Pregnancy Exposure Registries Research Articles

Population-based prevalence of congenital defects in a routine sentinel site-based surveillance system in the Western Cape, South Africa.

Lack of data on the burden and scope of congenital disorders (CDs) in South Africa undermines resource allocation and limits the ability to detect signals from potentially teratogenic pregnancy exposures. We used routine electronic data in the Western Cape Pregnancy Exposure Registry (PER) to determine the overall and individual prevalence of CD identified on neonatal surface examination at birth in the Western Cape, South Africa, 2016-2022. CD was confirmed by record review. The contribution of late (≤24 months) and antenatal diagnoses was assessed. We compared demographic and obstetric characteristics between women with/without pregnancies affected by CD. Women with a viable pregnancy (>22 weeks gestation; birth weight ≥ 500 g) (n = 32,494) were included. Of 1106 potential CD identified, 56.1% were confirmed on folder review. When internal and minor CD were excluded the prevalence of major CD identified on surface examination at birth was 7.2/1000 births. When missed/late diagnoses on examination (16.8%) and ultrasound (6.8%) were included, the prevalence was 9.2/1000 births: 8.9/1000 livebirths and 21.5/1000 stillbirths. The PER did not detect 21.5% of major CD visible at birth. Older maternal age and diabetes mellitus were associated with an increased prevalence of CD. Women living with/without HIV (or the timing of antiretroviral therapy, before/after conception), hypertension or obesity did not significantly affect prevalence of CD. A surveillance system based on routine data successfully determined the prevalence of major CD identified on surface examination at birth at rates slightly higher than in equivalent studies. Overall rates, modeled at ~2%, are likely underestimated. Strengthening routine neonatal examination and clinical record-keeping could improve CD ascertainment.

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.

0909 Pitolisant Pregnancy Registry: An Observational Study of the Safety of Pitolisant Exposure in Pregnant Women and Their Offspring

Abstract Introduction WAKIX (pitolisant) is a potent and highly selective histamine 3 receptor antagonist/inverse agonist approved for the treatment of excessive daytime sleepiness or cataplexy in adult patients with narcolepsy. The safety of pitolisant in pregnant women has not been established. Available case reports from clinical trials and postmarketing experience have not demonstrated a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. The registry is a prospective, observational cohort study designed to evaluate the association between pitolisant exposure during pregnancy and subsequent maternal, fetal, and infant outcomes. Methods The primary study population consists of 3 cohorts: pregnant women with a diagnosis of narcolepsy who are exposed to pitolisant during pregnancy, pregnant women with narcolepsy who are unexposed to pitolisant but exposed to comparator products during pregnancy, and pregnant women with narcolepsy who are neither exposed to pitolisant nor comparator products. Comparator products include modafinil, armodafinil, sodium oxybate, oxybate mixed salts, solriamfetol, methylphenidate, and amphetamines. Outcomes of interest include major congenital malformation (primary outcome), minor congenital malformation, pre-eclampsia, eclampsia, spontaneous abortion, stillbirth, elective termination, small for gestational age, preterm birth, postnatal growth deficiency, and infant developmental deficiency. Data are collected from enrolled pregnant women and healthcare providers involved in their care or the care of their infants, if applicable. Only data that are routinely documented in patients' medical records during usual care are collected. Participation in the registry is voluntary and participants may withdraw their consent to participate at any time. The registry design follows current FDA guidance for designing and implementing pregnancy exposure registries. Results The registry was initiated in May 2021. Presently, data are insufficient to assess an association between pitolisant exposure and any endpoint of interest. Study completion is planned in 2030. Conclusion Healthcare providers are encouraged to discuss this voluntary pregnancy registry with their eligible patients and assist women who are interested in enrolling. The study is registered on Clinicaltrials.gov (ID# NCT05536011). Support (if any) This study is sponsored by Harmony Biosciences LLC.

Pregnancy exposure registries for drugs and vaccines in low-income and middle-income countries: scoping review protocol

IntroductionData regarding the safety of drugs and vaccines in pregnant women are typically unavailable before licensure. Pregnancy exposure registries (PERs) are an important source of postmarketing safety information. PERs in...

Diroximel Fumarate Pregnancy Outcomes in EVOLVE-MS-1 and Study Design of Diroximel Fumarate Prospective MS Pregnancy Exposure Registry (P9-3.003)

Diroximel Fumarate Pregnancy Outcomes in EVOLVE-MS-1 and Study Design of Diroximel Fumarate Prospective MS Pregnancy Exposure Registry (P9-3.003)

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

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). 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. 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). The C-VIPER data show no evidence that mRNA COVID-19 vaccines increase the risk of SAB.

Recommended Adult Immunization Schedule, United States, 2023.

Recommended Adult Immunization Schedule, United States, 2023.

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

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. 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. 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. ClinicalTrials.gov NCT04705116. Registered on 12 January, 2021. EU PAS EUPAS39096. Registered on 20 January, 2021.

Analysis of Circulating C19MC MicroRNA as an Early Marker of Hypertension and Preeclampsia in Pregnant Patients: A Systematic Review.

Preeclampsia and hypertension complicate several pregnancies. Identifying women at risk of developing these conditions is essential to establish potential treatment modalities. Biomarkers such as C19MC microRNA in pregnant patients wopuld assist in defining pregnancy surveillance and implementing interventions. This study sought to analyze circulating C19MC microRNA as an early marker of hypertension and preeclampsia in pregnant patients. A systematic review was undertaken using the following registers: disease registries, pregnancy registries, and pregnancy exposure registries, and the following databases: PubMed, CINAHL, Web of Science, Scopus, and EMBASE. The risk of bias was assessed using the Cochrane technique. From the 45 publications retrieved from the registers and databases, only 21 were included in the review after the removal of duplicates, screening, and eligibility evaluation. All 210 publications had a low risk of bias and illuminated the potential use of circulating C19MC microRNA as an early marker of hypertension and preeclampsia in pregnant patients. Therefore, it was concluded that C19MC microRNA can be used as an early marker of gestational preeclampsia and hypertension.

Monitoring Drug Safety in Pregnancy with Scan Statistics: A Comparison of Two Study Designs.

Traditional surveillance of adverse infant outcomes following maternal medication exposures relies on pregnancy exposure registries, which are often underpowered. We characterize the statistical power of TreeScan, a data mining tool, to identify potential signals in the setting of perinatal medication exposures and infant outcomes. We used empirical data to inform background incidence of major congenital malformations and other birth conditions. Statistical power was calculated using two probability models compatible with TreeScan, Bernoulli and Poisson, while varying the sample size, magnitude of the risk increase, and incidence of a specified outcome. We also simulated larger referent to exposure matching ratios when using the Bernoulli model in the setting of fixed N:1 propensity score matching. Finally, we assessed the impact of outcome misclassification on power. The Poisson model demonstrated greater power to detect signals than the Bernoulli model across all scenarios and suggested a sample size of 4,000 exposed pregnancies is needed to detect a twofold increase in risk of a common outcome (approximately 8 per 1,000) with 85% power. Increasing the fixed matching ratio with the Bernoulli model did not reliably increase power. An outcome definition with high sensitivity is expected to have somewhat greater power to detect signals than an outcome definition with high positive predictive value. Use of the Poisson model with an outcome definition that prioritizes sensitivity may be optimal for signal detection. TreeScan is a viable method for surveillance of adverse infant outcomes following maternal medication use.

S751 The Vedolizumab Pregnancy Exposure Registry: An OTIS Pregnancy Study Update

Introduction: Vedolizumab is a gut-selective immunoglobulin (Ig) G1 monoclonal antibody that binds to α4β7 integrin; it is approved for the treatment of moderately to severely active Crohn’s disease (CD) and ulcerative colitis (UC) in the U.S. and elsewhere. Published studies on the effect of vedolizumab in human pregnancy are limited. Data from the ongoing Vedolizumab Pregnancy Exposure Registry (NCT02678052) in the U.S. and Canada have been collected by the MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (OTIS). This prospective observational pregnancy cohort study planned to enroll and analyze the outcomes of 100 vedolizumab-exposed (Vedo) participants compared to 100 disease-matched (DM) and 100 healthy comparison (HC) participants. Methods: Pregnant women treated with vedolizumab for UC or CD with at least one dose in the first trimester were enrolled in the Vedo group. Pregnant women with UC or CD but no exposure to vedolizumab were enrolled in the DM group. Pregnant women with no exposure to any biologic during pregnancy and not diagnosed with an auto-inflammatory or other exclusionary disease were enrolled in the HC group. Data were collected from telephone interviews and maternal and pediatric medical records; live-born children were followed to one year of age with a dysmorphological examination and developmental screening. The Short Quality of Life in Inflammatory Bowel Disease Questionnaire (SIBDQ) was administered to women with CD or UC. Results: Between December 2015 and March 2022, outcomes were collected for 301 women, 98 in the Vedo group, 104 in the DM group, and 99 in the HC group. SIBDQ mean scores were similar in the Vedo group, 5.8 (SD 1.0) and the DM group, 5.9 (SD 1.0). Preliminary descriptive outcome data are shown in Table. In the Vedo group 7.3% of pregnancies resulted in a fetus or infant with a major birth defect, compared to 7.8% in the DM group, and 4.7% in the HC group. No pattern of major birth defects was identified in the Vedo group. Conclusion: The proportion of pregnancies with vedolizumab exposure resulting in a major birth defect are similar to proportions in the disease comparison group, and did not represent a specific pattern. The Vedolizumab Pregnancy Exposure Registry is ongoing with formal statistical analysis planned once the study is completed in 2023. Table 1. - Pregnancy Outcomes in the Study Cohort Vedo-Total(N=98) DM-Total(N=104) HC-Total(N=99) Pregnancies ending with live born infant - n/N (%) 93/98 (94.9) 99/104 (95.2) 85/99 (85.9) Spontaneous abortion – N (Left Truncation Accounted Rate a ) 3 (8.7%) 3 (6.1%) 1 (6.4%) Termination - n/N (%) 0/98 (0.0) 0/104 (0.0) 0/99 (0.0) Stillbirth - n/N (%) 0/98 (0.0) 1/104 (1.0) 0/99 (0.0) Lost to follow-up (LTFU) - n/N (%) 2/98 (2.0) 1/104 (1.0) 13/99 (13.1) Preterm delivery – N (Rate b ) 13 (14.5%) 6 (6.1%) 6 (7.2%) Birth weight full term infants – mean g (SD) 3410.4 (436.7) 3428.8 (454.0) 3308.1 (432.3) Number of pregnancies with major birth defects among all pregnancies excluding LTFU – n/N’ (%) 7/96 (7.3) 8/103 (7.8) 4/86 (4.7) Serious infections in live born infants up to 1 year of age – n/N’(%) c 3/97 (3.1) 2/99 (2.0) 1/88 (1.1) Ages and Stages Screening at 1 year of age with concern – n/N’ (%) c 10/66 (15.2) 20/87 (23.0) 11/59 (18.6) aSpontaneous abortion rate computed using Fleming-Harrington estimate at 20 weeks' gestation, accounting for left truncation because women can enroll at various times in gestation;bComputed using Fleming-Harrington estimate at 37 weeks' gestation;cIncludes twins; % = (n/N') * 100. N' at each category: Number of pregnancies meeting the criteria specified in the row title.

Novel methods for pregnancy drug safety surveillance in the FDA Sentinel System.

It is a priority of the US Food and Drug Administration (FDA) to monitor the safety of medications used during pregnancy. Pregnancy exposure registries and cohort studies utilizing electronic health record data are primary sources of information but are limited by small sample sizes and limited outcome assessment. TreeScan™, a statistical data mining tool, can be applied within the FDA Sentinel System to simultaneously identify multiple potential adverse neonatal and infant outcomes after maternal medication exposure. We implemented TreeScan using the Sentinel analytic tools in a cohort of linked live birth deliveries and infants nested in the IBM MarketScan® Research Database. As a case study, we compared first trimester fluoroquinolone use and cephalosporin use. We used the Bernoulli and Poisson TreeScan statistics with compatible propensity score-based study designs for confounding control (matching and stratification) and used multiple propensity score models with various strategies for confounding control to inform best practices. We developed a hierarchical outcome tree including major congenital malformations and outcomes of gestational length and birth weight. A total of 1791 fluoroquinolone-exposed and 8739 cephalosporin-exposed mother-infant pairs were eligible for analysis. Both TreeScan analysis methods resulted in single alerts that were deemed to be due to uncontrolled confounding or otherwise not warranting follow-up. In this implementation of TreeScan using Sentinel analytic tools, we did not observe any new safety signals for fluoroquinolone use in the first trimester. TreeScan, with tailored or high-dimensional propensity scores for confounding control, is a valuable tool in addition to current safety surveillance methods for medications used during pregnancy.

Cohort profile: the Western Cape Pregnancy Exposure Registry (WCPER)

PurposeThe Western Cape Pregnancy Exposure Registry (PER) was established at two public sector healthcare sentinel sites in the Western Cape province, South Africa, to provide ongoing surveillance of drug exposures...

Seasonal influenza vaccine exposure in pregnancy: 5-year results from a pregnancy registry

ABSTRACT The World Health Organization recommends that all pregnant women receive seasonal influenza vaccine. Under a post-authorization safety study protocol (NCT02148211), a pregnancy exposure registry was established in the United States to monitor spontaneously reported pregnancy outcomes in women vaccinated with GSK’s seasonal inactivated influenza vaccines (IIVs). From 1 June 2014 to 31 May 2019, 507 pregnancies were prospectively reported: 352 (69.4%) were lost-to-follow-up and 40 (7.9%) were ongoing. Reported outcomes for the remaining 115 were: 101 (87.8%) live births without congenital anomalies; 3 (2.6%) live births with congenital anomalies; 2 (1.7%) spontaneous abortions with no congenital anomalies; 1 (0.9%) spontaneous abortion with a congenital anomaly; 1 stillbirth with no apparent congenital anomaly; 7 (6.1%) ‘Unknown’. Results from 493 prospective reports received via worldwide spontaneous, passive surveillance showed similar outcomes. All cases with congenital anomaly were assessed as not likely/unlikely/unrelated to vaccination. Despite the limited number of cases and outcomes, no safety signal was identified. The study findings are aligned with previously published data and should be confirmed with other robust data sources.

Maternal and neonatal data collection systems in low- and middle-income countries for maternal vaccines active safety surveillance systems: A scoping review

BackgroundMost post-licensure vaccine pharmacovigilance in low- and middle-income countries (LMICs) are passive reporting systems. These have limited utility for maternal immunization pharmacovigilance in LMIC settings and need to be supplemented with active surveillance. Our study’s main objective was to identify existing perinatal data collection systems in LMICs that collect individual information on maternal and neonatal health outcomes and could be developed to inform active safety surveillance of novel vaccines for use during pregnancy.MethodsA scoping review was performed following the Arksey and O’Malley six-stage approach. We included studies describing electronic or mixed paper-electronic data collection systems in LMICs, including research networks, electronic medical records, and custom software platforms for health information systems. Medline PubMed, EMBASE, Global Health, Cochrane Library, LILACS, Bibliography of Asian Studies (BAS), and CINAHL were searched through August 2019. We also searched grey literature including through Google and websites of existing relevant perinatal data collection systems, as well as contacted authors of key studies and experts in the field to validate the information and identify additional sources of relevant unpublished information.ResultsA total of 11,817 records were identified. The full texts of 264 records describing 96 data collection systems were assessed for eligibility. Eight perinatal data collection systems met our inclusion criteria: Global Network’s Maternal Newborn Health Registry, International Network for the Demographic Evaluation of Populations and their Health; Perinatal Informatic System; Pregnancy Exposure Registry & Birth Defects Surveillance; SmartCare; Open Medical Record System; Open Smart Register Platform and District Health Information Software 2. These selected systems were qualitatively characterized according to seven different domains: governance; system design; system management; data management; data sources, outcomes and data quality.ConclusionThis review provides a list of active maternal and neonatal data collection systems in LMICs and their characteristics as well as their outreach, strengths, and limitations. Findings could potentially help further understand where to obtain population-based high-quality information on outcomes to inform the conduct of maternal immunization active vaccine safety surveillance activities and research in LMICs.

First noncontrolled substance approved to treat narcolepsy in adults

In August, FDA approved pitolisant (Wakix—Harmony Biosciences) for treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy. The selective histamine-3 receptor antagonist/inverse agonist is the first and only treatment for narcolepsy that is not scheduled as a controlled substance. “The approval of Wakix provides health care professionals managing people living with narcolepsy a new and important treatment option for their patients,” said Jeffrey Dayno, MD, Harmony Bioscience’s chief medical officer, in a statement. “Wakix … offers an important benefit/risk profile to address the unmet medical need that exists in people living with narcolepsy.” Pitolisant is available as both a 4.45-mg and 17.8-mg tablet and should be stored at 20°C to 25°C (68°F to 77°F). FDA’s approval was based on Harmony 1 and Harmony 1bis—two multicenter, double-blind, placebo-controlled studies. The studies randomized 261 patients to receive pitolisant, placebo, or active control. Participants were treated for 8 weeks, including a 3-week dose-titration phase followed by a 5-week stable-dose phase. In both studies, patients treated with pitolisant showed statistically significant improvement in EDS, as measured by the Epworth Sleepiness Scale. Common adverse effects of pitolisant include insomnia, nausea, and anxiety. The drug may also cause QT interval prolongation. Pitolisant may interact with a number of drugs. Its use with strong CYP2D6 inhibitors, for instance, increases the amount of pitolisant that patients are exposed to by 2.2-fold. The dose of pitolisant should be reduced by one-half, with a maximum dosage of 17.8 mg once daily, for patients who are concurrently using strong CYP2D6 inhibitors. Use of pitolisant with strong CYP3A4 inducers decreases the amount of pitolisant exposure in the blood by 50%. In patients taking CYP3A4 inducers, a dose adjustment should be considered, as detailed in pitolisant’s prescribing information. Pitolisant works by increasing the synthesis and release of histamine, so use of the drug with histamine-1 (H1) receptor antagonists that cross the blood–brain barrier may reduce its effectiveness. Patients taking pitolisant should avoid using centrally acting H1 receptor antagonists. Because pitolisant can prolong the QT interval, the drug should not be used in combination with other drugs that cause QT prolongation, as this can increase the risk of cardiac arrhythmia. Pitolisant may also reduce the effectiveness of sensitive CYP3A4 substrates, including hormonal contraceptives. Before they begin treatment with pitolisant, advise patients to inform their physician if they are taking, or planning to take, any prescription or OTC drugs. Counsel patients to consult their physician immediately if they feel faint, lose consciousness, or have heart palpitations, as these could be signs of prolongation of the QT interval. Pitolisant (Wakix)Manufacturer: Harmony BiosciencesDrug class: Histamine-3 (H3) receptor antagonist/inverse agonistIndication: Treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsyDosage: 17.8 mg to 35.6 mg once daily, taken orally in the morning upon awakening. Week 1: Start with 8.9 mg. Week 2: Increase dosage to 17.8 mg. Week 3: May increase to the maximum-recommended dosage of 35.6 mg. See prescribing information for more details.Of note: Pitolisant is contraindicated in patients with severe hepatic impairment (Child-Pugh C). The drug may increase the QT interval and could reduce the efficacy of hormonal contraceptives. Manufacturer: Harmony Biosciences Drug class: Histamine-3 (H3) receptor antagonist/inverse agonist Indication: Treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy Dosage: 17.8 mg to 35.6 mg once daily, taken orally in the morning upon awakening. Week 1: Start with 8.9 mg. Week 2: Increase dosage to 17.8 mg. Week 3: May increase to the maximum-recommended dosage of 35.6 mg. See prescribing information for more details. Of note: Pitolisant is contraindicated in patients with severe hepatic impairment (Child-Pugh C). The drug may increase the QT interval and could reduce the efficacy of hormonal contraceptives. Pitolisant is metabolized extensively by the liver and is contraindicated in patients with severe hepatic impairment because the drug has not been studied in this population. Health care providers should monitor patients with moderate hepatic impairment, as these patients have shown increased amounts of the drug in their blood. Patients with mild hepatic impairment who are taking pitolisant should also be closely monitored. Emphasize to patients of reproductive potential that pitolisant may reduce the efficacy of hormonal contraceptives. Counsel these patients to use an alternative nonhormonal contraceptive method during treatment with pitolisant and for at least 21 days after discontinuing treatment. If a patient becomes pregnant during treatment with pitolisant, inform them that a pregnancy exposure registry is available to monitor pregnancy outcomes of the drug; patients can call 1-800-833-7460 to enroll or obtain information.

717 The Vedolizumab Pregnancy Exposure Registry: An OTIS Pregnancy Study Update

INTRODUCTION: Vedolizumab is a gut-selective immunoglobulin (Ig) G1 monoclonal antibody that binds to α4β7 integrin; it is approved for the treatment of moderately to severely active Crohn's disease (CD) and ulcerative colitis (UC) in the U.S. and elsewhere. Published studies on the effect of vedolizumab during human pregnancy are limited. Data from the ongoing Vedolizumab Pregnancy Exposure Registry (NCT02678052) in the U.S. and Canada have been collected by the MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (OTIS). This prospective observational cohort study intends to enroll and analyze the outcomes of 100 vedolizumab-exposed participants compared to 100 disease-matched (DM) comparison and 100 healthy comparison (HC) participants. This abstract describes progress of the study through March 1, 2019. METHODS: Pregnant women treated with vedolizumab for UC or CD for at least some part of the first trimester were enrolled in the vedolizumab-exposed group. Pregnant women with no exposure to vedolizumab were enrolled in a DM comparison group. Pregnant women with no exposure to any biologic during pregnancy and not diagnosed with an autoimmune disease or any other disease as defined by the OTIS Research Center were enrolled in a HC group. Pregnancy exposure and outcome data were collected from telephone interviews and medical records. The Short Quality of Life in Inflammatory Bowel Disease Questionnaire (SIBDQ) was administered to women with CD or UC at enrollment and 32 weeks' gestation. Follow-up of live born children included a dysmorphological exam, pediatric records review and developmental screening at one year of age. RESULTS: Between December 2015 and March 2019, outcomes were collected for 223 women, 53 in the vedolizumab group, 88 in the DM group, and 82 in the HC group. Preliminary descriptive data are shown in Table 1. No major structural birth defects were reported in the vedolizumab group, compared to 5 (5.7%) in the DM group, and 4 (5.3%) in the HC group. There was no evidence of a pattern of minor structural defects in the vedolizumab group. CONCLUSION: Updated data indicate pregnant women treated with vedolizumab in at least the 1st trimester have similar birth outcomes to disease-matched and healthy comparison women. The Vedolizumab Pregnancy Exposure Registry is ongoing with formal statistical analysis to be performed when the study is completed.

Birth outcomes following antiretroviral exposure during pregnancy: Initial results from a pregnancy exposure registry in South Africa.

BackgroundIn 2013, a pregnancy exposure registry and birth defects surveillance (PER/BDS) system was initiated in eThekwini District, KwaZulu-Natal (KZN), to assess the impact of antiretroviral treatment (ART) on birth outcomes.ObjectivesAt the end of the first year, we assessed the risk of major congenital malformations (CM) and other adverse birth outcomes (ABOs) detected at birth, in children born to women exposed to ART during pregnancy.MethodData were collected from women who delivered at Prince Mshiyeni Memorial Hospital, Durban, from 07 October 2013 to 06 October 2014, using medicine exposure histories and birth outcomes from maternal interviews, clinical records and neonatal surface examination. Singleton births exposed to only one ART regimen were included in bivariable analysis for CM risk and multivariate risk analysis for ABO risk.ResultsData were collected from 10 417 women with 10 517 birth outcomes (4013 [38.5%] HIV-infected). Congenital malformations rates in births exposed to Efavirenz during the first trimester (T1) (RR 0.87 [95% CI 0.12–6.4; p = 0.895]) were similar to births not exposed to ART during T1. However, T1 exposure to Nevirapine was associated with the increased risk of CM (RR 9.28 [95% CI 2.3–37.9; p = 0.002]) when compared to the same group. Other ABOs were more frequent in the combination of HIV/ART-exposed births compared to HIV-unexposed births (29.9% vs. 26.0%, adjusted RR 1.23 [1.14–1.31; p < 0.001]).ConclusionNo association between T1 use of EFV-based ART regimens and CM was observed. Associations between T1 NVP-based ART regimen and CM need further investigation. HIV- and ART-exposed infants had more ABOs compared to HIV-unexposed infants.

Safe Expectations: Current State and Future Directions for Medication Safety in Pregnancy Research

Medication use in pregnancy is common, but information about the safety of most medications in pregnant women or their infants is limited. In the absence of data from randomized clinical trials to guide decisions made by regulators, clinicians, and patients, we often have to rely on well-designed observational studies to generate valid evidence about the benefits and risks of medications in pregnancy. Spontaneous reporting, primary case–control and cohort studies, pregnancy exposure registries, and electronic health data have been used extensively for studying medication safety in pregnancy. This article discusses these data sources, their strengths and limitations, and possible strategies and approaches to mitigating limitations when planning studies or interpreting findings from the literature. Strategies discussed include combining data sources across institutional or national borders, developing and using more sophisticated study designs, and taking advantage of existing analytic methods for more complex data structures, such as time-varying exposure or unmeasured confounding. Finally, we make recommendations for study designs that aid in better risk-related communication.

Drug Safety in Pregnancy: Review of Study Approaches Requested by Regulatory Agencies

We reviewed postauthorization pregnancy safety studies requested by regulatory agencies to explore which study approaches have been typically requested and to what extent these have changed over time. The most common study approach requested by the US Food and Drug Administration (FDA) is pregnancy exposure registries (observational cohorts with prospective data collection), per the FDA’s Postmarketing Requirements and Commitments (PMR/PMC) database. Since 2017, this requirement has often been paired with a request for a database study (observational study using preexisting electronic health care data), both approaches assessing pregnancy and fetal outcomes. From studies registered in the European Union electronic Register of Post-Authorisation Studies, we observed a similar number of pregnancy exposure registries and database studies, both approaches also assessing pregnancy and fetal outcomes. In requests for drugs approved since 2014, preference appears to have shifted toward studies using preexisting electronic health care databases from multiple countries. Pregnancy exposure registries have been the most commonly requested study approach on drug safety in pregnancy. Recent regulatory requests and activities denote an increasing interest in other approaches.