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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).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.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.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.

ImportancePsychiatric disorders are common among female individuals of reproductive age. While antipsychotic medication use is increasing, the safety of such medications in pregnancy is an area with large evidence gaps.ObjectiveTo evaluate the risk of first-trimester antipsychotic exposure with respect to congenital malformations, focusing on individual drugs and specific malformation subtypes.Design, Setting, and ParticipantsThis cohort study used data from nationwide health registers from the 5 Nordic countries and the US and spanned 1996 to 2018. The Nordic cohort included all pregnancies resulting in singleton live-born infants, and the US cohort consisted of publicly insured mothers linked to their live-born infants nested in the nationwide Medicaid Analytic eXtract. Data were analyzed from November 2020 to April 2022.ExposuresOne or more first-trimester dispensing of any atypical, any typical, and individual antipsychotic drugs.Main Outcomes and MeasuresAny major congenital malformation and specific malformation subtypes previously suggested to be associated with antipsychotic exposure in utero: cardiovascular malformations, oral clefts, neural tube defects, hip dysplasia, limb reduction defects, anorectal atresia/stenosis, gastroschisis, hydrocephalus, other specific brain anomalies, and esophageal disorders. Propensity score stratification was used to control for potential confounders. Pooled adjusted estimates were calculated using indirect standardization.ResultsA total of 6 455 324 unexposed mothers (mean maternal age range across countries: 24-31 years), 21 751 mothers exposed to atypical antipsychotic drugs (mean age range, 26-31 years), and 6371 mothers exposed to typical antipsychotic drugs (mean age range, 27-32 years) were included in the study cohort. Prevalence of any major malformation was 2.7% (95% CI, 2.7%-2.8%) in unexposed infants, 4.3% (95% CI, 4.1%-4.6%) in infants with atypical antipsychotic drug exposure, and 3.1% (95% CI, 2.7%-3.5%) in infants with typical antipsychotic drug exposure in utero. Among the most prevalent exposure-outcome combinations, adjusted relative risks (aRR) were generally close to the null. One exception was olanzapine exposure and oral cleft (aRR, 2.1 [95% CI, 1.1-4.3]); however, estimates varied across sensitivity analyses. Among moderately prevalent combinations, increased risks were observed for gastroschisis and other specific brain anomalies after atypical antipsychotic exposure (aRR, 1.5 [95% CI, 0.8-2.6] and 1.9 [95% CI, 1.1-3.0]) and for cardiac malformations after chlorprothixene exposure (aRR, 1.6 [95% CI, 1.0-2.7]). While the association direction was consistent across sensitivity analyses, confidence intervals were wide, prohibiting firm conclusions.Conclusions and RelevanceIn this study, considering the evidence from primary and sensitivity analyses and inevitable statistical noise for very rare exposure-outcome combinations, in utero antipsychotic exposure generally was not meaningfully associated with an increased risk of malformations. The observed increased risks of oral clefts associated with olanzapine, gastroschisis, and other specific brain anomalies with atypical antipsychotics and cardiac malformations with chlorprothixene requires confirmation as evidence continues to accumulate.

Background and Purpose: We examined the impact of 3 anticonvulsant prophylaxis strategies on quality-adjusted life-years (QALYs) among patients with an incident acute ischemic stroke. Methods: We created a decision tree to evaluate 3 strategies: (1) long-term primary prophylaxis; (2) short-term secondary prophylaxis after an early seizure with lifetime prophylaxis if persistent or late seizures (LSs) developed; and (3) long-term secondary prophylaxis if either early, late, or persistent seizures developed. The outcome was quality-adjusted life expectancy (QALY). We created 4 base cases to simulate common clinical scenarios: (1) female patient aged 40 years with a 2% or 11% lifetime risk of an LS and a 33% lifetime risk of an adverse drug reaction (ADR); (2) male patient aged 65 years with a 6% or 29% LS risk and 60% ADR risk; (3) male patient aged 50 years with an 18% or 65% LS risk and 33% ADR risk; and (4) female patient aged 80 years with a 29% or 83% LS risk and 80% ADR risk. In sensitivity analyses, we altered the parameters and assumptions. Results: Across all 4 base cases, primary prophylaxis yielded the fewest QALYs when compared with secondary prophylaxis. For example, under scenario 1, strategies 2 and 3 resulted in 7.17 QALYs each, but strategy 1 yielded only 6.91 QALYs. Under scenario 4, strategies 2 and 3 yielded 2.85 QALYs compared with 1.40 QALYs for strategy 1. Under scenarios in which patients had higher ADR risks, strategy 2 led to the most QALYs. Conclusions: Short-term therapy with continued anticonvulsant prophylaxis only after postischemic stroke seizures arise dominates lifetime primary prophylaxis in all scenarios examined. Our findings reinforce the necessity of close follow-up and discontinuation of anticonvulsant seizure prophylaxis started during acute ischemic stroke hospitalization.

Background In the United States, pertussis circulation persists and primarily infects infants and children, despite routine vaccinations. To minimize infant morbidity and mortality from the disease before the first DTaP dose, the Advisory Committee on Immunization Practices recommends maternal Tdap vaccination in weeks 27-36 of pregnancy. Methods Cohorts of mother-infant pairs in the Medicaid Analytic eXtract (MAX) (2010-2014) and IBM MarketScan (2011-2015) databases were analyzed to estimate the effectiveness of prenatal Tdap vaccination compared to no vaccination to prevent infant pertussis in the first 6 months. Hazard ratios were estimated with Cox proportional hazards models and adjusted for potential confounders via inverse probability weights. The impact of preterm delivery on the risk of pertussis was analyzed. Results from the 2 databases were pooled. Results In MarketScan, women received Tdap vaccination before delivery in 114,067 (25.6%) of 445,638 pregnancies and in MAX, 33,286 (4.8%) of 695,262 pregnancies. Among pregnancies with preterm delivery, only 21.2% and 3.8% in MarketScan and MAX had been vaccinated. The risk of pertussis in unvaccinated term infants was 3.5 (MarketScan) and 17 (MAX) per 10,000; and in preterm infants, it was 8.4 (MarketScan) and 19.8 (MAX) per 10,000. The pooled hazard ratio for Tdap vaccination any time before delivery versus no vaccination was 0.64 [95% confidence interval (CI): 0.41-1.00]. The hazard ratio was 0.11 (95% CI: 0.03-0.36) for preterm and 0.78 (95% CI: 0.48-1.29) for term infants vaccinated before 37 weeks. The incidence of pertussis was higher and the protective hazard ratio stronger during pertussis outbreaks. Conclusions Prenatal Tdap vaccination reduces the risk of pertussis infections in the infants' first 6 months by 36%. Vaccination soon after 27 weeks of pregnancy, before when deliveries began, ensures vaccination includes those born preterm, who are at highest risk for pertussis and benefit particularly from this vaccination.

Background: With the development of multiple effective vaccines, reducing the global morbidity and mortality of COVID-19 will depend on the distribution, and ultimately acceptance, of COVID-19 vaccination. Estimates of global vaccine acceptance among pregnant women and mothers of young children are yet unknown. An understanding of the challenges and correlates to vaccine acceptance will aid the acceleration of vaccine administration within these key populations. Methods: Acceptance of COVID-19 vaccination among pregnant women and mothers of children younger than 18-year-old, as well as potential predictors, were assessed through an online survey. This survey was administered by Pregistry on several online platforms between October 28 and November 18, 2020. Findings: 17,871 total survey responses from 16 countries were obtained. Given a 90% COVID-19 vaccine efficacy, 52·0% of pregnant women (n=2747/5282) and 73·4% of non-pregnant women (n=9214/12562) indicated an intention to receive the vaccine. 69·2% of mothers (n=11800/17054), both pregnant and non-pregnant, indicated an intention to vaccinate their young children. Vaccine acceptance was generally highest in India, the Philippines, and all sampled countries in Latin America; it was lowest in Russia, the United States, and Australia. The strongest predictors of vaccine acceptance included confidence in vaccine safety or effectiveness, worrying about COVID-19, belief in the importance of vaccines to their own country, compliance to mask guidelines, trust of public health agencies, monitoring news media coverage of COVID-19 as well as general vaccine attitude. Interpretations: COVID-19 vaccine acceptance and its predictors among women vary globally. Current acceptance levels of a COVID-19 vaccine among women from the high-income countries included in this study are insufficient to meet the requirements for community immunity. Perceived risk of the virus and the disease, and public trust play key roles shaping the vaccine acceptance and confidence on top of the existing pre-COVID 19 vaccine attitudes. Funding Statement: Human Immunomics Initiative at the Harvard TH Chan School of Public Health; Pregistry, LLC Declaration of Interests: The authors disclose no potential conflicts of interest. Ethics Approval Statement: The study was classified exempt by the Harvard Longwood Campus Institutional Review Board (HLC IRB) per the regulations found at 45 CFR 46.104(d)(2) on the basis that it poses no greater than minimal risk and that the recorded information cannot readily identify the subject (directly or indirectly). The study protocol was reviewed and approved by the ethical review committee of Harvard Longwood Campus.

Purpose To evaluate chronic opioid utilization patterns during pregnancy using nationwide data from publicly and commercially insured women. Methods Pregnancy cohorts were identified using data from the Medicaid Analytic eXtract 2008-2014 and the IBM Health MarketScan Research Database 2008-2015. Opioid dispensing was evaluated using claims from filled prescriptions. Two different definitions of chronic opioid use were employed: ≥90 days' supply and ≥ 180 days' supply of prescription opioids during pregnancy. Patient characteristics were assessed and variations in the prevalence of chronic opioid therapy were described by geographic region and over time. Results 1.50% of 975 169 Medicaid-insured and 0.32% of 1 037 599 commercially insured beneficiaries filled opioid prescriptions for ≥90 days' supply; 0.78% (Medicaid) and 0.17% (commercially insured) filled prescriptions for ≥180 days' supply. Prevalence approximately doubled in Medicaid beneficiaries during the study period, while it remained relatively stable for commercial insurance beneficiaries. The most commonly prescribed opioid for chronic therapy was hydrocodone, followed by oxycodone and tramadol. Indications commonly associated with chronic use were back/neck pain, abdominal/pelvic pain, musculoskeletal pain and migraine/headache. Substantial regional variation was observed, with several states reporting a frequency of ≥90 days' supply in excess of 3% in Medicaid-insured patients. Conclusions Despite growing awareness of the risks associated with chronic opioid use and emphasis on improving opioid prescription patterns, prevalence of chronic use in pregnancy among publicly insured women nearly doubled from 2008-2014 and was 5-fold more common when compared to commercially insured women. Findings call for the development of guidelines on chronic pain management during pregnancy.

The scientific community relies on postmarketing approaches to define the risk of using medications in pregnancy because information available at the time of drug approval is limited. Most studies carried out in pregnancy focus on a single outcome or selected outcomes. However, women must balance the benefit of treatment against all possible adverse effects. We aimed to apply and evaluate a tree-based scan statistic data-mining method (TreeScan; Martin Kulldorff, Harvard Medical School, Boston, Massachusetts) as a safety surveillance approach that allows for simultaneous evaluation of a comprehensive range of adverse pregnancy outcomes, while preserving the overall rate of false-positive alerts. We evaluated TreeScan with a cohort design and adjustment via propensity score techniques, using 2 test cases: 1) opioids and neonatal opioid withdrawal syndrome and 2) valproate and congenital malformations, implemented in pregnancy cohorts nested within the Medicaid Analytic eXtract (January 1, 2000–December 31, 2014) and the IBM MarketScan Research Database (IBM, Armonk, New York) (January 1, 2003–September 30, 2015). In both cases, we identified known safety concerns, with only 1 previously unreported alert at the preset statistical alerting threshold. This evaluation shows the promise of TreeScan-based approaches for systematic drug safety monitoring in pregnancy. A targeted screening approach followed by deeper investigation to refine understanding of potential signals will ensure that pregnant women and their physicians have access to the best available evidence to inform treatment decisions.

Objective To describe longitudinal patterns of medication use throughout pregnancy in women with migraine. Methods We used the IBM MarketScan healthcare claims database in the US to create a cohort of pregnancies enrolled between 2011–2015 resulting in live or stillbirth. Migraine headache was identified based on ICD-9-CM diagnosis codes or procedure codes recorded in clinical encounters. Outcomes were patterns of prescriptions filled for medications that may be used to prevent migraine (antiepileptics, antihypertensives, antidepressants) or treat acute episodes (opioids, triptans, acetaminophen) and of other comorbid conditions (hypertension, psychiatric diagnoses, epilepsy). We used group-based multi-trajectory models to cluster women into similar longitudinal patterns of prescription fills. Results Of 859,501 pregnancies, 8168 had migraine. Within migraineurs, before pregnancy, the most commonly filled prescription was for a triptan (43.2%), followed by opioids (26.7%), acetaminophen (26.2%), antidepressants (24.9%), antiepileptics (18.6%) and antihypertensives (12.3%). Antiepileptics, antidepressants, and triptans were frequently discontinued early in pregnancy with few new users, while antihypertensives were discontinued by some users, but continued or initiated by a minority of users late in pregnancy. Opioids and acetaminophen were used intermittently throughout pregnancy. Comorbidities included hypertension (10.8%), epilepsy (4.7%), depression (14.0%), and anxiety (15.6%). Polypharmacy involving both preventive and acute medications was most common before pregnancy (31.4%) and declined in first trimester (14.7%). In all, 25.9% of women filled prescriptions for two or more acute medications before pregnancy. Conclusions Medication use patterns during pregnancy for women with migraine are complex. Patterns of polypharmacy and comorbidity during pregnancy highlight an under-studied area relevant for maternal and child health outcomes.

Background Population-level data spanning different countries describing oral and parenteral treatment in pregnant women with inflammatory bowel disease (IBD) are scarce. We studied treatment with sulfasalazine/5-aminosalicylates, corticosteroids, thiopurines/immunomodulators, and tumor necrosis factor (TNF)-inhibitors in the United States (Optum Clinformatics Data Mart and the Medicaid Analytics Extract [MAX]) and in the Swedish national health registers. Methods We identified 2975 pregnant women in Optum (2004–2013), 3219 women in MAX (2001–2013), and 1713 women in Sweden (2006–2015) with a recorded diagnosis of IBD. We assessed patterns of use for each drug class according to filled prescriptions, assessing frequency of treatment continuation in those that were treated in the prepregnancy period. Results The proportion of women with Crohn’s disease and ulcerative colitis on any treatment during pregnancy was 56.1% and 56.3% in Optum, 47.5% and 49.3% in MAX, and 61.3% and 64.7% in Sweden, respectively, and remained stable over time. Sulfasalazine/5-aminosalicylates was the most commonly used treatment in Crohn’s disease, ranging from 25.1% in MAX to 31.8% in Optum, and in ulcerative colitis, ranging from 34.9% in MAX to 53.6% in Sweden. From 2006 to 2012, the TNF-inhibitor use increased from 5.0% to 15.5% in Optum, from 3.6% to 8.5% in MAX, and from 0.7% to 8.3% in Sweden. Continuing TNF-inhibitor treatment throughout pregnancy was more common in Optum (55.8%) and in MAX (43.0%) than in Sweden (11.8%). Conclusions In this population-based study from 2 countries, the proportion of women with IBD treatment in pregnancy remained relatively constant. TNF-inhibitor use increased substantially in both countries.

Comorbidity scores are widely used to help address confounding bias in nonrandomized studies conducted within health-care databases, but existing scores were developed to predict all-cause mortality in adults and might not be appropriate for use in pediatric studies. We developed and validated a pediatric comorbidity index, using health-care utilization data from the tenth revision of the International Classification of Diseases. Within the MarketScan database of US commercial claims data, pediatric patients (aged ≤18 years) continuously enrolled between October 1, 2015, and September 30, 2017, were identified. Logistic regression was used to predict the 1-year risk of hospitalization based on 27 predefined conditions and empirically identified conditions derived from the most prevalent diagnoses among patients with the outcome. A single numerical index was created by assigning weights to each condition based on its β coefficient. We conducted internal validation of the index and compared its performance with existing adult scores. The pediatric comorbidity index consisted of 24 conditions and achieved a C statistic of 0.718 (95% confidence interval (CI): 0.714, 0.723). The index outperformed existing adult scores in a pediatric population (C statistics ranging from 0.522 to 0.640). The pediatric comorbidity index provides a summary measure of disease burden and can be used for risk adjustment in epidemiologic studies of pediatric patients.

Purpose To examine indications for, duration of use, and rate of adverse drug events (ADE) attributable to anticonvulsant initiation, as adjudicated by expert review of electronic health records (EHR) of older adults. Methods We identified a cohort of community dwelling Medicare beneficiaries with linked EHR (aged 65+, continuously enrolled with a large health system/until death between 2012 and 2014, n = 20 945) and drew a stratified EHR review sample (n = 1534). An expert reviewed all records to adjudicate anticonvulsant use, years of use, indication for use, and evidence of ADEs attributable to anticonvulsant initiation. After excluding patients with insufficient EHR data (n = 37; 2%), we reconstructed the cohort using inverse probability weights to resemble the original cohort of eligible beneficiaries (n = 20 380). Among incident users of a single anticonvulsant, we estimated the rate of ADEs and described the type and severity of ADEs. Results Overall, 12% (n = 2469) of eligible beneficiaries used at least one anticonvulsant in the 2012 to 2014 period (4% [n = 757] incident users, 8% [n = 1712] prevalent users). Incident users were most frequently prescribed gabapentin (n = 461/757, 61%), benzodiazepines (n = 122/757, 16%), and levetiracetam (n = 74/757, 10%); the most common indication was pain relief (n = 214; 28%) followed by epilepsy (n = 53; 7%). Among incident users, the overall ADE rate was 10/100 person-years (95% CI 4-20/100 person-years), of which 29% (n = 28/97) were life threatening (eg, somnolence). Most ADEs among incident monotherapy users were nervous system related (68%, n = 66/97). Conclusion Many older adult community dwelling traditional Medicare beneficiaries had clinically significant ADEs likely attributable to the initiation of anticonvulsant therapy, which was begun for a range of indications.

BACKGROUND: Risk factors for birth defects are frequently investigated using data limited to liveborn infants. By conditioning on survival, results of such studies may be distorted by selection bias, also described as “live birth bias”. However, the implications of live birth bias on risk estimation remain poorly understood. OBJECTIVES: We sought to quantify live birth bias and to investigate the conditions under which it arose. METHODS: We used data on 3,994 birth defects cases and 11,829 controls enrolled in the National Birth Defects Prevention Study to compare odds ratio (OR) estimates of the relationship between three established risk factors (antiepileptic drug use, smoking, and multifetal pregnancy) and four birth defects (anencephaly, spina bifida, omphalocele, and cleft palate) when restricted to live births as compared to among live births, stillbirths, and elective terminations. Exposures and birth defects represented varying strengths of association with live birth; all controls were liveborn. We performed a quantitative bias analysis to evaluate the sensitivity of our results to excluding terminated and stillborn controls. RESULTS: Cases ranged from 33% live born (anencephaly) to 99% (cleft palate). Smoking and multifetal pregnancy were associated with live birth among anencephaly (crude OR [cOR] 0.61 and cOR 3.15, respectively) and omphalocele cases (cOR 2.22 and cOR 5.22, respectively). For analyses of the association between exposures and birth defects, restricting to live births produced negligible differences in estimates except for anencephaly and multifetal pregnancy, which was two-fold higher among live births (adjusted OR [aOR] 4.93) as among all pregnancy outcomes (aOR 2.44). Within tested scenarios, bias analyses suggested that results were not sensitive to the restriction to liveborn controls. CONCLUSIONS: Selection bias was generally limited except for high mortality defects in the context of exposures strongly associated with livebirth. Findings indicate that substantial live birth bias is unlikely to affect studies of risk factors for most birth defects.

Background The Medicaid Analytic eXtract (MAX) is a health care utilization database from publicly insured individuals that has been used for studies of drug safety in pregnancy. Claims-based algorithms for defining many important maternal and neonatal outcomes have not been validated. Objective To validate claims-based algorithms for identifying selected pregnancy outcomes in MAX using hospital medical records. Methods The medical records of mothers who delivered between 2000 and 2010 within a single large healthcare system were linked to their claims in MAX. Claims-based algorithms for placental abruption, preeclampsia, postpartum hemorrhage, small for gestational age, and noncardiac congenital malformation were defined. Fifty randomly sampled cases for each outcome identified using these algorithms were selected, and their medical records were independently reviewed by two physicians to confirm the presence of the diagnosis of interest; disagreements were resolved by a third physician reviewer. Positive predictive values (PPVs) and 95% confidence intervals (CIs) of the claims-based algorithms were calculated using medical records as the gold standard. Results The linked cohort included 10,899 live-birth pregnancies. The PPV was 92% (95% CI, 82%-97%) for placental abruption, 82% (95% CI, 70%-91%) for preeclampsia, 74% (95% CI, 61%-85%) for postpartum hemorrhage, 92% (95% CI, 82%-97%) for small for gestational age, and 86% (95% CI, 74%-94%) for noncardiac congenital malformation. Conclusions Across the perinatal outcomes considered, PPVs ranged between 74% and 92%. These PPVs can inform bias analyses that correct for outcome misclassification.

IMPORTANCE: Neurodevelopmental disorders are associated with poor health and social outcomes. Population-based data on incidence, age at diagnosis, and demographic variations are essential to identify modifiable risk factors and inform the planning of services and interventions. OBJECTIVES: To assess the incidence and timing of diagnosis of neurodevelopmental disorders during childhood in the US and to evaluate differences by population characteristics. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study used nationwide data on birth cohorts nested in the 2000-2014 Medicaid Analytic eXtract and the 2003-2015 IBM MarketScan Research Database on 2 070 541 publicly and 1 309 900 privately insured children enrolled at birth. Data were analyzed between May 1, 2020, and June 30, 2021. MAIN OUTCOMES AND MEASURES: Neurodevelopmental disorders, autism spectrum disorders, attention-deficit/hyperactivity disorder, learning disabilities, speech or language disorders, developmental coordination disorders, intellectual disabilities, and behavioral disorders were identified based on validated algorithms. Kaplan-Meier analyses were used to estimate the incidence and timing of diagnosis, stratified by child’s sex, birth year, maternal age at delivery, and race and ethnicity. RESULTS: The cohorts comprised 2 070 541 publicly insured children (1 045 426 boys [50.5%]) and 1 309 900 privately insured children (667 607 boys [51.0%]) enrolled at birth. By 8 years of age, 23.9% of publicly insured children and 11.0% of privately insured children received a diagnosis of 1 or more neurodevelopmental disorders (autism spectrum disorder, 1.6% and 1.3%; attention-deficit/hyperactivity disorder, 14.5% and 5.8%; learning disability, 1.2% and 0.6%; speech or language disorder, 8.4% and 4.5%; developmental coordination disorder, 0.9% and 0.7%; intellectual disability, 0.7% and 0.1%; and behavioral disorder, 8.4% and 1.5%). Risks were substantially higher among boys (incidence of ≥1 neurodevelopmental disorder by age 8 years for boys vs girls: 30.7% vs 16.7% among publicly insured children and 15.0% vs 6.7% among privately insured children) and White children (30.2% vs 9.1% among Asian children, 23.0% among Black children, 15.4% among Hispanic children, and 22.7% among children of unknown race or ethnicity; information on race and ethnicity was available only for publicly insured children). The association of maternal age and birth year with incidence of neurodevelopmental disorders varied by outcome. Except for attention-deficit/hyperactivity disorder, the diagnosis tended to be established somewhat earlier for privately insured children. The association of race and ethnicity with age at diagnosis varied by outcome. Co-occurring neurodevelopmental disorders were common, especially among children with autism spectrum disorder and intellectual disability (>70% had ≥1 other disorder). CONCLUSIONS AND RELEVANCE: In this population-based cohort study, a relatively high incidence of and co-occurrence of neurodevelopmental disorders as well as the disparity in incidence and timing of diagnosis by insurance type and race and ethnicity were found. These findings represent important public health concerns and underscore the need for timely and accessible developmental assessments and educational services to help reduce the burden of these disorders.

Background Pregnant and postpartum women face unique challenges and concerns during the COVID-19 pandemic. Thus far, no studies have explored the factors associated with increased levels of worry in this population globally. The current study sought to assess the frequency and sources of worry during the COVID-19 pandemic in an international sample of pregnant and postpartum women. Methods We conducted an anonymous, online, cross-sectional survey in 64 countries between May and June 2020. The survey was available in 12 languages and hosted on the Pregistry platform for COVID-19 studies. Participants were sought mainly on social media platforms and online parenting forums. The survey included questions related to demographics, level of worry, support, stress, COVID-19 exposure, frequency of media usage, and mental health indicators. Results The study included 7561 participants. Eighty-three percent of all participants indicated that they were either ‘somewhat’ or ‘very’ worried. Women 13–28 weeks pregnant were significantly more likely to indicate that they were ‘very worried’ compared to those who were postpartum or at other stages of pregnancy. When compared with women living in Europe, those in Africa, Asia and Pacific, North America and South/Latin America were more likely to have increased levels of worry, as were those who more frequently interacted with social media. Different forms of support and stress also had an impact upon level of worry, while indicators of stress and anxiety were positively associated with worry level. Conclusion Pregnant and postpartum women are vulnerable to the changes in societal norms brought about by the COVID-19 pandemic. Understanding the factors associated with levels of worry within this population will enable society to address potential unmet needs and improve the current and future mental health of parents and children.

BACKGROUND Identifying pregestational diabetes in pregnant women using administrative claims databases is important for studies of the safety of antidiabetic treatment in pregnancy, but limited data are available on the validity of case-identifying algorithms. The purpose of this study was to evaluate the validity of an administrative claims-based algorithm to identify pregestational diabetes. METHODS Using a cohort of pregnant women nested within the Medicaid Analytic Extract (MAX) database, we developed an algorithm to identify pregestational type 1 and type 2 diabetes, distinct from gestational diabetes. Within a single large healthcare system in the Boston area, we identified women who delivered an infant between 2000 and 2010 and were covered by Medicaid, and linked their electronic health records to their Medicaid claims within MAX. Medical records were reviewed by two physicians blinded to the algorithm classification to confirm or rule out pregestational diabetes, with disagreements resolved by discussion. We calculated positive predictive values with 95% confidence intervals using the medical record as the reference standard. RESULTS We identified 49 pregnancies classified by the claims-based algorithm as pregestational diabetes that were linked to the electronic health records and had records available for review. The PPV for any pregestational diabetes was 92% [95% confidence interval (CI) 82%, 97%], type 2 diabetes 87% (68%, 95%), and type 1 diabetes 57% (37%, 75%). CONCLUSIONS The claims-based algorithm for pregestational diabetes and type 2 diabetes performed well; however, the PPV was low for type 1 diabetes.

PURPOSE To validate healthcare claim-based algorithms for neurodevelopmental disorders (NDD) in children using medical records as the reference. METHODS Using a clinical data warehouse of patients receiving outpatient or inpatient care at two hospitals in Boston, we identified children (≤14 years between 2010 and 2014) with at least one of the following NDDs according to claims-based algorithms: autism spectrum disorder/pervasive developmental disorder (ASD), attention deficit disorder/other hyperkinetic syndromes of childhood (ADHD), learning disability, speech/language disorder, developmental coordination disorder (DCD), intellectual disability, and behavioral disorder. Fifty cases per outcome were randomly sampled and their medical records were independently reviewed by two physicians to adjudicate the outcome presence. Positive predictive values (PPVs) and 95% confidence intervals (CIs) were calculated. RESULTS PPVs were 94% (95% CI, 83%-99%) for ASD, 88% (76%-95%) for ADHD, 98% (89%-100%) for learning disability, 98% (89%-100%) for speech/language disorder, 82% (69%-91%) for intellectual disability, and 92% (81%-98%) for behavioral disorder. A total of 19 of the 50 algorithm-based cases of DCD were confirmed as severe coordination disorders with functional impairment, with a PPV of 38% (25%-53%). Among the 31 false-positive cases of DCD were 7 children with coordination deficits that did not persist throughout childhood, 7 with visual-motor integration deficits, 12 with coordination issues due to an underlying medical condition and 5 with ADHD and at least one other severe NDD. CONCLUSIONS PPVs were generally high (range: 82%-98%), suggesting that claims-based algorithms can be used to study NDDs. For DCD, additional criteria are needed to improve the classification of true cases.

Little is known about the impact of dose, duration, and timing of prenatal prescription opioid exposure on the risk of neonatal opioid withdrawal syndrome (NOWS). Using a cohort of 18,869 prepregnancy chronic opioid users nested within the 2000–2014 Medicaid Analytic eXtract, we assessed average opioid dosage within biweekly gestational age intervals, created group-based trajectory models, and evaluated the association between trajectory groups and NOWS risk. Women were grouped into 6 distinct opioid use trajectories which, based on observed patterns, were categorized as 1) continuous very low-dose use, 2) continuous low-dose use, 3) initial moderate-dose use with a gradual decrease to very low-dose/no use, 4) initial high-dose use with a gradual decrease to very low-dose use, 5) continuous moderate-dose use, and 6) continuous high-dose use. Absolute risk of NOWS per 1,000 infants was 7.7 for group 1 (reference group), 28.8 for group 2 (relative risk (RR) = 3.7, 95% confidence interval (CI): 2.8, 5.0), 16.5 for group 3 (RR = 2.1, 95% CI: 1.5, 3.1), 64.9 for group 4 (RR = 8.4, 95% CI: 5.6, 12.6), 77.3 for group 5 (RR = 10.0, 95% CI: 7.5, 13.5), and 172.4 for group 6 (RR = 22.4, 95% CI: 16.1, 31.2). Trajectory models—which capture information on dose, duration, and timing of exposure—are useful for gaining insight into clinically relevant groupings to evaluate the risk of prenatal opioid exposure.

Objective: Second-generation antipsychotics (SGAs) are prescribed for a wide range of indications in women of reproductive age. The National Pregnancy Registry for Atypical Antipsychotics (NPRAA) was established to determine the risk of major malformations among infants exposed to these medications during the first trimester relative to a comparison group of unexposed infants of mothers with histories of psychiatric morbidity. Methods: Women, aged 18-45 years, with histories of psychiatric illness were prospectively followed through pregnancy and during the postpartum period. Pediatric and maternal medical records were obtained and screened for evidence of major malformations. Potential cases were adjudicated by a dysmorphologist who was blinded to drug exposure.. Recruitment to the Registry, which is based at the Ammon-Pinizzotto Center for Women's Mental Health at Massachusetts General Hospital (MGH), includes nationwide provider referral, self-referral, and advertisement through the MGH Center for Women's Mental Health website. Results: As of April 9, 2020, 1,906 women had enrolled, including 889 in the exposure group and 1,017 controls. A total of 1,311 women completed the study and were eligible for inclusion in the analysis. Medical records were obtained for 81.3% of participants. Among 640 live births in the exposure group, 16 (2.50%) had confirmed major malformations reported, and among 704 live births in the control group, 14 (1.99%) had confirmed major malformations reported. The estimated odds ratio for major malformations comparing exposed and unexposed infants was 1.48 (95% CI, 0.625-3.517). Conclusions: Data from the Registry assessing SGAs as a class indicate that they are unlikely to have a major teratogenic effect. These findings provide pertinent information for women and their health care providers regarding decisions about atypical antipsychotic use during pregnancy. Trial Registration: ClinicalTrails.gov identifier: NCT01246765.

OBJECTIVES To examine the long-term impact of assisted reproductive techniques (ART) on offspring neurodevelopment, accounting for parental factors and the role of infertility. METHODS Linkage of national registers allowed follow-up of >2.4 million children born in Sweden 1986–2012. Information on ART was retrieved from fertility clinics, medical records, and maternal self-report. Attention-deficit/hyperactivity disorder (ADHD) was identified from specialist diagnosis and/or use of medication through 2018. School performance was assessed from records of ninth year final grade averages (0–20) and eligibility for upper secondary school through 2017. RESULTS Children conceived with ART had lower risk of ADHD (hazard ratio 0.83; 95% confidence interval [CI]: 0.80 to 0.87) and did better in school (grade mean difference 1.15; 95% CI: 1.09 to 1.21 and eligibility odds ratio 1.53; 95% CI: 1.45 to 1.63) compared with all other children. Differences in parental characteristics explained and even reversed associations, whereas no disadvantage was seen when the comparison was restricted to children of couples with known infertility (adjusted hazard ratio 0.95; 95% CI: 0.90 to 1.00, adjusted mean difference 0.05; 95% CI: −0.01 to 0.11, and adjusted odds ratio 1.03; 95% CI: 0.96 to 1.10). Among children conceived with ART, there was furthermore no indication that intracytoplasmic sperm injection (compared with standard in vitro fertilization) or frozen (compared with fresh) embryo transfer had any adverse influence. CONCLUSIONS With this nationwide, long-term follow-up, we provide additional reassurance concerning offspring neurodevelopment after use of ART, finding no indication for concern about risk of ADHD or school performance in adolescence.

Purpose To evaluate the use of data from population-based surveys such as the National Health and Nutrition Examination Survey (NHANES) for external adjustment for confounders imperfectly measured in health care databases in the United States. Methods Our example study used Medicaid Analytic eXtract (MAX) data to estimate the relative risk (RR) for prenatal serotonin-norepinephrine reuptake inhibitors (SNRIs) exposure and cardiac defects. Smoking and obesity are known confounders poorly captured in databases. NHANES collects information on lifestyle factors, depression, and prescription medications. External adjustment requires information on the prevalence of confounders and their association with SNRI use; which was obtained from the NHANES. It also requires estimates of their association with the outcome, which were based on the literature and allowed us to correct the RR using sensitivity analyses. Results In MAX, the RR for the association between prenatal SNRI exposure and cardiac defects was 1.51 unadjusted and 1.20 adjusted for measured confounders and restricted to women with depression. In NHANES, among women of childbearing age with depression, the prevalence of smoking was 60.2% (95% Confidence Interval 43.2, 74.3) for SNRI users and 44.1% (39.6, 48.8) for nonusers of antidepressants. The corresponding estimates for obesity were 59.2% (43.2, 74.3) and 40.5% (35.9, 45.0), respectively. If the associations between smoking and obesity with cardiac defects are independent from each other and from other measured confounders, additional adjustment for smoking and obesity would move the RR from 1.20 to around 1.10. Conclusion National surveys like NHANES are readily available sources of information on potential confounders and they can be used to assess and improve the validity of RR estimates from observational studies missing data on known risk factors.

OBJECTIVE: To estimate the risk of stillbirth (fetal death at 20 weeks of gestation or more) associated with specific birth defects. METHODS: We identified a population-based retrospective cohort of neonates and fetuses with selected major birth defects and without known or strongly suspected chromosomal or single-gene disorders from active birth defects surveillance programs in nine states. Abstracted medical records were reviewed by clinical geneticists to confirm and classify all birth defects and birth defect patterns. We estimated risks of stillbirth specific to birth defects among pregnancies overall and among those with isolated birth defects; potential bias owing to elective termination was quantified. RESULTS: Of 19,170 eligible neonates and fetuses with birth defects, 17,224 were liveborn, 852 stillborn, and 672 electively terminated. Overall, stillbirth risks ranged from 11 per 1,000 fetuses with bladder exstrophy (95% CI 0–57) to 490 per 1,000 fetuses with limb-body-wall complex (95% CI 368–623). Among those with isolated birth defects not affecting major vital organs, elevated risks (per 1,000 fetuses) were observed for cleft lip with cleft palate (10; 95% CI 7–15), transverse limb deficiencies (26; 95% CI 16–39), longitudinal limb deficiencies (11; 95% CI 3–28), and limb defects due to amniotic bands (110; 95% CI 68–171). Quantified bias analysis suggests that failure to account for terminations may lead to up to fourfold underestimation of the observed risks of stillbirth for sacral agenesis (13/1,000; 95% CI 2–47), isolated spina bifida (24/1,000; 95% CI 17–34), and holoprosencephaly (30/1,000; 95% CI 10–68). CONCLUSION: Birth defect-specific stillbirth risk was high compared with the U.S. stillbirth risk (6/1,000 fetuses), even for isolated cases of oral clefts and limb defects; elective termination may appreciably bias some estimates. These data can inform clinical care and counseling after prenatal diagnosis.

Background Studies from multiple countries have suggested impaired immunity in perinatally human immunodeficiency virus (HIV)–exposed uninfected children (HEU), with elevated rates of all-cause hospitalization and infections. We estimated and compared the incidence of all-cause hospitalization and infection-related hospitalization in the first 2 years of life among HEU and HIV-unexposed uninfected children (HUU) in the United States. Among HEU, we evaluated associations of maternal HIV disease–related factors during pregnancy with risk of child hospitalization. Methods HEU data from subjects enrolled in the Surveillance Monitoring for Antiretroviral Therapy Toxicities Study (SMARTT) cohort who were born during 2006–2017 were analyzed. HUU comparison data were obtained from the Medicaid Analytic Extract database, restricted to states participating in SMARTT. We compared rates of first hospitalization, total hospitalizations, first infection-related hospitalization, total infection-related hospitalizations, and mortality between HEU and HUU using Poisson regression. Among HEU, multivariable Poisson regression models were fitted to evaluate associations of maternal HIV factors with risk of hospitalization. Results A total of 2404 HEU and 3 605 864 HUU were included in the analysis. HEU children had approximately 2 times greater rates of first hospitalization, total hospitalizations, first infection-related hospitalization, and total infection-related hospitalizations compared with HUUs. There was no significant difference in mortality. Maternal HIV disease factors were not associated with the risk of child infection or hospitalization. Conclusions Compared with HUU, HEU children in the United States have higher rates of hospitalization and infection-related hospitalization in the first 2 years of life, consistent with studies in other countries. Closer monitoring of HEU infants for infection and further elucidation of immune mechanisms is needed.

Purpose The purpose of the study is to develop an algorithm to identify pregnancies in administrative databases and apply it to assess pregnancy rates and outcomes in women prescribed isotretinoin or tretinoin. Methods Using the 2011 to 2015 Truven Health MarketScan Database, we identified pregnancies, including losses and terminations. In a cohort design, nonpregnant women filling a prescription for isotretinoin or tretinoin were matched to five women without either prescription. Women were followed for 365 days or until conception, medication discontinuation, or enrollment discontinuation ("prescription episode"). Rates of pregnancy, risks of pregnancy losses, and prevalence of infant malformations at birth were assessed by exposure. Results We identified 2 179 192 livebirths, 8434 stillbirths, 2521 mixed births, 415 110 spontaneous abortions, 124 556 elective terminations, and 8974 unspecified abortions. There were 86 834 isotretinoin and 973 587 tretinoin episodes, matched to 5 302 105 unexposed women. Pregnancy rates were 3 (isotretinoin), 19 (tretinoin), and 34 (unexposed) per 1000 person-years. Risk of spontaneous pregnancy losses were similar; however, terminations were more common in the isotretinoin-exposed (28% [95% CI: 21%-36%]) than the tretinoin-exposed (10% [95% CI: 9%-11%]) or unexposed pregnancies (6%). Malformations occurred in 4.5% (95% CI: 3.5%-5.6%) of the tretinoin-exposed pregnancies and 4.2% of the unexposed pregnancies (adjusted odds ratio: 1.16 [95% CI: 0.85-1.58]); isotretinoin-exposed births were too few to assess malformations. Conclusions Administrative databases can complement risk evaluation and mitigation strategies (REMS) for known teratogens and contribute to safety surveillance for other medications. Here, isotretinoin-exposed pregnancy rates were low, but existent, and many pregnancies were terminated. Tretinoin exposure was not associated with a meaningfully elevated risk of losses or malformations as compared with unexposed pregnancies.

As technology improves and becomes more widely accessible, more subclinical congenital malformations are being detected. Using a cohort of 1,780,156 pregnant women and their offspring nested in the 2000–2013 US Medicaid Analytic eXtract, we contrasted time trends in malformations which do not necessarily present with overt clinical symptoms early in life and are more likely to be diagnosed via imaging (secundum atrial septal defect, patent ductus arteriosus, ventricular septal defect, pulmonary artery anomalies, pulmonary valve stenosis, hydrocephalus) with trends in malformations that are unlikely to escape clinical diagnosis (tetralogy of Fallot, coarctation of the aorta, transposition of the great vessels, hypoplastic left heart syndrome, oral cleft, abdominal wall defect). Logistic regression was used to account for trends in risk factors while assessing the impact of increased screening intensity. Prevalence of the diagnosis of secundum atrial septal defect rose from 2.3‰ in 2000–2001 to 7.5‰ in 2012–2013, of patent ductus arteriosus from 1.9‰ to 4.1‰, and of ventricular septal defect from 3.6‰ to 4.5‰. Trends were not explained by changes in the prevalence of risk factors but were attenuated when accounting for screening tests. The other malformations showed no temporal trends. Findings suggest that increased screening partially explains the observed increase in diagnosis of milder cases of select common malformations.

Background and Objectives: Although absolute risks provide useful information on the number of excess cases attributable to a harmful exposure or the number of fewer cases attributable to an effective treatment, most research findings are reported in terms of multiplicative effects of exposure on the outcome. We aimed to examine patient and physician preferences for communicating research findings in terms of additive and multiplicative measures of effect and measures of heterogeneity of treatment effects. Methods: We conducted a cross-sectional study of 76 patients and 26 physicians at an academic medical center in Boston, Massachusetts. Trained study staff conducted interviews about interpretations of study findings. Results: Physicians were equally likely to prefer the number needed to harm or the risk ratio as the most useful measure for making informed health decisions, and patients strongly preferred risk ratios. Participants perceived changes in risk as larger when they were presented using multiplicative measures such as risk ratios than when presented as additive measures such as the risk differences or number needed to treat or harm. Conclusions: Despite the importance of considering absolute risks and benefits of treatment options, patients and physicians who rely on study findings for making informed decisions often prefer relative measures.

Purpose Because preapproval clinical trials typically exclude pregnant women, the evidence on drug safety during pregnancy required to inform drug labeling must come from postapproval controlled observational studies. Common designs have included pregnancy registries and case-control studies. Recently, pregnancy cohorts nested within healthcare utilization databases are increasingly being used. Despite clear advantages, these databases share some important limitations that may threaten the validity of studies emerging from them. Methods This paper describes the distinctive methodological aspects of conducting drug safety studies in healthcare utilization databases with special emphasis on design and analytic approaches to minimize biases. Results We describe considerations for study design, cohort definition, and follow-up. We then address issues related to exposure ascertainment based on prescription fills, including the importance of the etiologically relevant window and of properly accounting for preterm births. This is followed by a discussion of advantages and challenges when ascertaining maternal and infant outcomes based on secondary data. We then explore useful approaches to address confounding within the context of pregnancy research and of the potential for selection bias when restricting the cohort to live births. Finally, we consider issues related to external validity and statistical significance. The examples are mainly drawn from a pregnancy cohort nested in the Medicaid Analytic Extract. Conclusions The approaches presented provide guidance regarding the important methodological considerations that need to be attended to in order to generate valid, minimally biased risk when using large healthcare utilization databases for drug safety surveillance in pregnancy.

Background Uncertain validity of epilepsy diagnoses within health insurance claims and other large datasets have hindered efforts to study and monitor care at the population level. Objectives To develop and validate prediction models using longitudinal Medicare administrative data to identify patients with actual epilepsy among those with the diagnosis. Research design, subjects, measures We used linked electronic health records and Medicare administrative data including claims to predict epilepsy status. A neurologist reviewed electronic health record data to assess epilepsy status in a stratified random sample of Medicare beneficiaries aged 65+ years between January 2012 and December 2014. We then reconstructed the full sample using inverse probability sampling weights. We developed prediction models using longitudinal Medicare data, then in a separate sample evaluated the predictive performance of each model, for example, area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity. Results Of 20,945 patients in the reconstructed sample, 2.1% had confirmed epilepsy. The best-performing prediction model to identify prevalent epilepsy required epilepsy diagnoses with multiple claims at least 60 days apart, and epilepsy-specific drug claims: AUROC=0.93 [95% confidence interval (CI), 0.90-0.96], and with an 80% diagnostic threshold, sensitivity=87.8% (95% CI, 80.4%-93.2%), specificity=98.4% (95% CI, 98.2%-98.5%). A similar model also performed well in predicting incident epilepsy (k=0.79; 95% CI, 0.66-0.92). Conclusions Prediction models using longitudinal Medicare data perform well in predicting incident and prevalent epilepsy status accurately.

Purpose The purpose of this study is to describe dispensing patterns and comparative safety of disease-modifying therapies (DMTs) during pregnancy in women with multiple sclerosis (MS). Methods We identified pregnancies from the Truven Health Marketscan® Commercial Claims and Encounters Database (2011-2015) and ascertained MS before delivery from inpatient and outpatient claims. We computed the proportion of women with DMT dispensing claims around pregnancy and estimated risk ratios of spontaneous abortion, infections, cesarean section, preterm delivery, poor fetal growth, preeclampsia, and major structural malformations by DMT exposure. Results Of 984 058 pregnancies, 1649 were to women with MS. Thirty-five percent of women with MS filled a prescription for a DMT in the 90 days before pregnancy. DMT use declined during pregnancy but increased again after delivery. Glatiramer acetate and interferon beta were most commonly dispensed. Pregnancies with and without early DMT exposure had similar risks of outcomes to one another and to pregnancies in women without MS. Small numbers did not allow evaluation of specific DMTs. Conclusions Approximately one third of commercially insured women with MS in the United States uses DMTs before conception. Neither MS itself nor early pregnancy use of DMTs overall seems to be associated with a substantial risk of adverse pregnancy outcomes.

Background: As mass vaccination campaigns against COVID-19 accelerate worldwide, there remains only limited evidence regarding vaccine effectiveness (VE) among pregnant women. Pregnant women have been shown to be at risk for severe COVID-19, resulting in adverse obstetrics outcomes, and their immune system is known to undergo alterations during pregnancy. Phase III clinical trials of the approved mRNA COVID-19 vaccines excluded pregnant women, yet current guidelines encourage offering the vaccine to pregnant women. In this study, we examine data from Israel’s largest healthcare organization to evaluate the effectiveness of the BNT162b2 mRNA vaccine among pregnant women. Methods: We conducted an observational cohort study of pregnant women 16 years or older, with no history of SARS-CoV-2, who were vaccinated between December 20, 2020 and June 3, 2021. Vaccinated subjects were matched to unvaccinated controls according to a set of demographic and clinical characteristics. Study outcomes included documented infection with SARS-CoV-2, symptomatic COVID-19, COVID-19-related hospitalization, severe illness and death. For each outcome, VE was estimated at several periods following vaccination as one minus the risk ratio using the Kaplan–Meier estimator. Results: 10,861 vaccinated women were matched to an identical number of unvaccinated controls. Estimated VE from 7 through 28 days after the second dose was 97% (95% CI 91%-100%) for any documented infection, 96% (86-100%) for infections with documented symptoms, and 85% (32%-100%) for COVID-19-related hospitalization. Only one event of severe illness was observed in the unvaccinated group, and no deaths were observed in either group -- insufficient incidence for estimating VE for these outcomes. Discussion: The BNT162b2 mRNA vaccine was found to have high VE among pregnant women. Since high VE has been reported as one of the strongest predictors of COVID-19 vaccine acceptance among pregnant women, the high VE estimates found in this study have the potential to increase vaccine acceptance in this group. In addition, the present VE estimates are similar to those reported in the general population for the same variants, suggesting that it may be possible to infer the VE for pregnant women from studies in the general population for both current and future variants.

Stress is a complex condition that can have a profound effect on an individual’s sense of wellbeing and their ability to live a happy and healthy life. COVID-19 and its associated stressors have the potential to disrupt numerous facets of our everyday lives. Pregnant and postpartum women are especially vulnerable to changes in the availability of routine health and social care services and of their support networks. The current study sought to explore stress levels and their influencers among an international cohort of pregnant and postpartum women during the COVID-19 pandemic. We conducted an anonymous, online, cross-sectional survey in 64 countries between May and June 2020. The survey was hosted on the Pregistry platform and made available in 12 languages, with respondents sought through a variety of social media platforms and parenting forums. In addition to levels of stress, we collected data related to demographics, COVID-19 exposure and worries, lifestyle changes, traditional and social media use, precautionary measures related to COVID-19, and mental health. In total, 7185 women were included in our sample. We found statistically significant (p-value

Opioids affect placental development and function in animal models, but human data on their association with ischemic placental disease are limited. Using a cohort of pregnant women in the US nationwide Medicaid Analytic eXtract (2000–2014), we compared women with ≥2 opioid dispensings in pregnancy with unexposed women. Given an uncertain etiologically relevant window, we assessed exposure occurring in early pregnancy, late and not early pregnancy, and both early and late pregnancy. For placental abruption, preterm delivery, small for gestational age (SGA), and preeclampsia, we estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) using Cox proportional hazard models adjusting for demographic factors, indications/comorbidities, and medications. Among 1,833,871 eligible pregnancies, ≥2 opioid dispensings were filled in 6.5%. We observed an early exposure aHR of 1.34 (95% CI: 1.26, 1.43) for placental abruption, 1.21 (95% CI: 1.18, 1.23) for preterm delivery, 1.13 (95% CI: 1.09, 1.17) for SGA, and 0.95 (0.91, 0.98) for preeclampsia. Estimates for late exposure were attenuated. Early and late exposure was associated with higher aHRs for placental abruption, 1.62 (95% CI: 1.47, 1.78); preterm delivery, 1.37 (95% CI: 1.33, 1.42); and SGA, 1.26 (95% CI: 1.19, 1.33); but not preeclampsia, 0.99 (95% CI: 0.93, 1.05). Prescription opioids may modestly increase risk of placental abruption, preterm birth and SGA, but they do not appear to be associated with preeclampsia.

Hydroxychloroquine is generally considered safe in pregnancy for the treatment of rheumatic conditions, but studies have been too small to evaluate teratogenicity. Quantifying the risk of congenital malformations associated with early pregnancy exposure to hydroxychloroquine is important in both the context of its ongoing use for rheumatological disorders and its potential future use for coronavirus disease 2019 prophylaxis, for which a number of clinical trials are ongoing despite initial trials for coronavirus disease 2019 treatment having been negative.The study objective was to evaluate the risk of major congenital malformations associated with exposure to hydroxychloroquine during the first trimester of pregnancy, the period of organogenesis.We performed a population-based cohort study nested in the Medicaid Analytic eXtract (MAX, 2000-2014) and IBM MarketScan Research Database (MarketScan, 2003-2015). The source cohort included 2045 hydroxychloroquine-exposed pregnancies and 3,198,589 pregnancies not exposed to hydroxychloroquine continuously enrolled in their respective insurance program for 3 months before the last menstrual period through at least 1 month after delivery; infants were enrolled for at least 3 months after birth. We compared the risk of congenital malformations in women using hydroxychloroquine during the first trimester of pregnancy with that of those not using hydroxychloroquine, restricting the cohort to women with rheumatic disorders and using propensity score matching to control for indication, demographics, medical comorbidities, and concomitant medications (1867 hydroxychloroquine-exposed pregnancies and 19,080 pregnancies not exposed to hydroxychloroquine). The outcomes considered included major congenital malformations diagnosed during the first 90 days after delivery and specific malformation types for which there were at least 5 exposed events: oral cleft, cardiac, respiratory, gastrointestinal, genital, urinary, musculoskeletal, and limb defects.Overall, 54.8 per 1000 infants exposed to hydroxychloroquine were born with a major congenital malformation versus 35.3 per 1000 unexposed infants, corresponding to an unadjusted relative risk of 1.51 (95% confidence interval, 1.27-1.81). Patient characteristics were balanced in the restricted, propensity score-matched cohort. The adjusted relative risk was 1.26 (95% confidence interval, 1.04-1.54); it was 1.33 (95% confidence interval, 1.08-1.65) for a daily dose of ≥400 mg and 0.95 (95% confidence interval, 0.60-1.50) for a daily dose of400 mg. Among the different malformation groups considered, more substantial increases in the risk of oral clefts, respiratory anomalies, and urinary defects were observed, although estimates were imprecise. No pattern of malformation was identified.Our findings suggest a small increase in the risk of malformations associated with first-trimester hydroxychloroquine use. For most patients with autoimmune rheumatic disorders, the benefits of treatment during pregnancy will likely outweigh this risk. If hydroxychloroquine were shown to be effective for coronavirus disease 2019 prophylaxis in ongoing trials, the risk of malformations would need to be balanced against such benefits.

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.

BackgroundPregnant and postpartum women face unique challenges during the COVID-19 pandemic that may put them at elevated risk of mental health problems. However, few large-scale and no cross-national studies have been conducted to date that investigate modifiable pandemic-related behavioral or cognitive factors that may influence mental health in this vulnerable group. This international study sought to identify and measure the associations between pandemic-related information seeking, worries, and prevention behaviors on perinatal mental health during the COVID-19 pandemic.Methods and FindingsAn anonymous, online, cross-sectional survey of pregnant and postpartum women was conducted in 64 countries between May 26 2020 and June 13 2020. The survey, available in twelve languages, was hosted on the Pregistry platform for COVID-19 studies (https://corona.pregistry.com), and advertised predominantly in social media channels and online parenting forums. Participants completed measures on demographic characteristics, COVID-19 exposure and worries, media exposure, COVID-19 prevention behaviors, and mental health symptoms including posttraumatic stress symptoms via the IES-6, anxiety/depression via the PHQ-4, and loneliness via the UCLA-3. Of the 6,894 participants, substantial proportions of women scored at or above the cut-offs for elevated posttraumatic stress (2,979 [43%]), anxiety/depression (2,138 [31%], and loneliness (3,691 [53%]). Information seeking from any source (e.g., social media, news, talking to others) five or more times per day was associated with more than twice the odds of elevated posttraumatic stress and anxiety/depression, in adjusted models. A large majority of women (86%) reported being somewhat or very worried about COVID-19. The most commonly reported worries were related to pregnancy and delivery, including family being unable to visit after delivery (59%), the baby contracting COVID-19 (59%), lack of a support person during delivery (55%), and COVID-19 causing changes to the delivery plan (41%). Greater worries related to children (i.e. inadequate childcare, their infection risk) and missing medical appointments were associated with significantly higher odds of posttraumatic stress, anxiety/depression and loneliness. Engaging in hygiene-related COVID-19 prevention behaviors (face mask-wearing, washing hands, disinfecting surfaces) were not related to mental health symptoms or loneliness.ConclusionsClinically significant posttraumatic stress, anxiety/depression, and loneliness are highly prevalent in pregnant and postpartum women across 64 countries during the COVID-19 pandemic. Excessive information seeking and worries related to children and medical care are associated with clinically significant symptoms, whereas engaging in hygiene-related preventive measures were not. In addition to screening and monitoring mental health symptoms, reinforcing healthy information seeking, addressing worries about access to medical care and the well-being of their children, and strategies to target loneliness (e.g., online support groups) should be part of intervention efforts for perinatal women. Public and mental health interventions need to explicitly address the impact of COVID-19 on both physical and mental health in perinatal women, as prevention of viral exposure itself does not mitigate the mental health impact of the pandemic.

We assessed the teratogenicity of tenofovir, a human immunodeficiency virus (HIV) drug similar to remdesivir that is currently being evaluated for the treatment of coronavirus disease 2019 (COVID-19). Using US Medicaid Analytic eXtract (MAX) claims data (2000–2014), we identified a population-based pregnancy cohort of women with HIV who filled at least 1 prescription for antiretroviral therapies (ART) during the first trimester. Women on tenofovir disoproxil fumarate (TDF) were compared with women receiving ART without TDF. Major malformations were identified by International Classification of Diseases, Ninth Revision, codes using validated algorithms. Relative risks and 95% confidence intervals were estimated using propensity score stratification to control for potential confounders. We incorporated the results into prior knowledge by conducting a systematic literature review and a meta-analysis. Major congenital malformations were diagnosed in 37 out of 866 (4.27%) infants exposed to TDF and 38 out of 1,020 (3.73%) infants exposed to ART other than TDF; the adjusted relative risk was 1.21 (95% confidence interval: 0.77, 1.90). Estimates for specific malformations were imprecise. The pooled relative risk from the meta-analysis with 6 prior studies was 0.88 (95% confidence interval: 0.75, 1.03). Based on evidence accumulated in patients with HIV, first-trimester TDF use does not increase the risk of major congenital malformations overall in the newborn compared with other ART.

Importance Congenital cytomegalovirus (cCMV) has received far less clinical and public health attention as a teratogenic infection than the Zika virus epidemic. However, cCMV may be responsible for a large fraction of microcephaly cases in the United States. Objective To evaluate the association between cCMV and the prevalence at birth of microcephaly in the United States. Design, Setting, and Participants This population-based cohort study included pregnant women and their newborns identified in 2 insurance claims databases from the United States: Medicaid Analytic eXtract (January 1, 2000, to December 31, 2013) and IBM Research MarketScan, a database for employer-sponsored private health insurance (January 1, 2011, to September 30, 2015). All pregnancies that resulted in live births in women with full health benefits were included. Analysis began June 2016 and ended May 2020. Exposures Congenital cytomegalovirus infection documented in inpatient or outpatient newborn claims records. Main Outcomes and Measures The primary outcome was microcephaly at birth documented in inpatient or outpatient newborn and/or maternal claims records. Cases with chromosomal abnormalities or neural tube defects were excluded. The association between cCMV and microcephaly was estimated in the pooled cohort using prevalence ratios (PRs) and 95% CIs. Results In the pooled cohort of 2 338 580 pregnancies (2 075 410 pregnancies [88.7%] were among women younger than 35 years), 336 infants (0.014%) had a cCMV diagnosis. The prevalence of microcephaly among newborns with and without a cCMV diagnosis was 655 and 2.8 per 10 000 live births, respectively (PR, 232; 95% CI, 154-350). After restricting to CMV-tested newborns (572 [0.024%]) to correct for preferential testing of infants with microcephaly, the PR was 15 (95% CI, 5.2-41). However, this PR is biased if other cCMV-related outcomes (eg, hearing loss) trigger testing because cCMV prevalence in tested infants, with ([46%]) or without microcephaly (22 of 559 [3.9%]), would overestimate that in the source population. Therefore, the prevalence of cCMV in overall infants with microcephaly (22 of 669 [3.2%]) was compared with that from an external unbiased sample of US infants screened at birth (449 of 100 332 [0.45%]) to estimate a PR of 7.4 (95% CI, 4.8-11.5) as a conservative lower bound. Conclusions and Relevance Congenital cytomegalovirus infection increases the prevalence of microcephaly at birth by at least 7-fold. Prevention of CMV infection during pregnancy might substantially reduce the number of newborns with microcephaly and other cCMV-related outcomes in the United States.

Importance Concerns exist that use of selective serotonin reuptake inhibitors (SSRIs) increases the risk of developing type 2 diabetes (T2D) in adults, but evidence in children and adolescents is limited. In the absence of a randomized clinical trial, evidence must be generated using real-world data. Objective To evaluate the safety of SSRI use in children and adolescents with respect to the associated risk of T2D. Design, Setting, and Participants This cohort study of patients aged 10 to 19 years with a diagnosis for an SSRI treatment indication was conducted within the nationwide Medicaid Analytic eXtract (MAX; January 1, 2000, to December 31, 2014) and the IBM MarketScan (January 1, 2003, to September 30, 2015) databases. Data were analyzed from November 1, 2018, to December 6, 2019. Exposures New users of an SSRI medication and comparator groups with no known metabolic adverse effects (no antidepressant exposure, bupropion hydrochloride exposure, or psychotherapy exposure). Within-class individual SSRI medications were compared with fluoxetine hydrochloride. Main Outcomes and Measures Incident T2D during follow-up. Intention-to-treat effects were estimated using Cox proportional hazards regression models, adjusting for confounding through propensity score stratification. As-treated effects to account for continuous treatment were estimated using inverse probability weighting and marginal structural models. Results A total of 1 582 914 patients were included in the analysis (58.3% female; mean [SD] age, 15.1 [2.3] years). The SSRI-treated group included 316 178 patients in the MAX database (publicly insured; mean [SD] age, 14.7 [2.1] years; 62.2% female) and 211 460 in the MarketScan database (privately insured; mean [SD] age, 15.8 [2.3] years; 63.9% female) with at least 2 SSRI prescriptions filled, followed up for a mean (SD) of 2.3 (2.0) and 2.2 (1.9) years, respectively. In publicly insured patients, initiation of SSRI treatment was associated with a 13% increased hazard of T2DM (intention-to-treat adjusted hazard ratio [aHR], 1.13; 95% CI, 1.04-1.22) compared with untreated patients. The association strengthened for continuous SSRI treatment (as-treated aHR, 1.33; 95% CI, 1.21-1.47), corresponding to 6.6 (95% CI, 4.2-10.4) additional cases of T2D per 10 000 patients treated for at least 2 years. Adjusted HRs were lower in privately insured patients (intention-to-treat aHR, 1.01 [95% CI, 0.84-1.23]; as-treated aHR, 1.10 [95% CI, 0.88-1.36]). Findings were similar when comparing SSRI treatment with psychotherapy (publicly insured as-treated aHR, 1.44 [95% CI, 1.25-1.65]; privately insured as-treated aHR, 1.21 [95% CI, 0.93-1.57]), whereas no increased risk was observed compared with bupropion treatment publicly insured as-treated aHR, 1.01 [95% CI, 0.79-1.29]; privately insured as-treated aHR, 0.87 [95% CI, 0.44-1.70]). For the within-class analysis, no medication had an increased hazard of T2D compared with fluoxetine. Conclusions and Relevance These findings suggest that children and adolescents initiating SSRI treatment may be at a small increased risk of developing T2D, particularly publicly insured patients. The magnitude of association was more modest than previously reported, and the absolute risk was small. The potential small risk should be viewed in relation to the efficacy of SSRIs for its major indications in young patients.

When studying the effect of a prenatal treatment on events in the offspring, failure to produce a live birth is a competing event for events in the offspring. A common approach to handle this competing event is reporting both the treatment-specific probabilities of live births and of the event of interest among live births. However, when the treatment affects the competing event, the latter probability cannot be interpreted as the causal effect among live births. Here we provide guidance for researchers interested in the effects of prenatal treatments on events in the offspring in the presence of the competing event “no live birth”. We review the total effect of treatment on a composite event and the total effect of treatment on the event of interest. These causal effects are helpful for decision making, but are agnostic about the pathways through which treatment affects the event of interest. Therefore, based on recent work, we also review three causal effects that explicitly consider the pathways through which treatment may affect the event of interest in the presence of competing events: the direct effect of treatment on the event of interest under an intervention to eliminate the competing event, the separable direct and indirect effects of treatment on the event of interest, and the effect of treatment in the principal stratum of those who would have had a live birth irrespective of treatment choice. As an illustrative example, we use a randomized trial of fertility treatments and risk of neonatal complications.

OBJECTIVES: The human papillomavirus (HPV) vaccine was recommended in 2006 for girls and in 2011 for boys. The Healthy People 2020 goal for 2-dose HPV vaccination coverage is 80% by age 15 for girls and boys. We used nationwide population-based data to describe trends in HPV vaccination in children. METHODS: We conducted a cohort study nested within the MarketScan health care database between January 2003 and December 2017. Children were followed from the year they turned 9 until HPV vaccination, insurance disenrollment, or the end of the year when they turned 17, whichever came first. We estimated the cumulative incidence of at least 1- and 2-dose HPV vaccination, stratified by birth year, sex, and state. In secondary analyses, we evaluated the association between state-level vaccination policies and HPV vaccination coverage. RESULTS: This study included 7 837 480 children and 19.8 million person-years. The proportion of 15-year-old girls and boys with at least a 1-dose HPV vaccination increased from 38% and 5% in 2011 to 57% and 51% in 2017, respectively; the proportion with at least a 2-dose vaccination went from 30% and 2% in 2011 to 46% and 39% in 2017, respectively. By 2017, 2-dose HPV vaccination coverage varied from 80% in Washington, District of Columbia, among girls to 15% in Mississippi among boys and was positively correlated with legislation for HPV vaccine education and pediatrician availability. CONCLUSIONS: Despite the increasing trends in uptake, HPV vaccine coverage among commercially insured children in the United States remains behind target levels, with substantial disparities by state.

AIM To describe the patterns of non-insulin antidiabetic medication use, initiation and adherence in the paediatric population. METHODS We conducted a descriptive study of non-insulin antidiabetic medication use in children and adolescents (aged 10-18 years) using real-world data from a nationwide US commercial claims database (January 2004-September 2019). Trends in the prevalence of non-insulin antidiabetic medication use overall and by class were evaluated. Among new users of non-insulin antidiabetic agents, medication adherence was examined using group-based trajectory models. RESULTS In a cohort of more than 1 million paediatric patients, the prevalence of any non-insulin antidiabetic medication use was 75.7 per 100 000 patients in 2004 and more than doubled to 162.0 per 100 000 in 2019. Biguanides (metformin) was by far the most widely used medication class. The use of newer classes was low (

ObjectiveTo examine the risk of congenital malformations associated with exposure to oral fluconazole at commonly used doses in the first trimester of pregnancy for the treatment of vulvovaginal candidiasis.DesignPopulation based cohort study.SettingA cohort of pregnancies publicly insured in the United States, with data from the nationwide Medicaid Analytic eXtract 2000-14.ParticipantsPregnancies of women enrolled in Medicaid from three or more months before the last menstrual period to one month after delivery, and infants enrolled for three or more months after birth.InterventionsUse of fluconazole and topical azoles was established by requiring one or more prescriptions during the first trimester of pregnancy.Main outcome measuresRisk of musculoskeletal malformations, conotruncal malformations, and oral clefts (primary outcomes), associated with exposure to oral fluconazole, diagnosed during the first 90 days after delivery, were examined.ResultsThe study cohort of 1 969 954 pregnancies included 37 650 (1.9%) pregnancies exposed to oral fluconazole and 82 090 (4.2%) pregnancies exposed to topical azoles during the first trimester. The risk of musculoskeletal malformations was 52.1 (95% confidence interval 44.8 to 59.3) per 10 000 pregnancies exposed to fluconazole versus 37.3 (33.1 to 41.4) per 10 000 pregnancies exposed to topical azoles. The risks of conotruncal malformations were 9.6 (6.4 to 12.7) versus 8.3 (6.3 to 10.3) per 10 000 pregnancies exposed to fluconazole and topical azoles, respectively; risks of oral clefts were 9.3 (6.2 to 12.4) versus 10.6 (8.4 to 12.8) per 10 000 pregnancies, respectively. The adjusted relative risk after fine stratification of the propensity score was 1.30 (1.09 to 1.56) for musculoskeletal malformations, 1.04 (0.70 to 1.55) for conotruncal malformations, and 0.91 (0.61 to 1.35) for oral clefts overall. Based on cumulative doses of fluconazole, the adjusted relative risks for musculoskeletal malformations, conotruncal malformations, and oral clefts overall were 1.29 (1.05 to 1.58), 1.12 (0.71 to 1.77), and 0.88 (0.55 to 1.40) for 150 mg of fluconazole; 1.24 (0.93 to 1.66), 0.61 (0.26 to 1.39), and 1.08 (0.58 to 2.04) for more than 150 mg up to 450 mg of fluconazole; and 1.98 (1.23 to 3.17), 2.30 (0.93 to 5.65), and 0.94 (0.23 to 3.82) for more than 450 mg of fluconazole, respectively.ConclusionsOral fluconazole use in the first trimester was not associated with oral clefts or conotruncal malformations, but an association with musculoskeletal malformations was found, corresponding to a small adjusted risk difference of about 12 incidents per 10 000 exposed pregnancies overall.

IntroductionWith increasing rates of opioid overdoses in the US, a surveillance tool to identify high-risk patients may help facilitate early intervention.ObjectiveTo develop an algorithm to predict overdose using routinely-collected healthcare databases.MethodsWithin a US commercial claims database (2011-2015), patients with ≥1 opioid prescription were identified. Patients were randomly allocated into the training (50%), validation (25%), or test set (25%). For each month of follow-up, pooled logistic regression was used to predict the odds of incident overdose in the next month based on patient history from the preceding 3-6 months (time-updated), using elastic net for variable selection. As secondary analyses, we explored whether using simpler models (few predictors, baseline only) or different analytic methods (random forest, traditional regression) influenced performance.ResultsWe identified 5,293,880 individuals prescribed opioids; 2,682 patients (0.05%) had an overdose during follow-up (mean: 17.1 months). On average, patients who overdosed were younger and had more diagnoses and prescriptions. The elastic net model achieved good performance (c-statistic 0.887, 95% CI 0.872-0.902; sensitivity 80.2, specificity 80.1, PPV 0.21, NPV 99.9 at optimal cutpoint). It outperformed simpler models based on few predictors (c-statistic 0.825, 95% CI 0.808-0.843) and baseline predictors only (c-statistic 0.806, 95% CI 0.787-0.26). Different analytic techniques did not substantially influence performance. In the final algorithm based on elastic net, the strongest predictors were age 18-25 years (OR: 2.21), prior suicide attempt (OR: 3.68), opioid dependence (OR: 3.14).ConclusionsWe demonstrate that sophisticated algorithms using healthcare databases can be predictive of overdose, creating opportunities for active monitoring and early intervention.

Objective To evaluate the risk of adverse maternal and infant outcomes following in utero exposure to duloxetine. Design Cohort study nested in the Medicaid Analytic eXtract for 2004-13. Setting Publicly insured pregnancies in the United States. Participants Pregnant women 18 to 55 years of age and their liveborn infants. Interventions Duloxetine exposure during the etiologically relevant time window, compared with no exposure to duloxetine, exposure to selective serotonin reuptake inhibitors, exposure to venlafaxine, and exposure to duloxetine before but not during pregnancy. Main outcome measures Congenital malformations overall, cardiac malformations, preterm birth, small for gestational age infant, pre-eclampsia, and postpartum hemorrhage. Results Cohort sizes ranged from 1.3 to 4.1 million, depending on the outcome. The number of women exposed to duloxetine varied by cohort and exposure contrast and was around 2500-3000 for early pregnancy exposure and 900-950 for late pregnancy exposure. The base risk per 1000 unexposed women was 36.6 (95% confidence interval 36.3 to 36.9) for congenital malformations overall, 13.7 (13.5 to 13.9) for cardiovascular malformations, 107.8 (107.3 to 108.3) for preterm birth, 20.4 (20.1 to 20.6) for small for gestational age infant, 33.6 (33.3 to 33.9) for pre-eclampsia, and 23.3 (23.1 to 23.4) for postpartum hemorrhage. After adjustment for measured potential confounding variables, all baseline characteristics were well balanced for all exposure contrasts. In propensity score adjusted analyses versus unexposed pregnancies, the relative risk was 1.11 (95% confidence interval 0.93 to 1.33) for congenital malformations overall and 1.29 (0.99 to 1.68) for cardiovascular malformations. For preterm birth, the relative risk was 1.01 (0.92 to 1.10) for early exposure and 1.19 (1.04 to 1.37) for late exposure. For small for gestational age infants the relative risks were 1.14 (0.92 to 1.41) and 1.20 (0.83 to 1.72) for early and late pregnancy exposure, respectively, and for pre-eclampsia they were 1.12 (0.96 to 1.31) and 1.04 (0.80 to 1.35). The relative risk for postpartum hemorrhage was 1.53 (1.08 to 2.18). Results from sensitivity analyses were generally consistent with the findings from the main analyses. Conclusions On the basis of the evidence available to date, duloxetine is unlikely to be a major teratogen but may be associated with an increased risk of postpartum hemorrhage and a small increased risk of cardiac malformations. While continuing to monitor the safety of duloxetine as data accumulate over time, these potential small increases in risk of relatively uncommon outcomes must be weighed against the benefits of treating depression and pain during pregnancy in a given patient. Trial registration EUPAS 15946.

OBJECTIVE: To describe the characteristics, treatment, and outcomes of pregnant women with opioid use disorder. METHODS: Women attending an obstetric and addiction recovery clinic in Boston from 2015 to 2016 were enrolled in a prospective cohort study and followed through delivery (N=113). Buprenorphine or methadone was initiated clinically. The Addiction Severity Index (ASI) was administered at enrollment. Prenatal and delivery data were systematically abstracted from medical charts. RESULTS: Most women in the cohort were non-Hispanic white (80.5%), with a mean age of 28 years. Few women were married (8.9%). Over half of the cohort had been incarcerated, 29.2% had current legal involvement, and 15.0% generally had unstable housing. A majority (70.8%) was infected with hepatitis C and histories of sexual (56.6%) and physical (65.5%) abuse were prevalent. Regular substance used included heroin (92.0%), injection heroin (83.2%), other opioids (69.0%), marijuana (73.5%), alcohol (56.6%), and cocaine (26.6%). Fifty-nine women (52.2%) were treated initially with prenatal buprenorphine and 54 (47.8%) with methadone; 49.6% also were taking concomitant psychotropic medications. Employment (0.766±0.289) and psychological (0.375±0.187) ASI scores were the highest, indicating the most severe problems in these areas. Opioid use–relapse did not differ by treatment (44.7% overall)Thirteen (22.5%) of 59 women treated with buprenorphine transitioned to methadone mainly because of positive opioid screens. Overall, 23.0% (N=26) of the cohort discontinued clinical care. The number of pregnancy losses was small (three therapeutic abortions, four miscarriages, one still birth), with an overall live-birth rate of 90.8% (95% CI: 82.7, 95.9). CONCLUSIONS: These data on the social circumstances, substance use, treatment, and treatment outcomes of pregnant women with opioid use disorder may help clinicians to understand and treat this clinically complex population.

Few studies have assessed the risk of adverse pregnancy outcomes in women with multiple sclerosis (MS). We used 2 large US administrative databases, the Truven Health MarketScan Database (2011–2015; Truven Health Analytics Inc., Ann Arbor, Michigan) and the Nationwide Inpatient Sample (2007–2011), to identify delivery cohorts. MS and pregnancy outcomes (infections, cesarean delivery, preterm delivery, poor fetal growth, preeclampsia, chorioamnionitis, postpartum hemorrhage, stillbirth, and infant malformations) were identified during pregnancy and at delivery. We calculated adjusted risk ratios according to MS status and relapse(s) in the year before delivery. Among over 5 million pregnancies, we identified 3,875 pregnancies in women with MS. Women with MS had an increased risk of infections during pregnancy (Truven Health: adjusted risk ratio (aRR) = 1.22, 95% confidence interval (CI): 1.16, 1.27) and preterm delivery (Truven Health: aRR = 1.19 (95% CI: 1.04, 1.35); Nationwide Inpatient Sample: aRR = 1.30 (95% CI: 1.16, 1.44)). The risks of other outcomes were similar for women with and without MS. In the Truven Health database, risk ratios for the pregnancy outcomes in women experiencing relapses versus those without relapses were between 0.9 and 1.4, and confidence intervals overlapped the null. Overall, women with MS had an increased risk of infections and preterm delivery; however, their risks for other adverse pregnancy outcomes were not elevated. Disease activity before delivery was not a strong predictor of outcomes.

ObjectiveTo examine the risk of postpartum hemorrhage (PPH) and neonatal bleeding complications associated with late-pregnancy exposure to anticonvulsant drugs (ACDs) that induce cytochrome P450 enzymes (ACDi) and alter the metabolism of vitamin K compared to other ACDs.MethodsWe used a population-based cohort study stemming from a nationwide sample of publicly insured pregnant women with a liveborn infant from the 2000 to 2010 Medicaid Analytic eXtract. ACDi (carbamazepine, phenobarbital, phenytoin, oxcarbazepine, topiramate) were compared to other ACDs dispensed during the last month of pregnancy. Relative risks (RRs) and 95% confidence intervals (CIs) of PPH and neonatal bleeding complications were estimated using generalized linear models with fine stratification on the propensity score to control for indication and other potential confounders.ResultsAmong 11,572 women with an ACD prescription overlapping delivery, 2.6% (135/5,109) in the ACDi group and 3.6% (231/6,463) in the other ACDs group had a diagnosis of PPH: unadjusted RR 0.74 (95% CI 0.60–0.91), adjusted RR 0.77 (95% CI 0.58–1.00). The prevalence of neonatal bleeding complications was 3.1% (157/5,109) in the ACDi group and 3.5% (229/6,463) in the other ACDs group: unadjusted RR 0.87 (95% CI 0.71–1.06), adjusted RR 0.83 (95% CI 0.64–1.08).ConclusionsEvidence from this large observational study suggests that use of ACDi near delivery does not increase the risk of bleeding complications compared to other ACDs in clinical settings where neonatal intramuscular or oral vitamin K administration is considered standard of care. These findings provide reassurance for clinicians and pregnant women successfully treated with ACDi.

INTRODUCTION: Use of paraben-containing medications has been shown to be associated with urinary paraben concentrations among couples undergoing fertility treatment, but it is unknown whether this association is also present among the general population. METHODS: A list of prescription medications of interest was developed based on their likelihood of containing parabens and the ability to identify users in the National Health and Nutrition Examination Survey (NHANES); alendronate, escitalopram oxalate, fluoxetine, and olanzapine were chosen. Participants reported whether they had used each medication in the past month. Linear regression models were used to compare model-based mean urinary concentrations of each paraben among users and non-users of these four medications. RESULTS: A total of 10,302 respondents were included in the analysis, 265 (2.6%) of whom had reported using a paraben-containing prescription medication in the previous month. Users of alendronate had mean concentrations of ethyl paraben that were approximately three-fold higher than non-users (p≥0.001 in unadjusted and adjusted models), which was likely due to three participants with very high concentrations. No other differences in paraben concentrations were found for any of the medications of interest (all p≥0.13). Compared to non-users, a significantly greater proportion of alendronate users had butyl and ethyl paraben concentrations above the 95(th) percentile (17.8% and 12.3%, respectively) compared to non-users (5.0% and 5.0%, respectively; both p≤0.01), despite ethyl paraben not being an expected ingredient in the brand name formulation of alendronate. CONCLUSION: Despite previous work showing that medications can be an important source of paraben exposure, there was no clear overall evidence of associations between the use of paraben-containing medications and increases in urinary paraben concentrations among participants in NHANES 2005-2012. These results highlight the difficulties inherent in proper assessment of exposures with short half-lives based on a single cross-sectional biologic sample.

Background To assess the extent to which multiple gestations mediate risk of pregnancy complications from fertility treatment and to address possible confounding by the underlying infertility. Methods From the nearly 1.8 million pregnancies recorded in the Swedish Medical Birth Register between 1996 and 2013, we selected the 9.9% (N = 174 067) that occurred to couples with known trouble conceiving (clinical infertility). Fertility treatment was identified from self-reports, medical records and procedural information from fertility clinics. We used logistic regression to estimate odds ratios (ORs) and their 95% confidence intervals (CIs), and decomposed the total effect into direct and mediated effects to estimate the proportion mediated by multiple gestations. Results Compared with pregnancies achieved without any assistance, those having received some treatment had higher odds of all studied complications except gestational diabetes. Associations with placenta previa (OR 2.17, 95% CI 1.95-2.40) and placental abruption (OR 1.77, 95% CI 1.54-2.03) were almost entirely independent of multiple gestations. In contrast, the majority of the associations with preterm birth (OR 1.69, 95% CI 1.62-1.77), caesarean delivery (RR 1.15, 95% CI 1.13-1.17) and pre-eclampsia (OR 1.17, 95% CI 1.11-1.22) were mediated by multiple gestations (87%, 62% and 91% of the effect mediated, respectively). Both direct and mediated pathways contributed to the remaining positive associations with chorioamnionitis, labour induction and postpartum haemorrhage. Results were similar when considering primi- and multi-parous women separately, and after restriction to assisted reproductive technologies only. Conclusion Multiple gestations are responsible for a large proportion of pregnancy complications associated with fertility treatment, suggesting that interventions to restrict the occurrence of multiples could reduce excess risk of pre-eclampsia, preterm birth and caesarean delivery after fertility treatment. However, the elevated risk of serious placental complications after fertility treatment appears to be largely independent of multiple gestations.