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Objective: This sequential, prospective meta-analysis sought to identify risk factors among pregnant and postpartum women with COVID-19 for adverse outcomes related to disease severity, maternal morbidities, neonatal mortality and morbidity, and adverse birth outcomes. Data sources: We prospectively invited study investigators to join the sequential, prospective meta-analysis via professional research networks beginning in March 2020. Study eligibility criteria: Eligible studies included those recruiting at least 25 consecutive cases of COVID-19 in pregnancy within a defined catchment area. Methods: We included individual patient data from 21 participating studies. Data quality was assessed, and harmonized variables for risk factors and outcomes were constructed. Duplicate cases were removed. Pooled estimates for the absolute and relative risk of adverse outcomes comparing those with and without each risk factor were generated using a 2-stage meta-analysis. Results: We collected data from 33 countries and territories, including 21,977 cases of SARS-CoV-2 infection in pregnancy or postpartum. We found that women with comorbidities (preexisting diabetes mellitus, hypertension, cardiovascular disease) vs those without were at higher risk for COVID-19 severity and adverse pregnancy outcomes (fetal death, preterm birth, low birthweight). Participants with COVID-19 and HIV were 1.74 times (95% confidence interval, 1.12-2.71) more likely to be admitted to the intensive care unit. Pregnant women who were underweight before pregnancy were at higher risk of intensive care unit admission (relative risk, 5.53; 95% confidence interval, 2.27-13.44), ventilation (relative risk, 9.36; 95% confidence interval, 3.87-22.63), and pregnancy-related death (relative risk, 14.10; 95% confidence interval, 2.83-70.36). Prepregnancy obesity was also a risk factor for severe COVID-19 outcomes including intensive care unit admission (relative risk, 1.81; 95% confidence interval, 1.26-2.60), ventilation (relative risk, 2.05; 95% confidence interval, 1.20-3.51), any critical care (relative risk, 1.89; 95% confidence interval, 1.28-2.77), and pneumonia (relative risk, 1.66; 95% confidence interval, 1.18-2.33). Anemic pregnant women with COVID-19 also had increased risk of intensive care unit admission (relative risk, 1.63; 95% confidence interval, 1.25-2.11) and death (relative risk, 2.36; 95% confidence interval, 1.15-4.81). Conclusion: We found that pregnant women with comorbidities including diabetes mellitus, hypertension, and cardiovascular disease were at increased risk for severe COVID-19-related outcomes, maternal morbidities, and adverse birth outcomes. We also identified several less commonly known risk factors, including HIV infection, prepregnancy underweight, and anemia. Although pregnant women are already considered a high-risk population, special priority for prevention and treatment should be given to pregnant women with these additional risk factors.

In many perinatal pharmacoepidemiologic studies, exposure to a medication is classified as “ever exposed” versus “never exposed” within each trimester or even over the entire pregnancy. This approach is often far from real-world exposure patterns, may lead to exposure misclassification, and does not to incorporate important aspects such as dosage, timing of exposure, and treatment duration. Alternative exposure modeling methods can better summarize complex, individual-level medication use trajectories or time-varying exposures from information on medication dosage, gestational timing of use, and frequency of use. We provide an overview of commonly used methods for more refined definitions of real-world exposure to medication use during pregnancy, focusing on the major strengths and limitations of the techniques, including the potential for method-specific biases. Unsupervised clustering methods, including k-means clustering, group-based trajectory models, and hierarchical cluster analysis, are of interest because they enable visual examination of medication use trajectories over time in pregnancy and complex individual-level exposures, as well as providing insight into comedication and drug-switching patterns. Analytical techniques for time-varying exposure methods, such as extended Cox models and Robins’ generalized methods, are useful tools when medication exposure is not static during pregnancy. We propose that where appropriate, combining unsupervised clustering techniques with causal modeling approaches may be a powerful approach to understanding medication safety in pregnancy, and this framework can also be applied in other areas of epidemiology.

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.

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.

Background: Mediation analysis requires strong assumptions of no unmeasured confounding. Sibling designs offer a method for controlling confounding shared within families, but no previous research has done mediation analysis using sibling models. Methods: We demonstrate the validity of the sibling mediation approach using simulation, and show its application using the example of prenatal antidepressant exposure and toddler anxiety and depression, with gestational age at birth as a mediator. We used data from the Norwegian Mother and Child Cohort Study, a cohort comprising 41% of births in Norway between 1999 and 2008 to identify 91,333 pregnancies, of which 25,776 were part of sibling groups. Results: In simulations, sibling models were less biased than cohort models in cases where non-shared confounding was weaker than shared confounding, and when stronger non-shared confounding was controlled, but more biased otherwise. In the full cohort, the estimated mean difference in depression/anxiety scale z-scores for natural direct effects (NDE) were 0.31 (95% confidence interval 0.23 to 0.39) and 0.14 (95% CI 0.03 to 0.24), without and with adjustment for non-shared confounders, respectively. The natural indirect effect was 0.01 (95% CI 0.00 to 0.02) after adjustment. Adjustment for shared and non-shared confounding showed similar point estimates with wider confidence intervals (NDE 0.18, 95% CI -0.21 to 0.47; NIE -0.01, 95% CI -0.06 to 0.06).Conclusions: Findings suggest that the modest association between prenatal antidepressant exposure and anxiety/depression is not mediated by gestational age and is likely explained by both shared confounders and non-shared confounders, and chance.

Objective To characterize nationwide utilization patterns of migraine pharmacotherapy before, during, and after pregnancy in women with triptan use. Methods Population-based data were obtained by linking the Medical Birth Registry of Norway and the Norwegian Prescription Database from 2006 to 2017. We included 22,940 pregnancies among 19,669 women with at least one filled triptan prescription, a proxy for migraine, in the year before pregnancy or during pregnancy. The population was classified into four groups: i) continuers; ii) discontinuers; iii) initiators, and vi) post-partum re-initiators. Participant characteristics and prescription fills for other drugs such as analgesics, antinauseants, and preventive drugs among the groups were examined, along with an array of triptan utilization parameters. Results In total, 20.0% of the women were classified as triptan continuers, 54.1% as discontinuers, 8.0% as initiators, and 17.6% as re-initiators. Extended use of triptans (≥15 daily drug doses/month) occurred among 6.9% of the continuers in the first trimester. The top 10% of triptan continuers and initiators accounted for 41% (95% CI: 39.2% - 42.5%) and 33% (95% CI: 30.3% - 35.8%) of the triptan volume, respectively. Triptan continuers and initiators had similar patterns of acute co-medication during pregnancy, but use of preventive drugs was more common among the continuers before, during, and after pregnancy. Conclusion Among women using triptans before and during pregnancy, one in four continued triptan treatment during pregnancy, and extended triptan use was relatively low. Triptan discontinuation during and in the year after pregnancy was common. Use of other acute migraine treatments was higher among both continuers and initiators of triptans. Women using preventive migraine treatment were most commonly triptan continuers and re-initiators after pregnancy. Prescribing to and counseling of women with migraine should be tailored to the condition severity and their information needs to promote optimal migraine management in pregnancy.

Background and aims Hazardous drinking (i.e. alcohol consumption that places drinkers at risk for adverse health outcomes) during pregnancy is associated with adverse child outcomes. To address whether the associations are causal, we aimed to estimate the effect of maternal hazardous drinking during the first trimester on offspring emotional and behavioural problems throughout the pre-school age. We adjusted for: (1) measured confounding (e.g. smoking), (2) familial risk factors by sibling control design and (3) non-shared environmental risk factors by using hazardous drinking the 3 months before pregnancy as an instrumental variable. Design Prospective cohort study. Participants were recruited between 1999 and 2009 at ultrasound examination offered to all pregnant women in Norway. Data were collected during the 17th and the 30th weeks of gestation, and when the children were aged 1.5, 3 and 5 years. Setting Norway, 1999-2015. Participants The sample consisted of 14 639 mothers with 25 744 offspring siblings from the Norwegian Mother and Child Cohort Study. Measurements Respondents self-reported on: alcohol consumption, children's emotional problems (i.e. emotional reactive, anxiety/depression, somatic complaints) and children's behavioural problems (i.e. attention and aggressive behaviour) throughout pre-school age. We used longitudinal latent growth curve models to estimate the effect of maternal drinking during the first trimester on offspring emotional and behavioural problems. Findings Most associations were strongly reduced after controlling for both familial and measured environmental risk factors. After adjustment, exposed children were more emotionally reactive [β = 2.33; 95% confidence interval (CI) = 0.13-4.53] and had more somatic complaints (β = 1.93; 95% CI = 0.09-3.77) at age 3, but not at age 5. Exposed children were less aggressive than unexposed siblings at age 5 (β = -2.27; 95% CI = -4.02 to -0.52). Conclusions Children exposed to their mothers' hazardous drinking during the first trimester appear to be more emotionally reactive and have more somatic complaints at age 3, but not at age 5, and are less aggressive at age 5 compared with unexposed siblings.

Purpose Father's medication use is of interest in fertility studies and as negative control exposures in pregnancy medication safety studies. We sought to compare self-report to prescription records to understand how reliably each of these sources of information may be used. Methods We compared self-reported medication use in the 6 months prior to pregnancy from fathers participating in the Norwegian Mother and Child Cohort Study to records of dispensed prescriptions from the Norwegian Prescription Database that overlapped in time. Medications from 3 main categories were assessed: prescription medications used chronically, prescription medications used episodically, and over-the-counter/prescription medications (predominantly obtained without prescription). We calculated agreement between self-report and dispensing records using Cohen's kappa statistic. Results We included 42 848 pregnancies with the father's prescription data available for the 9 months before pregnancy. Prescription medications used chronically including antiepileptics, antipsychotics, and antidepressants showed substantial agreement between self-report and prescription records: kappa statistics 0.87, 0.63, and 0.74, respectively. Prescription medications used episodically like anti-infectives, opioids, anxiolytics, and hypnotics and sedatives showed worse agreement: kappa 0.19, 0.32, 0.40, 0.32. Over-the-counter/prescription medications like paracetamol and nonsteroidal anti-inflammatory drugs had slight agreement: kappa 0.02 and 0.20. Conclusions There is good agreement between paternal self-report and prescription data for prescribed medications used chronically and substantially less for medications used episodically. Suboptimal agreement for episodic medications suggests poor recall (for questionnaires) or false positives due to noncompliance (prescription data). Not surprisingly, use of medications available both with and without a prescription is not well captured using prescription databases alone.

Despite FDA and EMA warnings of long-term use, little is known regarding the time to onset (TTO) of neurological adverse drug reactions (ADR) for metoclopramide. The aims of this study were, first, to evaluate whether neurological ADRs are more commonly reported for metoclopramide than for other medications, and second, to describe how time to onset of neurological ADRs differs by age and gender. All ADR reports with metoclopramide as the suspected/interacting drug were extracted from the WHOs Global ADR database Vigibase® between 1967 and May 2016. Cox proportional hazards models were fit using TTO of neurological ADRs as the outcome and age, gender, and type of ADR as predictors. Proportional Reporting Ratios (PRRs) for neurological ADRs were compared across age and gender. Lawyer reports were excluded in the analysis. Over 47,000 ADR reports with metoclopramide were identified. Over one third (35.6%) of the reports came from lawyers. The majority of ADRs in general and neurological ADRs in specific occurred within the first 5 days of metoclopramide use (median 1 day). TTO increased with age. Neurological ADRs were reported two to four times as frequently for metoclopramide than for other drugs, with the highest PRRs observed in children (PRR = 4.24 for girls and 4.60 for boys). Most adverse drug reactions occur within the first 5 days of treatment with metoclopramide. Patients requiring use of metoclopramide should be carefully monitored for neurological ADRs during the first days of treatment.

Purpose of Review Administrative claims databases, which collect reimbursement-related information generated from healthcare encounters, are increasingly used to evaluate medication safety in pregnancy. We reviewed the strengths and limitations of claims-only databases and how other data sources may be used to improve the accuracy and completeness of information critical for studying medication safety in pregnancy. Recent Findings Research on medication safety in pregnancy requires information on pregnancy episodes, mother-infant linkage, medication exposure, gestational age, maternal and birth outcomes, confounding factors, and (in some studies) long-term follow-up data. Claims data reliably identifies live births and possibly other pregnancies. It allows mother-infant linkage and has prospectively collected prescription medication information. Its diagnosis and procedure information allows estimation of gestational age. It captures maternal medical conditions but generally has incomplete data on reproductive and lifestyle factors. It has information on certain, typically short-term maternal and infant outcomes that may require chart review confirmation. Other data sources including electronic health records and birth registries can augment claims data or be analyzed alone. Interviews, surveys, or biological samples provide additional information. Nationwide and regional birth and pregnancy registries, such as those in several European and North American countries, generally contain more complete information essential for pregnancy research compared to claims-only databases. Summary Claims data offers several advantages in medication safety in pregnancy research. Its limitations can be partially addressed by linking it with other data sources or supplementing with primary data collection. Rigorous assessment of data quality and completeness is recommended regardless of data sources.

Background Women with unplanned pregnancies use folic acid less frequently, and more often use potentially teratogenic medications in the first trimester. Yet most studies based on routinely collected data lack information on pregnancy planning. Further, only pregnancies proceeding beyond a certain gestational age appear in routinely collected data, creating the possibility for collider-stratification bias. If pregnancy intention could be identified, pregnancies could be ascertained earlier. This study aimed to investigate fertility treatment and discontinuation of oral contraception (OC) as proxies for pregnancy planning by describing variations in patterns of prescription fills for antibiotics and analgesics during the peri-pregnancy period by these proxies of pregnancy intention. Methods Fertility treatment with clomiphene and discontinuation of OC were identified in the Norwegian Prescription Database (NorPD) and linked with data from the Medical Birth Registry of Norway for the years 2006 to 2017. Filled prescriptions for antibiotics and analgesics from NorPD were displayed for women on fertility treatment, women who discontinued OC before pregnancy, and women who discontinued during pregnancy. Results Of 172,585 included pregnancies, fertility treatment was identified in 19,449, and OC discontinuation before or during pregnancy in 153,136. Women who discontinued OC during pregnancy were less likely to use preconception folic acid (25.4%) than women who discontinued before pregnancy (32.9%), and women on fertility treatment (51.0%). Proportions of first trimester prescription fills were 4.9% (analgesics) and 12.8% (antibiotics) for women who discontinued OC during pregnancy, compared to 4.0 and 11.4% in women who discontinued OC before pregnancy, and 4.7 and 11.0% in women on fertility treatment. Conclusions There were no substantial differences in patterns of prescription fills for analgesics and antibiotics before or during pregnancy by fertility treatment and OC discontinuation. This suggests that there were few differences in medication use between women with planned and unplanned pregnancies, or that fertility treatment and timing of OC discontinuation from routinely collected health data cannot stand alone in the identification of unplanned pregnancies. A narrower definition of OC discontinuation during pregnancy seemed to be a better proxy, but this should be confirmed in other studies.

Purpose To assess the validity of dispensed prescription to classify exposure to medications used episodically during pregnancy, and to explore individual trajectories of episodic medication use across pregnancy, using triptans for migraine as the motivating example. Methods We compared self-reported triptan use during pregnancy in The Norwegian Mother, Father and Child Cohort Study (MoBa) to dispensed prescriptions in The Norwegian Prescription Database and calculated Cohen's kappa coefficient (κ), sensitivity, specificity and predictive values using MoBa as reference standard. We used group-based trajectory modeling to estimate exposure trajectories in MoBa according to probability of triptan use across pregnancy. Results We identified 6051 pregnancies where mothers filled at least one triptan prescription or reported migraine or triptan use in the 6 months before or during pregnancy. Sensitivity of prescribed triptans during pregnancy was low (39.1%), but specificity was quite high (95.4%). Agreement between the two data sources was fair (κ 0.36). We identified three trajectory groups in MoBa including constant-high, decreasing-medium and decreasing-low probability of triptan use across pregnancy. Conclusions Using dispensed prescriptions rather than self-report to classify exposure to triptans during pregnancy is likely to result in substantial under-estimation of exposure. In this study, traditional definitions of ever-exposed vs never-exposed failed to capture variations in drug utilization during pregnancy.

Purpose There is an increasing number of children with in utero exposure to opioids. Knowledge about opioid safety in pregnancy, particularly for outcomes later in childhood is scarce. It has been suggested that opioids can modulate immune system and increase the risk of infections. Our goal was to study the impact of in utero opioid exposure on the immune system and the risk of infections in childhood. Methods This population-based cohort study used nationwide registers from Denmark, Norway, and Sweden. Among pregnant women we identified users of opioids for two different indications, opioids used in opioid maintenance therapy (OMT) and opioids used for treatment of pain. We followed the exposed children and studied susceptibility for infections measured as number of antibiotic prescriptions expressed as Incidence rate ratios (IRRs) and diagnoses in specialist health care expressed as hazard ratios (HRs). Results After adjustment we did not observe increased risk for filling antibiotic prescriptions in children exposed to OMT opioids compared with OMT discontinuers (IRR, 1.08; 95% CI 0.81-1.44 in Norway and Sweden, and IRR, 0.74; 95% CI 0.63-0.88 in Denmark), or for diagnosis of infection in specialist health care (HR 0.83; 95% CI 0.55-1.26 in Norway and Sweden, and 0.82; 95% CI 0.62-1.10 in Denmark). Conclusions In this population-based cohort study, we did not observe increased risk of infections among children prenatally exposed to OMT opioids when compared to OMT discontinuers, nor long-term analgesic opioids exposed when compared to short-term analgesic opioids exposed.

Pharmacoepidemiological studies on the safety of medication during pregnancy are all susceptible to missing data (ie, data that should have been recorded but for some reason were not). Missing data are ubiquitous, irrespective of the data source used. Bias can arise when incomplete data on confounders, outcome measures, pregnancy duration, or even cohort selection criteria are used to estimate prenatal exposure effects that would be obtained from the fully observed data, if these were available for each mother–child dyad. This commentary describes general missing data mechanisms and methods, and illustrates how missing data were handled in recent medication in pregnancy research, according to the utilized data source. We further present one applied example on missing data analysis within MoBa (the Norwegian Mother, Father and Child Cohort Study), and finally illustrate how the causal diagram framework can be helpful in assessing risk of bias due to missing data in perinatal pharmacoepidemiology research. We recommend that applied researchers limit missing data during data collection, carefully diagnose missingness, apply strategies for missing data mitigation under different assumptions, and finally include evaluations of robustness results under these assumptions. Following this set of recommendations can aid future perinatal pharmacoepidemiology research in avoiding the problems that result from failure to consider this important source of bias.

Background Maternal antidepressant use in pregnancy has been associated with both shorter gestational length and child anxiety. We employed paternal antidepressant use as a negative-control exposure to indirectly assess whether confounding by genetic or shared familial environmental factors associated with depression may explain these associations. Methods The study sample came from the population-based Norwegian Mother and Child Cohort Study (MoBa) that recruited participants from 1999 to 2008. We included 70 959 families where the father completed a questionnaire about medication use in the 6 months prior to pregnancy. In 42 511 infants who completed the 3-year follow-up, we computed Z-scores for the anxiety domain of the Child Behavior Checklist. We used linear and logistic regression to assess the association between paternal antidepressant use, gestational age at birth and child anxiety. Results Antidepressants were used by 1.1% (n = 755) of fathers. Paternal antidepressant use was not associated with gestational age at birth [β = 0.63 days, 95% confidence interval (CI) –1.56, 0.31] whereas it was positively associated with a child anxiety symptom Z-score and high anxiety symptoms (odds ratio 1.33, 95% CI 0.90, 1.97) in unadjusted analyses. This association was attenuated when controlling for maternal and paternal history of depression and other measured factors (odds ratio 1.14, 95% CI 0.76, 1.69). Conclusions These results support the suggested effect of maternal use of antidepressants in pregnancy on shorter gestation; however, they suggest familial confounding could explain the association between maternal use of antidepressants and anxiety traits in the offspring.

Background Triptans are commonly prescribed for migraine, a pain condition that is highly prevalent in women of childbearing age. No prior studies have investigated associations between exposure to triptans during fetal life and risk of externalising and internalising behaviours in children. Methods This study was set in the Norwegian Mother and Child Cohort study, a prospective birth cohort. A total of 41 173 live, singleton births without major malformations present at 36-month post-partum follow-up were included in this study; 396 used a triptan during pregnancy, 798 used a triptan prior to pregnancy only, 3291 reported migraine without triptan use, and 36 688 reported no history of migraine or triptan use. Marginal structural models were used to analyse the association between timing of triptan exposure and neurodevelopmental outcome. Results Children exposed to triptans during pregnancy had a 1.39-fold increased risk of externalising behaviours compared with those whose mothers used triptans prior to pregnancy only (95% CI 0.97, 1.97), a 1.36-fold increased risk compared with the unmedicated migraine group (95% CI 1.02, 1.81), and a 1.41-fold increased risk compared with the population comparison group (95% CI 1.08, 1.85). The greatest risk was associated with first trimester exposure (RR 1.77, 95% CI 0.98, 3.14). Risk differences were small, ranging from 3–6%. Conclusions This study found an increased risk of clinically relevant externalising behaviours in children with prenatal exposure to triptans, and this risk was highest for first trimester exposure. Absolute risks were small, and the results may be due to confounding by underlying migraine severity.

Background Triptans are commonly used to treat migraine headaches, but data on the long-term safety of these medications during pregnancy are sparse. Triptans have a biologically plausible mechanism for effects on the fetal brain through binding to 5-HT1 -receptors, and previous studies show increased risks of externalising behaviour problems in toddlers exposed to triptans during pregnancy. Methods We included 3784 children in the Norwegian Mother and Child Cohort Study, whose mothers returned the 5-year-questionnaire and reported a history of migraine or triptan use; 353 (9.3%) mothers reported use of triptans during pregnancy, 1509 (39.9%) reported migraine during pregnancy but no triptan use, and 1922 (50.8%) had migraine prior to pregnancy only. We used linear and log-binomial models with inverse probability weights to examine the association between prenatal triptan exposure and internalising and externalising behaviour, communication, and temperament in 5-year-old children. Results Triptan-exposed children scored higher on the sociability trait than unexposed children of mothers with migraine (β 1.66, 95% confidence interval [0.30, 3.02]). We found no other differences in temperament, or increased risk of behaviour or communication problems. Conclusions Contrary to results from previous studies in younger children, we found no increased risk of externalising behaviour problems in 5-year-old children exposed to triptans in fetal life. Triptan-exposed children did have slightly more sociable temperaments, but the clinical meaning of this finding is uncertain.

Contains fulltext : 190453.pdf (Publisher’s version ) (Open Access) Understanding the safety of medication use during pregnancy relies on observational studies: However, confounding in observational studies poses a threat to the validity of estimates obtained from observational data. Newer methods, such as marginal structural models and propensity calibration, have emerged to deal with complex confounding problems, but these methods have seen limited uptake in the pregnancy medication literature. In this article, we provide an overview of newer advanced methods for confounding control and show how these methods are relevant for pregnancy medication safety studies.

PURPOSE: To investigate the ability of the propensity score to reduce confounding bias in the presence of nondifferential misclassification of treatment, using simulations. METHODS: Using an example from the pregnancy medication safety literature, we carried out simulations to quantify the effect of nondifferential misclassification of treatment under varying scenarios of sensitivity and specificity, exposure prevalence (10%, 50%), outcome type (continuous and binary), true outcome (null and increased risk), confounding direction, and different propensity score applications (matching, stratification, weighting, regression), and obtained measures of bias and 95% confidence interval coverage. RESULTS: All methods were subject to substantial bias towards the null due to nondifferential exposure misclassification (range: 0% to 47% for 50% exposure prevalence and 0% to 80% for 10% exposure prevalence), particularly if specificity was low (

Background Few studies have investigated the drug utilization patterns and factors predicting drug use in pregnant women with migraine. This longitudinal drug utilization study aimed to describe patterns of analgesic use in a sample of Norwegian pregnant women according to their migraine history, and to identify predictors for analgesic use among these women. Methods Pregnant women giving birth at Akershus University Hospital between 2008 and 2010 were recruited at ultrasound examination in gestational week 17. Data were collected by questionnaires in gestational weeks 17 and 32, and at 8 weeks postpartum, and linked to birth records. Women were grouped into four categories according to migraine history: no migraine history, previous migraine history, recent migraine history (within 1 year prior to pregnancy) and migraine in pregnancy. Patterns of use of analgesics were analyzed descriptively. Multivariable logistic regression was used to identify factors predicting analgesic use. Results Out of 1981 women, 5.0% reported having migraine in pregnancy, 13.2% had a recent history of migraine, 11.5% had a previous history of migraine, and 68.8% reported no history of migraine. Analgesic use declined during pregnancy. Many women switched from triptans and non-steroidal anti-inflammatory drugs to paracetamol, which constituted most of the analgesic use. Factors associated with analgesic use included recent migraine history (OR 1.6, 95% CI 1.2–2.2), more severe headache intensity (OR 1.3, 95% CI 1.3–1.4), smoking (OR 1.9, 95% CI 1.1–3.3) and multiparity (OR 1.4, 95% CI 1.1–1.7). Conclusions Women with migraine stop or switch medications during pregnancy. Analgesic use in pregnancy is affected by migraine characteristics and intensity, and also by socio-demographic factors. Clinicians should bear this in mind when giving advice on adequate management of migraine in pregnancy and safe analgesic use.

Objective This study sought to determine whether changes in neurodevelopmental outcomes between 18 and 36 months of age were associated with prenatal exposure to triptan medications, a class of 5-HT receptor agonists used in the treatment of migraine. Method Using data from the Norwegian Mother and Child Cohort Study, a prospective birth cohort that includes nearly 40% of all pregnancies in Norway from 1999 to 2008, we identified 50 469 mother–child dyads who met inclusion criteria and were present for at least one follow-up assessment at 18 or 36 months postpartum. Neurodevelopment was assessed using the Child Behaviour Checklist, the Emotionality, Activity, and Shyness Questionnaire, and the Ages and Stages Questionnaire. We used generalised estimating equations to evaluate change from 18 to 36 months for children prenatally exposed to triptans, relative to contrast groups, and used marginal structural models with inverse probability of treatment and censoring weights to address time-varying exposure and confounding as well as loss to follow-up. Results Among eligible participants (n=50 469), 1.0% used a triptan during pregnancy, 2.0% used triptans prior to pregnancy only, 8.0% reported migraine without triptan use and 89.0% had no history of migraine. Children with prenatal triptan exposure had greater increases in emotionality (r-RR 2.18, 95% CI 1.03 to 4.53) and activity problems (r-RR 1.70, 95% CI 1.02 to 2.8) compared to children born to mothers who discontinued triptan use prior to pregnancy. Conclusion Prenatal triptan exposure was associated with changes over time in externalising-type behaviours such as emotionality and activity, but not with internalising-type behaviours.

Background Previous studies showed that children exposed to paracetamol during fetal life might have an increased risk of neurodevelopmental problems. Since paracetamol is one of the most commonly used medications during pregnancy, even small increases in the risk of neurodevelopmental problems may have considerable implications for public health. Methods Using data from the Norwegian Mother and Child Cohort Study, we applied propensity score (PS) matching to examine associations between prenatal paracetamol exposure and neurodevelopmental problems among children at 18 months of age. Paracetamol use was classified into short-term (< 28 days) and long-term (≥ 28 days) of exposure. Results Of the 51 200 pregnancies included in our study, 40.5% of mothers ( n = 20 749) used paracetamol at least once during pregnancy. In the PS-matched analyses, long-term paracetamol exposure during pregnancy was associated with communication problems [odds ratio (OR): 1.38, 95% confidence interval (CI) 0.98-1.95) and delayed motor milestone attainment (OR: 1.35, 95% CI 1.07-1.70). We did not observe increased risks after short-term exposure. Sensitivity analyses for several indications showed similar effects as the PS-matched analyses, suggesting no confounding by indication. Conclusion Long-term exposure to paracetamol in utero was associated with modestly increased risks of motor milestone delay and impaired communication skills among children at 18 months. Caution is warranted when considering long-term use of paracetamol during pregnancy; however, women with severe pain conditions should not be deprived of appropriate pharmacotherapy.

Children need opportunities to have physical activity (PA). Using exergames could be a feasible and acceptable way to boost PA in middle schools. Our goal was to increase PA by 40 minutes per week and to determine how much time, if any, was spent in moderate-to-vigorous PA (MVPA).Eighty-four middle school youth were in a pilot study for 20 weeks: half in the Generation Fit (GenFit) intervention group and half in the control group. The GenFit group played the exergame for the first 10 weeks (Session 1), and the control group joined from 10 to 20 weeks (Session 2). The main outcome was exergaming time per student per week.Fifty-eight students completed the pilot after 26 youth at School C were excluded for administrative reasons. Of those remaining, 40 students at School A and 18 students at School B, the average age of the sample was 13.7 years (SD=0.6), and average body mass index percentile was close to 70. During Session 1, the average dance time per child was 49 minutes per week, versus 54 minutes per week in Session 2. Mean body mass index percentile decreased by 5.6 for children who participated in GenFit, compared with 0.2 for children in the control group. At end point, accelerometers showed over half of the dance time was spent in MVPA. Qualitative data showed that most children found the exergame acceptable.A dance exergame in middle schools offered opportunities for PA. About half of the exergame time was spent in MVPA. Exergames may be feasible and acceptable in middle schools to boost PA, and access could provide a way for schools to support the health of students.

The article “Administrative Claims Data Versus Augmented Pregnancy Data for the Study of Pharmaceutical Treatments in Pregnancy,” written by Susan E. Andrade, Anick Berard, Hedvig M.E. Nordeng, Mollie E. Wood, Marleen M.H.J. van Gelder, and Sengwee Toh, was originally published Online First without open access.

Objective To investigate the association between in utero exposure to antidepressants and risk of psychiatric disorders. Design Population based cohort study. Setting Danish national registers. Participants 905 383 liveborn singletons born during 1998-2012 in Denmark and followed from birth until July 2014, death, emigration, or date of first psychiatric diagnosis, whichever came first. The children were followed for a maximum of 16.5 years and contributed 8.1×106 person years at risk. Exposures for observational studies Children were categorised into four groups according to maternal antidepressant use within two years before and during pregnancy: unexposed, antidepressant discontinuation (use before but not during pregnancy), antidepressant continuation (use both before and during pregnancy), and new user (use only during pregnancy). Main outcome measure First psychiatric diagnosis in children, defined as first day of inpatient or outpatient treatment for psychiatric disorders. Hazard ratios of psychiatric disorders were estimated using Cox regression models. Results Overall, psychiatric disorders were diagnosed in 32 400 children. The adjusted 15 year cumulative incidence of psychiatric disorders was 8.0% (95% confidence interval 7.9% to 8.2%) in the unexposed group, 11.5% (10.3% to 12.9%) in the antidepressant discontinuation group, 13.6% (11.3% to 16.3%) in the continuation group, and 14.5% (10.5% to 19.8%) in the new user group. The antidepressant continuation group had an increased risk of psychiatric disorders (hazard ratio 1.27, 1.17 to 1.38), compared with the discontinuation group. Conclusions In utero exposure to antidepressants was associated with increased risk of psychiatric disorders. The association may be attributable to the severity of underlying maternal disorders in combination with antidepressant exposure in utero. The findings suggest that focusing solely on a single psychiatric disorder among offspring in studies of in utero antidepressant exposure may be too restrictive.