancy.