Prenatal exposure to benzodiazepine and z-hypnotics and fifth-grade scholastic skills - emulating target trials using data from the Norwegian Mother, Father and Child Cohort Study.

Evidence is limited regarding the effect of prenatal benzodiazepine and z-hypnotic exposure and long-term neurodevelopment in childhood. The objective of this study was to investigate the effects of initiating benzodiazepine or z-hypnotic treatment in early, mid and late pregnancy on fifth-grade numeracy and literacy scholastic skills in children, by emulating three target trials. The trials are identical except for the timing of enrollment and the number of eligible individuals. Eligibility to the trials required a history of anxiety and/or depression prior to pregnancy. We used data from the Norwegian Mother, Father and Child Cohort Study, linked to the Medical Birth Registry of Norway, to emulate the trials. We adjusted for baseline covariates that were available at time 0 for each trial by inverse probability of treatment weighting using the propensity score. The findings of this study did not show any effect of mothers' initiation of treatment with benzodiazepines or z-hypnotics in early, mid or late pregnancy on the children's 5th grade test scores in numeracy and literacy. The study results provide reassurance for patients in need of benzodiazepines and z-hypnotics during pregnancy; however, these findings need to be interpreted with caution due to low study power in some of the analyses.

Identification and characterization of migraine in pregnancy: A Norwegian registry-based cohort study.

BACKGROUND: Migraine is common in women of reproductive age. Migraine's episodic manifestation and acute and preventive pharmacological treatment options challenge studying drug safety for this condition during pregnancy. To improve such studies, we aimed to develop algorithms to identify and characterize migraines in electronic healthcare registries and to assess the level of care. METHODS: We linked four registries to detect pregnancies from 2009-2018 and used three algorithms for migraine identification: i) diagnostic codes, ii) triptans dispensed, and iii) a combination of both. We assessed migraine severity using dispensed drugs as proxies. ICD-10 diagnostic subcodes of migraine (G43) allowed the allocation of four subtypes: complicated and/or status migrainosus; with aura; without aura; other/unspecified. RESULTS: We included 535,089 pregnancies in 367,908 women with available one-year lookback. The prevalence of migraines identified was 2.9%-4.3% before, and 0.8%-1.5% during pregnancy, depending on algorithm used. Pregnant women with migraine were mostly managed in primary care. CONCLUSIONS: Primary care data in combination with drug dispensation records were instrumental for identification of migraine in electronic healthcare registries. Data from secondary care and drug dispensations allow better characterization of migraines. Jointly, these algorithms may contribute to improved perinatal pharmacoepidemiological studies in this population by addressing confounding by maternal migraine indication.

Impact of the early COVID-19 pandemic on adult mental health-related dispensed medications, hospitalizations and specialist outpatient visits in Norway and Sweden: Interrupted time series analysis.

AIMS: Norway and Sweden had different early pandemic responses that may have impacted mental health management. The aim was to assess the impact of the early COVID-19 pandemic on mental health-related care. METHODS: We used national registries in Norway and Sweden (1 January 2018-31 December 2020) to define 2 cohorts: (i) general adult population; and (ii) mental health adult population. Interrupted times series regression analyses evaluated step and slope changes compared to prepandemic levels for monthly rates of medications (antidepressants, antipsychotics, anxiolytics, hypnotics/sedatives, lithium, opioid analgesics, psychostimulants), hospitalizations (for anxiety, bipolar, depressive/mood, eating and schizophrenia/delusional disorders) and specialist outpatient visits. RESULTS: In Norway, immediate reductions occurred in the general population for medications (-12% antidepressants to -7% hypnotics/sedatives) except for antipsychotics; and hospitalizations (-33% anxiety disorders to -17% bipolar disorders). Increasing slope change occurred for all medications except psychostimulants (+1.1%/month hypnotics/sedatives to +1.7%/month antidepressants); and hospitalization for anxiety disorders (+5.5%/month), depressive/mood disorders (+1.7%/month) and schizophrenia/delusional disorders (+2%/month). In Sweden, immediate reductions occurred for antidepressants (-7%) and opioids (-10%) and depressive/mood disorder hospitalizations (-11%) only with increasing slope change in psychostimulant prescribing of (0.9%/month). In contrast to Norway, increasing slope changes occurred in specialist outpatient visits for depressive/mood disorders, eating disorders and schizophrenia/delusional disorders (+1.5, +1.9 and +2.3%/month, respectively). Similar changes occurred in the pre-existing mental health cohorts. CONCLUSION: Differences in early COVID-19 policy response may have contributed to differences in adult mental healthcare provision in Norway and Sweden.

A population pharmacokinetic model for sertraline in women during the perinatal period-A contribution from the ConcePTION project.

AIMS: Sertraline is frequently prescribed for mental health conditions in both pregnant and breastfeeding women. According to the limited available data, only small amounts of sertraline are transferred into human milk, yet with a large amount of unexplained interindividual variability. This study aimed to develop a population pharmacokinetic (popPK) model to describe the pharmacokinetics of sertraline during the perinatal period and explain interindividual variability. METHODS: Pregnant women treated with sertraline were enrolled in the multicenter prospective cohort SSRI-Breast Milk study. A popPK model for sertraline maternal plasma and breast milk concentrations was developed and allowed estimating the milk-to-plasma ratio (MPR). An additional fetal compartment allowed cord blood concentrations to be described. Several covariates were tested for significance. Ultimately, model-based simulations allowed infant drug exposure through placenta and breast milk under various conditions to be predicted. RESULTS: Thirty-eight women treated with sertraline were included in the study and provided 89 maternal plasma, 29 cord blood and 107 breast milk samples. Sertraline clearance was reduced by 42% in CYP2C19 poor metabolizers compared to other phenotypes. Doubling milk fat content increased the MPR by 95%. Simulations suggested a median daily infant dosage of 6.9 µg kg-1 after a 50 mg maternal daily dose, representing 0.95% of the weight-adjusted maternal dose. Median cord blood concentrations could range from 3.29 to 33.23 ng mL-1 after maternal daily doses between 25 and 150 mg. CONCLUSIONS: Infant exposure to sertraline, influenced by CYP2C19 phenotype and breast milk fat content, remains low, providing reassurance regarding the use of sertraline during pregnancy and breastfeeding.

Drug utilisation in children and adolescents before and after the start of the COVID-19 pandemic: Interrupted time-series analyses in three European countries.

BACKGROUND: The COVID-19 pandemic has affected children and adolescents in several ways, including worsened mental health, improvement of asthma, and increases in diabetes ketoacidosis. Less is known about how medication use in children and adolescents has been affected by the pandemic. OBJECTIVES: To explore how the COVID-19 pandemic affected drug utilisation in children and adolescents in Norway, Sweden, and Italy, by child age. METHODS: We conducted a longitudinal drug utilisation study among all children and adolescents (<18 years old) in Norway and Sweden and a nationwide paediatric database covering 3% of the paediatric population in Italy. We conducted an interrupted time-series analysis from January 2018 to December 2021, with March 2020 as the interruption point. Dispensing or prescription rates of antidepressants, anxiolytics, sleep medications, attention-deficit/hyperactivity disorder (ADHD) medications, insulin, and asthma medications were examined. RESULTS: The study population in January 2018 consisted of 3,455,521 children and adolescents (136,188 from Italy, 1,160,431 from Norway, and 2,158,902 from Sweden). For sleep medications and insulin, there were only minor changes in level or trend in some age groups after March 2020. For asthma medications, the pandemic was associated with an immediate decrease in dispensing in Norway and Sweden (range of change in level: -19.2 to -3.7 dispensings per 1000 person-months), and an increasing trend in all countries afterward (range of change in trend: 0.3-6.4 dispensings per 1000 person-months), especially for the youngest age groups. Among adolescents, the pandemic was associated with an increased trend for ADHD medications, antidepressants, and anxiolytics in Norway and Sweden, but not in Italy. CONCLUSIONS: The increasing trend of psychotropic medication dispensing, especially among adolescents after the start of the pandemic, is concerning and should be investigated further. Aside from a temporary effect on asthma medication dispensing, the pandemic did not greatly affect the dispensing of the medications investigated.

Neonatal outcomes after in utero exposure to antipsychotics: a systematic review and meta-analysis.

Adverse neonatal outcomes following in utero antipsychotic exposure remain unclear. This systematic review and meta-analysis aimed to investigate associations between in utero first- and second-generation antipsychotic exposure and various neonatal outcomes. The primary outcome was small for gestational age. Secondary outcomes included other birth weight-related measures, prematurity and neonatal outcomes. MEDLINE, EMBASE, CENTRAL, ICTRP, and ClinicalTrials.gov were searched for on 8th July 2023. Two reviewers independently selected studies reporting associations between exposure and neonatal outcomes (all designs were eligible, no language or time restriction) and extracted data. ROBINS-I was used for risk of bias assessment. Meta-analyses were performed. Measures of association were odds ratios and mean differences. Thirty-one observational studies were included. Regarding small for gestational age < 10th percentile, meta-analysis was only performed for second-generation antipsychotics and showed no evidence for an association (OR 1.31 [95%CI 0.83; 2.07]; I²=46%; phet=0.13, n = 4 studies). First-generation antipsychotics were associated with an increased risk of small for gestational age < 3rd percentile (OR 1.37 [95%CI 1.02; 1.83]; I²=60%; phet=0.04, n = 5) and a lower mean birthweight (MD -135 g [95%CI -203; -66]; I²=53%; phet=0.07, n = 5). Second-generation antipsychotics were associated with large for gestational age > 97th percentile (OR 1.56 [95%CI 1.31; 1.87]; I²=4%; phet=0.37, n = 4) and Apgar score < 7 (OR 1.64 [95%CI 1.09; 2.47]; I²=47%; phet=0.13, n = 4). Both types of antipsychotics were associated with increased risks of preterm birth and neonatal hospitalization. Despite potential confounding in the studies, this systematic review and meta-analysis showed that newborns of mothers using antipsychotics during pregnancy are potentially at risk of adverse neonatal outcomes. Data sources: MEDLINE, EMBASE, CENTRAL, ICTRP, ClinicalTrials.gov. Prospero Registration Number CRD42023401805.

COVID-19 and pregnancy: A European study on pre- and post-infection medication use.

PURPOSE: The COVID-19 pandemic has impacted medication needs and prescribing practices, including those affecting pregnant women. Our goal was to investigate patterns of medication use among pregnant women with COVID-19, focusing on variations by trimester of infection and location. METHODS: We conducted an observational study using six electronic healthcare databases from six European regions (Aragon/Spain; France; Norway; Tuscany, Italy; Valencia/Spain; and Wales/UK). The prevalence of primary care prescribing or dispensing was compared in the 30-day periods before and after a positive COVID-19 test or diagnosis. RESULTS: The study included 294,126 pregnant women, of whom 8943 (3.0%) tested positive for, or were diagnosed with, COVID-19 during their pregnancy. A significantly higher use of antithrombotic medications was observed particularly after COVID-19 infection in the second and third trimesters. The highest increase was observed in the Valencia region where use of antithrombotic medications in the third trimester increased from 3.8% before COVID-19 to 61.9% after the infection. Increases in other countries were lower; for example, in Norway, the prevalence of antithrombotic medication use changed from around 1-2% before to around 6% after COVID-19 in the third trimester. Smaller and less consistent increases were observed in the use of other drug classes, such as antimicrobials and systemic corticosteroids. CONCLUSION: Our findings highlight the substantial impact of COVID-19 on primary care medication use among pregnant women, with a marked increase in the use of antithrombotic medications post-COVID-19. These results underscore the need for further research to understand the broader implications of these patterns on maternal and neonatal/fetal health outcomes.

Detecting and Dating Early Non-live Pregnancy Outcomes: Generation of a Novel Pregnancy Algorithm From Norwegian Linked Health Registries.

PURPOSE: Pregnancies ending before gestational week 12 are common but not notified to the Medical Birth Registry of Norway. Our goal was to develop an algorithm that more completely detects and dates all possible pregnancy outcomes (i.e., miscarriages, elective terminations, ectopic pregnancies, molar pregnancies, stillbirths, and live births) by using diagnostic codes from primary and secondary care registries to complement information from the birth registry. METHODS: We used nationwide linked registry data between 2008 and 2018 in a hierarchical manner: We developed the UiO pregnancy algorithm to arrive at unique pregnancy outcomes, considering codes within 56 days as the same event. To estimate the gestational age of pregnancy outcomes identified in the primary and secondary care registries, we inferred the median gestational age of pregnancy markers (45 ICD-10 codes and 9 ICPC-2 codes) from pregnancies registered in the medical birth registry. When no pregnancy markers were available, we assigned outcome-specific gestational age estimates. The performance of the algorithm was assessed by blinded clinicians. RESULTS: Using only the medical birth registry, we identified 649 703 pregnancies, including 1369 (0.2%) miscarriages and 3058 (0.5%) elective terminations. With the new algorithm, we detected 859 449 pregnancies, including 642 712 live-births (74.8%), 112 257 miscarriages (13.1%), 94 664 elective terminations (11.0%), 6429 ectopic pregnancies (0.7%), 2564 stillbirths (0.3%), and 823 molar pregnancies (0.1%). The median gestational age was 10+1 weeks (IQR 10+0-12+2) for miscarriages and 8+0 weeks (IQR 8+0-9+6) for elective terminations. Gestational age could be inferred using pregnancy markers for 66.3% of miscarriages and 47.2% of elective terminations. CONCLUSION: The UiO pregnancy algorithm improved the detection and dating of early non-live pregnancy outcomes that would have gone unnoticed if relying solely on the medical birth registry information.

COVID-19-related medicine utilization study in pregnancy: The COVI-PREG cohort.

AIM: The objective of this study was to describe the use of COVID-19-related medicines during pregnancy and their evolution between the early/late periods of the pandemic. METHODS: Pregnant women who tested positive for SARS-CoV-2 from March 2020 to July 2021 were included using the COVI-PREG registry. Exposure to the following COVID-19-related medicines was recorded: antibiotics, antivirals, hydroxychloroquine, corticosteroids, anti-interleukin-6 and immunoglobulins. We described the prevalence of medicines used, by trimester of pregnancy, maternal COVID-19 severity level and early/late period of the pandemic (before and after 1 July 2020). FINDINGS: We included 1964 pregnant patients who tested positive for SARS-CoV-2. Overall, 10.4% (205/1964) received at least one COVID-19-related medicine including antibiotics (8.6%; 169/1694), corticosteroids (3.2%; 62/1964), antivirals (2.0%; 39/1964), hydroxychloroquine (1.4%; 27/1964) and anti-interleukin-6 (0.3%; 5/1964). The use of at least one COVID-19-related medicine was 3.1% (12/381) in asymptomatic individuals, 4.2% (52/1233) in outpatients, 19.7% (46/233) in inpatients without oxygen, 72.1% (44/61) in those requiring standard oxygen, 95.7% (22/23) in those requiring high flow oxygen, 96.2% (25/26) in patients who required intubation and 57.1% (4/7) among patients who died. The proportion who received medicines to treat COVID-19 was higher before than after July 2020 (16.7% vs. 7.7%). Antibiotics, antivirals and hydroxychloroquine had lower rates of use during the late period. CONCLUSION: Medicine use in pregnancy increased with disease severity. The trend towards increased use of corticosteroids seems to be aligned with changing guidelines. Evidence is still needed regarding the effectiveness and safety of COVID-19-related medicines in pregnancy.

Longitudinal Methods for Modeling Exposures in Pharmacoepidemiologic Studies in Pregnancy.

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.

Ondansetron use in nausea and vomiting during pregnancy: A descriptive analysis of prescription patterns and patient characteristics in UK general practice.

AIMS: The objective of this study was to describe ondansetron drug utilization patterns during pregnancy to treat nausea and vomiting in pregnancy (NVP). Moreover, we aimed to describe the maternal factors associated with NVP and antiemetic use. METHODS: The data consist of pregnancies with a live birth(s) within an IMRD-UK registered GP practice. Descriptive statistics were used to investigate patterns of ondansetron use in pregnancy and to describe maternal characteristics associated with NVP and antiemetic drug utilization. We differentiate first- from second-line use during pregnancy using antiemetic prescription pathways. RESULTS: The dataset included 733 633 recorded complete pregnancies from 2005 to 2019. NVP diagnosis and ondansetron prescription prevalence increased from 2.7% and 0.1% in 2005 to 4.8% and 2.5% in 2019 respectively. Over the period 2015-2019, the most common oral daily dosages were 4 mg/d (8.5%), 8 mg/d (37.1%), 12 mg/d (37.5%) and between 16 and 24 mg/d (16.9%). Prescription of ondansetron was initiated during the first trimester of pregnancy in 40% of the cases and was moderately used as a first-line therapy (2.8%), but preferred choice of second-line therapy. Women with mental health disorders, asthma and/or prescribed folic acid were more likely to experience NVP and use antiemetics in pregnancy than their counterparts. CONCLUSION: This study confirms that ondansetron is increasingly used off-label to treat NVP during pregnancy, also in the first trimester and before other prescription antiemetics have been prescribed. Several maternal comorbidities and folic acid use were more common among women experiencing NVP and using antiemetics, including ondansetron.

Incidence, antibiotic treatment and outcomes of lactational mastitis: Findings from The Norwegian Mother, Father and Child Cohort Study (MoBa).

BACKGROUND: Mastitis is a common and distressing maternal postpartum condition, but the relationship between mastitis timing and antibiotic treatment and breastfeeding outcomes and postnatal mental health is unclear. OBJECTIVES: To describe the incidence of mastitis and treatment with antibiotics in first 6 months postpartum, and to investigate the impact of mastitis timing and antibiotic treatment on breastfeeding practices and postnatal mental health. METHODS: This study is based on 79,985 mother-infant dyads in the Norwegian Mother, Father and Child Cohort Study (MoBa). Women were classified according to self-reported mastitis within first month ('early') or 1-6 months ('later') postpartum and antibiotic treatment. Breastfeeding outcomes included predominant or any breastfeeding and abrupt breastfeeding cessation until 6 months postpartum. Maternal mental health was assessed by self-report at 6 months postpartum. RESULTS: The incidence of mastitis was 18.8%, with 36.8% reporting treatment with antibiotics. Women reporting early mastitis were less likely to report predominant breastfeeding (adjustedd relative risk [aRR] 0.92, 95% confidence interval [CI] 0.86, 0.99) and any breastfeeding for 6 months (aRR 0.97, 95% CI 0.96, 0.98) than women who did not report mastitis, and more likely to report abrupt breastfeeding cessation (aRR 1.37, 95% CI 1.23, 1.53). Late-onset mastitis was not associated with poorer breastfeeding outcomes. Among women reporting mastitis, the risk of abrupt breastfeeding cessation was higher in those also reporting antibiotic use. Mastitis was associated with an increased risk of mental health problems postpartum which was highest among those reporting no antibiotic use (aRR 1.29, 95% CI 1.18, 1.41), in contrast to those also reporting antibiotic use (aRR 1.08, 95% CI 0.96, 1.22). CONCLUSIONS: Lactational mastitis and its associated treatment with antibiotics are common. Early (<1 month postpartum) mastitis appears to be a modest risk factor for suboptimal breastfeeding outcomes. In addition, mastitis is associated with poorer mental health.

Association between antidepressant use in pregnancy and gestational diabetes mellitus: Results from the Norwegian Mother, Father and Child Cohort Study.

PURPOSE: This study sought to determine the association between gestational diabetes mellitus (GDM) and antidepressant exposure during early-mid pregnancy, overall and according to antidepressant affinity to the histamine-1 (H1 ) receptor. METHODS: Data originate from the nation-wide, Norwegian Mother, Father and Child Cohort Study conducted in 1999-2008, linked to the national Medical Birth Registry. The study included 6647 pregnancies within women with depressive/anxiety disorders during and/or 6 months prior to pregnancy. Pregnancies exposed in early-mid gestation to antidepressants having low (group 1, n = 814) or high (group 2, n = 77) affinity to the H1 receptor were compared to non-medicated (n = 5756). We fit crude and weighted modified Poisson regression models using inverse probability of treatment weighting (IPTW). RESULTS: Overall, 84 (1.3%) of the pregnancies developed GDM. Relative to non-medicated pregnancies, the risk of GDM was slightly lower in antidepressant group 1 exposed (1.3% vs 1.1%), but more elevated in those exposed to group 2 antidepressants (3.9%). In the weighted analysis, there was no evidence for an association between antidepressant group 1 exposure in early-mid pregnancy and risk of GDM [relative risk (RR): 0.69, 95% confidence interval: 0.31-1.51]. CONCLUSIONS: Gestational use of antidepressants with low H1 receptor affinity, mainly SSRIs and SNRIs, does not pose a substantial risk of GDM in women with depressive/anxiety disorders in pregnancy, compared to no use.

Perinatal antidepressant use and breastfeeding outcomes: Findings from the Norwegian Mother, Father and Child Cohort Study.

INTRODUCTION: Antidepressant use is common in the perinatal period, but there are concerns that it can negatively impact on breastfeeding outcomes. The aim of this study was to examine the effects of perinatal antidepressant use on breastfeeding initiation and duration. MATERIAL AND METHODS: This was a retrospective analysis of 80 882 mother-infant dyads in the Norwegian Mother, Father and Child Cohort Study (MoBa). Women were first classified according to self-reported mental disorders and timing of antidepressant use before and/or after gestational week 28 (i.e., early-mid-gestation and/or late-gestation use). We subsequently classified women according to self-reported mental disorders and antidepressant use postpartum and whether antidepressants were continued from late gestation or were new/restarted. Breastfeeding outcomes included breastfeeding initiation as well as predominant or any breastfeeding and abrupt breastfeeding discontinuation until 6 months. RESULTS: Late-gestation antidepressant use was associated with a reduced likelihood of breastfeeding initiation (adjusted relative risk [aRR] 0.93; 95% confidence interval [CI] 0.90-0.97) but not predominant (aRR 0.96; 95% CI 0.67-1.39) or any (aRR 1.00; 95% CI 0.93-1.07) breastfeeding at 6 months compared with unexposed women with mental disorders. When examined according to postnatal antidepressant use, no differences in predominant (aRR 0.94; 95% CI 0.60-1.48) or any breastfeeding (aRR 0.99; 95% CI 0.91-1.07) at 6 months were evident among women who continued antidepressant use from late gestation into the postpartum period compared with unexposed women with mental disorders. In contrast, new/restarted antidepressant use postpartum was associated with a reduced likelihood of predominant (aRR 0.37; 95% CI 0.22-0.61) and any (aRR 0.49; 95% CI 0.42-0.56) breastfeeding at 6 months, as well as increased risk of abrupt breastfeeding discontinuation (aRR 2.64; 95% CI 2.07-3.37) compared with the unexposed women with mental disorders. CONCLUSIONS: A complex relation exists between depression, antidepressant use, and breastfeeding outcomes. Antidepressant use in late pregnancy was associated with a reduced likelihood of breastfeeding initiation but not breastfeeding duration or exclusivity. In contrast, initiating or restarting antidepressants postpartum was associated with poorer breastfeeding outcomes. Overall, women taking antidepressants and women with a mental disorder may benefit from additional education and support to improve breastfeeding rates and promote maternal and infant health and wellbeing.

Maternal Medication Use and Childhood Cancer in Offspring-Systematic Review and Considerations for Researchers.

Cancer is an important cause of childhood mortality, yet the etiology is largely unknown. A combination of pre- and postnatal factors is thought to be implicated, including maternal medication use. We aimed to provide: 1) a systematic review of peer-reviewed publications on associations between maternal medication use and childhood cancer, with a focus on study design and methodology; and 2) suggestions for how to increase transparency, limit potential biases, and improve comparability in studies on maternal medication use and childhood cancer. We conducted a systematic search in the PubMed, Embase, Scopus, Cochrane, and Web of Science databases to June 8, 2020. Altogether, 112 studies were identified. The reviewed studies were heterogeneous in study design, exposure, and outcome classification. In 21 studies (19%), the outcome was any childhood cancer. Of the 91 papers that reported on specific types of cancer, 62% did not report the cancer classification system. The most frequently investigated medication groups were sex hormones (46 studies, excluding fertility medications), and antiinfectives (37 studies). Suggestions for strengthening future pharmacoepidemiologic studies on maternal medication use and childhood cancer relate to choice of cancer classification system, exposure windows, and methods for identification of, and control for, potential confounders.

Management of cluster headache and other trigeminal autonomic cephalalgias in pregnancy and breastfeeding.

Many clinicians lack experience in managing trigeminal autonomic cephalalgias (TACs) in pregnancy and lactation. In addition to cluster headache, TACs include hemicrania continua, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing/autonomic symptoms (SUNCT/SUNA). Treating these rare, severe headache conditions often requires off-label drugs that have uncertain teratogenic potential. In the last few years, several new treatment options and safety documentation have emerged, but clinical guidelines are lacking. This narrative review aimed to provide an updated clinical guide and good clinical practice recommendations for the management of these debilitating headache disorders in pregnancy and lactation.

Antithyroid drug use during pregnancy and the risk of birth defects in offspring: systematic review and meta-analysis of observational studies with methodological considerations.

AIMS: Maternal antithyroid drug (ATD) use during pregnancy has been associated with an increased risk of birth defects in offspring. Uncertainty remains on the size of this risk and how it compares to untreated hyperthyroidism due to methodological limitations of previous studies. METHODS: Systematic review of MEDLINE and EMBASE identifying observational studies examining ATD use during pregnancy and risk of birth defects by 28 August 2020. Data were extracted on study characteristics, effect estimates and comparator groups. Adjusted effect estimates were pooled using a random-effects generic inverse variance method and absolute risk calculated. RESULTS: Seven cohort studies and 1 case-control study involving 6 212 322 pregnancies and 388 976 birth defects were identified reporting regression effect estimates. Compared to an unexposed population comparison, the association between ATD use during pregnancy and birth defects in offspring was: adjusted risk ratio (aRR) 1.16 95% confidence interval (CI) 1.08-1.25 for propylthiouracil (PTU); aRR 1.28 95%CI 1.06-1.54 for methimazole/carbimazole (MMI/CMZ); aRR 1.51, 95%CI 1.16-1.97 for both MMI/CMZ and PTU; and aRR 1.15 95%CI 1.02-1.29 for untreated hyperthyroidism. The excess risk of any and major birth defects per 1000, respectively, was: 10.2 and 1.3 for PTU; 17.8 and 2.3 for MMI/CMZ; 32.5 and 4.1 for both MMI/CMZ and PTU; and 9.6 and 1.2 for untreated hyperthyroidism. CONCLUSIONS: When appropriately analysed the risk of birth defects associated with ATD use in pregnancy is attenuated. Although still elevated, the risk of birth defects is smallest with PTU compared to MMI/CMZ and may be similar to that of untreated hyperthyroidism.

Prenatal exposure to non-steroidal anti-inflammatory drugs and risk of attention-deficit/hyperactivity disorder: A follow-up study in the Norwegian mother, father and child cohort.

PURPOSE: To estimate the association between Attention-Deficit/Hyperactivity Disorder (ADHD) in children in preschool and primary school, and prenatal exposure to non-steroidal anti-inflammatory drugs (NSAIDs) by timing and duration. METHODS: This study was based on the Norwegian Mother, Father and Child Cohort Study linked to the Medical Birth Registry of Norway, the Norwegian Patient Registry (NPR) and the Norwegian Prescription Database (NorPD). NSAID exposure was identified by maternal self-report in pregnancy. Child diagnosis of ADHD was obtained from NPR and NorPD. Symptoms of ADHD at age 5 years were measured using Conners' Parent Rating Scale-Revised, where higher scores correspond to more symptoms. To account for time-varying exposure and confounders, marginal structural models were fitted to estimate hazard ratios and mean difference in z-scores. RESULTS: The analyses on ADHD diagnosis and ADHD symptoms included 56 340 and 34 961 children respectively. Children exposed to NSAIDs prenatally had no increased risk of ADHD diagnosis (first trimester: HR 1.12, 95% CI 0.86;1.45, second trimester: HR 0.98, 95% CI 0.69;1.38, third trimester: HR 0.68, 95% CI 0.31; 1.46) or ADHD symptoms (first trimester: standardized mean difference 0.03, 95% CI -0.03;0.09, second trimester: standardized mean difference 0.03, 95% CI -0.04;0.11, third trimester: standardized mean difference 0.11, 95% CI -0.03; 0.25). There was no duration-response relationship for either outcome. CONCLUSION: Though non-differential misclassification of the exposure may have attenuated results, these findings are reassuring and suggest no substantially increased risk of ADHD diagnosis or symptoms in children prenatally exposed to NSAIDs, regardless of timing or duration.

Thyroid hormone replacement therapy in pregnancy and motor function, communication skills, and behavior of preschool children: The Norwegian Mother, Father, and Child Cohort Study.

PURPOSE: Limited research has focused on the association between prenatal thyroid hormone replacement therapy (THRT) and motor function, communication skills, and behavior in preschool children. Here, we estimated the association between THRT during pregnancy and the first trimester and these developmental outcomes. METHODS: This study was based on the Norwegian Mother, Father, and Child Cohort Study (MoBa) and other national registries. We included mother-child pairs exposed to THRT during pregnancy (n = 663), after delivery (n = 728), or unexposed (n = 28 040). Exposure to THRT was defined according to filled prescriptions. Child outcomes, presented as T-score differences, were parent-reported using the Ages and Stages Questionnaire, Strengths and Difficulties Questionnaire, and Child Behavior Checklist. RESULTS: Of 29 431 mother-child pairs, 2.3% were prenatally exposed to THRT. We found no difference between prenatally exposed and unexposed children in regards to gross motor function (ß: 0.17, 95% CI -1.19, 1.54), fine motor function (ß: -0.17, 95% CI -1.14, 0.80), communication (ß: -0.31, 95% CI -1.58, 0.96), externalizing (ß: -0.03, 95% CI -1.07, 1.01), internalizing (ß: 0.89, 95% CI -0.20, 1.97), or social behaviors (ß: -0.04, 95% CI -0.92, 0.84). Somatic complaints were higher in THRT-exposed children (ß: 0.98, 95% CI 0.08, 1.87), and children whose mothers were exposed after delivery had more sleep problems than unexposed children (ß: 0.99, 95% CI 0.24, 1.74). CONCLUSIONS: Children prenatally exposed to THRT have developmental outcomes as positive as unexposed children on motor function, communication, and behavior. The association with somatic complaints and sleep were not clinically relevant.

Mental health status of pregnant and breastfeeding women during the COVID-19 pandemic-A multinational cross-sectional study.

INTRODUCTION: Evidence on perinatal mental health during the coronavirus disease 2019 (COVID-19) pandemic and its potential determinants is limited. Therefore, this multinational study aimed to assess the mental health status of pregnant and breastfeeding women during the pandemic, and to explore potential associations between depressive symptoms, anxiety, and stress and women's sociodemographic, health, and reproductive characteristics. MATERIAL AND METHODS: A cross-sectional, web-based study was performed in Ireland, Norway, Switzerland, the Netherlands, and the UK between 16 June and 14 July 2020. Pregnant and breastfeeding women up to 3 months postpartum who were older than 18 years of age were eligible. The online, anonymous survey was promoted through social media and hospital websites. The Edinburgh Depression Scale (EDS), the Generalized Anxiety Disorder seven-item scale (GAD-7), and the Perceived Stress Scale (PSS) were used to assess mental health status. Regression model analysis was used to identify factors associated with poor mental health status. RESULTS: In total, 9041 women participated (including 3907 pregnant and 5134 breastfeeding women). The prevalence of major depressive symptoms (EDS ≥ 13) was 15% in the pregnancy cohort and and 13% the breastfeeding cohort. Moderate to severe generalized anxiety symptoms (GAD ≥ 10) were found among 11% and 10% of the pregnant and breastfeeding women. The mean (±SD) PSS scores for pregnant and breastfeeding women were 14.1 ± 6.6 and 13.7 ± 6.6, respectively. Risk factors associated with poor mental health included having a chronic mental illness, a chronic somatic illness in the postpartum period, smoking, having an unplanned pregnancy, professional status, and living in the UK or Ireland. CONCLUSIONS: This multinational study found high levels of depressive symptoms and generalized anxiety among pregnant and breastfeeding women during the COVID-19 outbreak. The study findings underline the importance of monitoring perinatal mental health during pandemics and other societal crises to safeguard maternal and infant mental health.