The risk of miscarriage after COVID-19 vaccination before and during pregnancy.

PURPOSE: Pregnant women are at higher risk of severe illness and adverse pregnancy outcomes due to a SARS-CoV-2 infection, which can be prevented by vaccination. Observational studies are needed to ascertain the safety of COVID-19 vaccination during pregnancy. We aimed to determine whether COVID-19 vaccination before and during pregnancy is associated with the risk of miscarriage. METHODS: In this cohort study, we included 4640 pregnant women (mean age: 32.8 ± 3.7 years) from the Dutch Pregnancy Drug Register between February 2021 and August 2022. Information on COVID-19 vaccinations, miscarriage, and confounders was self-reported, using web-based questionnaires. The hazard ratio (HR) of miscarriage (in gestational weeks 6-20) after a COVID-19 vaccination, was estimated using the survival analyses. A COVID-19 vaccination during pregnancy (≥1 COVID-19 vaccination between week 2 and 20 of pregnancy) was included as a time-dependent exposure and vaccination prior to pregnancy was included as a binary exposure. RESULTS: A total of 3202 pregnant women (69%) received ≥1 COVID-19 vaccine in gestational week 2-20. We observed no association of vaccination during pregnancy with the risk of miscarriage (adjusted HR = 1.29, 95% CI = 0.93-1.74). Vaccination prior to pregnancy, however, was associated with a decreased risk of miscarriage (adjusted HR = 0.69, 95% CI = 0.48-0.99). CONCLUSIONS: We demonstrated that COVID-19 vaccination during pregnancy is not associated with an increased risk of miscarriage in gestational weeks 6-20. This study adds to the growing body of evidence demonstrating the safety of COVID-19 vaccination during pregnancy.

Genetic and environmental factors driving congenital solitary functioning kidney.

BACKGROUND: Congenital solitary functioning kidney (CSFK) is an anomaly predisposing to hypertension, albuminuria and chronic kidney disease. Its aetiology is complex and includes genetic and environmental factors. The role of gene-environment interactions (G×E), although relevant for other congenital anomalies, has not yet been investigated. Therefore, we performed a genome-wide G×E analysis with six preselected environmental factors to explore the role of these interactions in the aetiology of CSFK. METHODS: In the AGORA (Aetiologic research into Genetic and Occupational/environmental Risk factors for Anomalies in children) data- and biobank, genome-wide single-nucleotide variant (SNV) data and questionnaire data on prenatal exposure to environmental risk factors were available for 381 CSFK patients and 598 healthy controls. Using a two-step strategy, we first selected independent significant SNVs associated with one of the six environmental risk factors. These SNVs were subsequently tested in G×E analyses using logistic regression models, with Bonferroni-corrected P-value thresholds based on the number of SNVs selected in step one. RESULTS: In step one, 7-40 SNVs were selected per environmental factor, of which only rs3098698 reached statistical significance (P = .0016, Bonferroni-corrected threshold 0.0045) for interaction in step two. The interaction between maternal overweight and this SNV, which results in lower expression of the Arylsulfatase B (ARSB) gene, could be explained by lower insulin receptor activity in children heterozygous for rs3098698. Eight other G×E interactions had a P-value <.05, of which two were biologically plausible and warrant further study. CONCLUSIONS: Interactions between genetic and environmental factors may contribute to the aetiology of CSFK. To better determine their role, large studies combining data on genetic and environmental risk factors are warranted.

Maternal depressive symptoms during pregnancy and infant wheezing up to 2 years of age.

PURPOSE: To determine whether maternal depressive symptoms at multiple time points during pregnancy are associated with infant wheezing in the first 2 years of life to assess etiologically relevant time windows. METHODS: We included Dutch women participating in the PRIDE Study with delivery in 2013-2019. Maternal depressive symptoms were assessed with the Hospital Anxiety and Depression Scale and Edinburgh Depression Scale at enrollment and in gestational weeks 17 and 34. The International Study of Asthma and Allergies in Childhood questionnaire was used to assess infant wheezing biannually postpartum. Adjusted risk ratios (RRs) and 95% confidence intervals (CIs) were estimated with modified Poisson regression. RESULTS: Among 5294 pregnancies included, maternal depressive symptoms in gestational weeks 15-22 was associated with any wheezing in the first 2 years of life (RR 1.36, 95% CI 1.04-1.78) and with current wheezing at 12 (RR 1.29, 95% CI 1.03-1.61) and 18 months (RR 1.33, 1.04-1.69). Depressive symptoms in gestational weeks 32-35 seemed to be associated with any wheezing reported at two years (RR 1.27, 95% CI 0.96-1.69) and current wheezing at 12 months (RR 1.28, 95% CI 1.02-1.60). Four trajectories of depressive symptoms were identified. Only the trajectory with increasing symptoms throughout pregnancy seemed to be associated with infant wheezing (RR 1.36, 95% CI 0.97-1.89). CONCLUSIONS: Maternal depressive symptoms in mid- and late pregnancy may be associated with development of infant wheezing, particularly those with onset in the second half of pregnancy. Research is needed to identify biological pathways and associations with more objective, long-term respiratory morbidity.

[Designing observational studies by target trial emulation]. / De hypothetische trial.

Ideally, causal research questions will be answered with randomized trials, but this is not always feasible for practical, ethical, or methodological reasons. To obtain a reliable answer to causal questions with observational data, target trial emulation has been introduced, in which an observational study is designed, conducted, and analyzed emulating the target trial. After phrasing a causal question, this framework first addresses seven components of the target trial protocol: eligibility criteria, treatment strategies, assignment procedures, follow-up period, outcome of interest, causal contrast of interest, and statistical analysis plan. Subsequently, these elements are emulated in the observational study. This approach addresses methodological pitfalls before initiating the study, draws more unambiguous conclusions, and provides a structured assessment of limitations of observational studies as well as randomized trials. The use of the target trial framework to support the design of observational studies is increasing.

Associations of periconceptional oral contraceptive use with pregnancy complications and adverse birth outcomes.

BACKGROUND: Periconceptional use of oral contraceptives (OCs) has been reported to increase risks of pregnancy complications and adverse birth outcomes, but risks are suggested to differ depending on the timing of discontinuation, amount of oestrogen and progestin content. METHODS: Prospective cohort study among 6470 pregnancies included in the PRegnancy and Infant DEvelopment (PRIDE) Study in 2012-19. Exposure was defined as any reported use of OCs within 12 months pre-pregnancy or after conception. Outcomes of interest were gestational diabetes, gestational hypertension, pre-eclampsia, pre-term birth, low birthweight and small for gestational age (SGA). Multivariable Poisson regression using stabilized inverse probability weighting estimated relative risks (RRs) with 95% CIs. RESULTS: Any periconceptional OC use was associated with increased risks of pre-eclampsia (RR 1.38, 95% CI 0.99-1.93), pre-term birth (RR 1.38, 95% CI 1.09-1.75) and low birthweight (RR 1.45, 95% CI 1.10-1.92), but not with gestational hypertension (RR 1.09, 95% CI 0.91-1.31), gestational diabetes (RR 1.02, 95% CI 0.77-1.36) and SGA (RR 0.96, 95% CI 0.75-1.21). Associations with pre-eclampsia were strongest for discontinuation 0-3 months pre-pregnancy, for OCs containing ≥30 µg oestrogen and for first- or second-generation OCs. Pre-term birth and low birthweight were more likely to occur when OCs were discontinued 0-3 months pre-pregnancy, when using OCs containing <30 µg oestrogen and when using third-generation OCs. Associations with SGA were observed for OCs containing <30 µg oestrogen and for third- or fourth-generation OCs. CONCLUSIONS: Periconceptional OC use, particularly those containing oestrogen, was associated with increased risks of pre-eclampsia, pre-term birth, low birthweight and SGA.

Adherence to prescription medication during pregnancy: Do pregnant women use pharmacological treatment as prescribed?

AIMS: Pregnant women are hypothesized to have low adherence to prescribed medication, because of concerns about harmful effects on the unborn child. However, very little is known about the actual adherence to prescribed medication during pregnancy. We determined to what extent women follow treatment recommendations regarding prescribed medication use in mid-pregnancy. METHODS: Dutch women participating in the PRIDE Study completed a 6-week diary on medication use. Additionally, pharmacy records were obtained. For each medication dispensed, we determined 3 measures of adherence: (i) whether use was reported in the diary (actual use); (ii) difference between dispensing date and date of first reported use (initiation time); and (iii) proportion of days with at least the correct number of doses taken (implementation adherence). RESULTS: During the 6-week study period, 235 of 816 women (29%) were dispensed medication. Actual use was highest for medications used for chronic conditions (88%; 95% confidence interval [95% CI] 81-93), followed by medication for pregnancy-related conditions (79%; 95% CI 71-86) and medication for occasional and short-time use (69%; 95% CI 60-77). We observed a ≥1-day delay in treatment initiation for 42% of medications dispensed for the first time in the study period. Mean implementation adherence was 74.2% (95% CI 69.3-79.2) for medications that were actually used. CONCLUSION: Although actual use of medications dispensed was high, many pregnant women did not adhere to treatment recommendations. This nonadherence may impact maternal and child health and lead to overestimation of medication use in studies in perinatal pharmacoepidemiology relying on administrative databases.

Associations Between Late-Onset Preeclampsia and the Use of Calcium-Based Antacids and Proton Pump Inhibitors During Pregnancy: A Prospective Cohort Study.

Purpose: Preeclampsia is a leading cause of maternal morbidity and mortality. Calcium-based antacids and proton pump inhibitors (PPIs) are commonly used during pregnancy to treat symptoms of gastroesophageal reflux disease. Both have been hypothesized to reduce the risk of preeclampsia. We determined associations of calcium-based antacid and PPI use during pregnancy with late-onset preeclampsia (≥34 weeks of gestation), taking into account dosage and timing of use. Patients and Methods: We included 9058 pregnant women participating in the PRIDE Study (2012-2019) or The Dutch Pregnancy Drug Register (2014-2019), two prospective cohorts in The Netherlands. Data were collected through web-based questionnaires and obstetric records. We estimated risk ratios (RRs) for late-onset preeclampsia for any use and trajectories of calcium-based antacid and PPI use before gestational day 238, and hazard ratios (HRs) for time-varying exposures after gestational day 237. Results: Late-onset preeclampsia was diagnosed in 2.6% of pregnancies. Any use of calcium-based antacids (RR 1.2 [95% CI 0.9-1.6]) or PPIs (RR 1.4 [95% CI 0.8-2.4]) before gestational day 238 was not associated with late-onset preeclampsia. Use of low-dose calcium-based antacids in gestational weeks 0-16 (<1 g/day; RR 1.8 [95% CI 1.1-2.9]) and any use of PPIs in gestational weeks 17-33 (RR 1.6 [95% CI 1.0-2.8]) seemed to increase risks of late-onset preeclampsia. We did not observe associations between late-onset preeclampsia and use of calcium-based antacids (HR 1.0 [95% CI 0.6-1.5]) and PPIs (HR 1.4 [95% CI 0.7-2.9]) after gestational day 237. Conclusion: In this prospective cohort study, use of calcium-based antacids and PPIs during pregnancy was not found to reduce the risk of late-onset preeclampsia.

Correction: Protocol of the Healthy Brain Study: An accessible resource for understanding the human brain and how it dynamically and individually operates in its bio-social context.

[This corrects the article DOI: 10.1371/journal.pone.0260952.].

Associations between maternal awakening salivary cortisol levels in mid-pregnancy and adverse birth outcomes.

PURPOSE: Elevated levels of maternal cortisol have been hypothesized as the intermediate process between symptoms of depression and psychosocial stress during pregnancy and adverse birth outcomes. Therefore, we examined associations between cortisol levels in the second trimester of pregnancy and risks of three common birth outcomes in a nested case-control study. METHODS: This study was embedded in the PRIDE Study (n = 3,019), from which we selected all cases with preterm birth (n = 64), low birth weight (n = 49), and small-for-gestational age (SGA; n = 65), and 260 randomly selected controls, among the participants who provided a single awakening saliva sample in approximately gestational week 19 in 2012-2016. Multivariable linear and logistic regression was performed to assess the associations between continuous and categorized cortisol levels and the selected outcomes. RESULTS: We did not observe any associations between maternal cortisol levels and preterm birth and low birth weight. However, high cortisol levels (≥ 90th percentile) seemed to be associated with SGA (adjusted odds ratio 2.1, 95% confidence interval 0.9-4.8), in particular among girls (adjusted odds ratio 3.7, 95% confidence interval 1.1-11.9, based on eight exposed cases) in an exploratory analysis. CONCLUSION: The results of this study showed no suggestions of associations between maternal awakening cortisol levels in mid-pregnancy and adverse birth outcomes, except for an increased risk of SGA.

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.

Protocol of the Healthy Brain Study: An accessible resource for understanding the human brain and how it dynamically and individually operates in its bio-social context.

The endeavor to understand the human brain has seen more progress in the last few decades than in the previous two millennia. Still, our understanding of how the human brain relates to behavior in the real world and how this link is modulated by biological, social, and environmental factors is limited. To address this, we designed the Healthy Brain Study (HBS), an interdisciplinary, longitudinal, cohort study based on multidimensional, dynamic assessments in both the laboratory and the real world. Here, we describe the rationale and design of the currently ongoing HBS. The HBS is examining a population-based sample of 1,000 healthy participants (age 30-39) who are thoroughly studied across an entire year. Data are collected through cognitive, affective, behavioral, and physiological testing, neuroimaging, bio-sampling, questionnaires, ecological momentary assessment, and real-world assessments using wearable devices. These data will become an accessible resource for the scientific community enabling the next step in understanding the human brain and how it dynamically and individually operates in its bio-social context. An access procedure to the collected data and bio-samples is in place and published on https://www.healthybrainstudy.nl/en/data-and-methods/access. Trail registration: https://www.trialregister.nl/trial/7955.

Associations Between Maternal Depression, Antidepressant Use During Pregnancy, and Adverse Pregnancy Outcomes: An Individual Participant Data Meta-analysis.

OBJECTIVE: To evaluate the associations of depressive symptoms and antidepressant use during pregnancy with the risks of preterm birth, low birth weight, small for gestational age (SGA), and low Apgar scores. DATA SOURCES: MEDLINE, EMBASE, ClinicalTrials.gov, and PsycINFO up to June 2016. METHODS OF STUDY SELECTION: Data were sought from studies examining associations of depression, depressive symptoms, or use of antidepressants during pregnancy with gestational age, birth weight, SGA, or Apgar scores. Authors shared the raw data of their studies for incorporation into this individual participant data meta-analysis. TABULATION, INTEGRATION, AND RESULTS: We performed one-stage random-effects meta-analyses to estimate odds ratios (ORs) with 95% CIs. The 215 eligible articles resulted in 402,375 women derived from 27 study databases. Increased risks were observed for preterm birth among women with a clinical diagnosis of depression during pregnancy irrespective of antidepressant use (OR 1.6, 95% CI 1.2-2.1) and among women with depression who did not use antidepressants (OR 2.2, 95% CI 1.7-3.0), as well as for low Apgar scores in the former (OR 1.5, 95% CI 1.3-1.7), but not the latter group. Selective serotonin reuptake inhibitor (SSRI) use was associated with preterm birth among women who used antidepressants with or without restriction to women with depressive symptoms or a diagnosis of depression (OR 1.6, 95% CI 1.0-2.5 and OR 1.9, 95% CI 1.2-2.8, respectively), as well as with low Apgar scores among women in the latter group (OR 1.7, 95% CI 1.1-2.8). CONCLUSION: Depressive symptoms or a clinical diagnosis of depression during pregnancy are associated with preterm birth and low Apgar scores, even without exposure to antidepressants. However, SSRIs may be independently associated with preterm birth and low Apgar scores. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42016035711.

Prior use of therapeutic anticoagulation does not protect against COVID-19 related clinical outcomes in hospitalized patients: A propensity score-matched cohort study.

The hypercoagulable state observed in COVID-19 could be responsible for morbidity and mortality. In this retrospective study we investigated whether therapeutic anticoagulation prior to infection has a beneficial effect in hospitalized COVID-19 patients. This study included 1154 COVID-19 patients admitted to 6 hospitals in the Netherlands between March and May 2020. We applied 1:3 propensity score matching to evaluate the association between prior therapeutic anticoagulation use and clinical outcome, with in hospital mortality as primary endpoint. In total, 190 (16%) patients used therapeutic anticoagulation prior to admission. In the propensity score matched analyses, we observed no associations between prior use of therapeutic anticoagulation and overall mortality (risk ratio 1.02 [95% confidence interval; 0.80-1.30]) or length of hospital stay (7.0 [4-12] vs. 7.0 [4-12] days, P = .69), although we observed a lower risk of pulmonary embolism (0.19 [0.05-0.80]). This study shows that prior use of therapeutic anticoagulation is not associated with improved clinical outcome in hospitalized COVID-19 patients.

Questionnaires and salivary cortisol to measure stress and depression in mid-pregnancy.

The hypothalamic-pituitary-adrenal axis, with cortisol as its final metabolite, has been proposed as a potential underlying biological mechanism for associations between depression and stress symptoms during pregnancy and adverse perinatal outcomes. In this study, we explored associations between salivary cortisol as a potential biomarker for stress and depressive symptoms and several self-completed psychological measurement scales among pregnant women. In total, 652 pregnant women participating in the PRegnancy and Infant DEvelopment (PRIDE) Study completed the Edinburgh Depression Scale (EDS), Patient Health Questionnaire-2 (PHQ-2), Pregnancy-Related Anxiety Questionnaire-Revised (PRAQ-R), and Tilburg Pregnancy Distress Scale (TPDS) and collected a single awakening salivary cortisol sample around gestational week 17. Odds ratios, Spearman's correlation coefficients (ρs) and Cohen's Kappa coefficients (κ) were calculated to examine the associations between the EDS, PHQ-2, PRAQ-R, TPDS, and maternal cortisol levels. The overall correlation coefficient between the score on the EDS and the salivary cortisol level was 0.01 (p = 0.89) with κ = -0.01 (95% confidence interval [CI] -0.08-0.06). We did not observe agreement between the PHQ-2 and cortisol levels either (κ = 0.06 (95% CI -0.02-0.14)). The results for the PRAQ-R and TPDS were similar with overall correlations with maternal cortisol levels of ρs = 0.01 (p = 0.81) and ρs = 0.06 (p = 0.35) and agreements of κ = 0.02 (95% CI -0.06-0.09) and κ = -0.02 (95% CI -0.11-0.07), respectively. Maternal awakening salivary cortisol levels and measures of maternal psychological distress, anxiety, depressive symptoms, and pregnancy-related anxiety, assessed by self-completed questionnaires, did not seem to be related in mid-pregnancy.

Antiemetic Prescription Fills in Pregnancy: A Drug Utilization Study Among 762,437 Pregnancies in Norway.

OBJECTIVE: To determine antiemetic prescription fill patterns during pregnancy in Norway, with special focus on the use of ondansetron and recurrent use in subsequent pregnancies. METHODS: We conducted a population-based registry study based on data from the Medical Birth Registry of Norway linked to the Norwegian Prescription Database for 762,437 pregnancies >12 gestational weeks ending in live or non-live births between 2005 and 2017. Prescription fills of medications used for nausea and vomiting of pregnancy were summarized in treatment pathways to determine drug utilization patterns. Logistic regression analyses were used to estimate associations between maternal and pregnancy characteristics and antiemetic prescription fills. RESULTS: The prescription fill rate for antiemetic medication during pregnancy was 7.6%. However, prescription fill rates were 35.5% in the second pregnancy after filling an antiemetic prescription in the first pregnancy and 53.5% for women who filled antiemetic prescriptions in the previous 2 pregnancies. Among pregnancies with antiemetic prescription fills, 62.2% were dispensed metoclopramide, 28.2% meclizine, and 17.2% promethazine. First-line treatment started with monotherapy in 97.4% of these pregnancies, which was the only treatment received in 78.7%. Prescriptions for ondansetron were filled in 0.3% of pregnancies, with 76.9% being initially filled in the first trimester. Ondansetron as first-line prescription medication and/or use in the first trimester was associated with proxies for more severe nausea and vomiting of pregnancy, including a diagnosis of hyperemesis gravidarum, multiple gestations, a higher obstetric comorbidity index, and concomitant use of medication for gastroesophageal reflux disease and nervous system medications. Women who filled an antiemetic prescription in their first pregnancy were less likely to have subsequent pregnancies than women who did not fill an antiemetic prescription in their first pregnancy (OR 0.93, 95% CI 0.90-0.96). CONCLUSION: Complex patterns of antiemetic prescription fills in pregnancy may mirror the challenge of optimal management of nausea and vomiting of pregnancy in clinical practice, especially for women with severe symptoms.

Changes in parental smoking during pregnancy and risks of adverse birth outcomes and childhood overweight in Europe and North America: An individual participant data meta-analysis of 229,000 singleton births.

BACKGROUND: Fetal smoke exposure is a common and key avoidable risk factor for birth complications and seems to influence later risk of overweight. It is unclear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy, or when only fathers smoke. We aimed to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight. METHODS AND FINDINGS: We performed an individual participant data meta-analysis among 229,158 families from 28 pregnancy/birth cohorts from Europe and North America. All 28 cohorts had information on maternal smoking, and 16 also had information on paternal smoking. In total, 22 cohorts were population-based, with birth years ranging from 1991 to 2015. The mothers' median age was 30.0 years, and most mothers were medium or highly educated. We used multilevel binary logistic regression models adjusted for maternal and paternal sociodemographic and lifestyle-related characteristics. Compared with nonsmoking mothers, maternal first trimester smoking only was not associated with adverse birth outcomes but was associated with a higher risk of childhood overweight (odds ratio [OR] 1.17 [95% CI 1.02-1.35], P value = 0.030). Children from mothers who continued smoking during pregnancy had higher risks of preterm birth (OR 1.08 [95% CI 1.02-1.15], P value = 0.012), small size for gestational age (OR 2.15 [95% CI 2.07-2.23], P value < 0.001), and childhood overweight (OR 1.42 [95% CI 1.35-1.48], P value < 0.001). Mothers who reduced the number of cigarettes between the first and third trimester, without quitting, still had a higher risk of small size for gestational age. However, the corresponding risk estimates were smaller than for women who continued the same amount of cigarettes throughout pregnancy (OR 1.89 [95% CI 1.52-2.34] instead of OR 2.20 [95% CI 2.02-2.42] when reducing from 5-9 to ≤4 cigarettes/day; OR 2.79 [95% CI 2.39-3.25] and OR 1.93 [95% CI 1.46-2.57] instead of OR 2.95 [95% CI 2.75-3.15] when reducing from ≥10 to 5-9 and ≤4 cigarettes/day, respectively [P values < 0.001]). Reducing the number of cigarettes during pregnancy did not affect the risks of preterm birth and childhood overweight. Among nonsmoking mothers, paternal smoking was associated with childhood overweight (OR 1.21 [95% CI 1.16-1.27], P value < 0.001) but not with adverse birth outcomes. Limitations of this study include the self-report of parental smoking information and the possibility of residual confounding. As this study only included participants from Europe and North America, results need to be carefully interpreted regarding other populations. CONCLUSIONS: We observed that as compared to nonsmoking during pregnancy, quitting smoking in the first trimester is associated with the same risk of preterm birth and small size for gestational age, but with a higher risk of childhood overweight. Reducing the number of cigarettes, without quitting, has limited beneficial effects. Paternal smoking seems to be associated, independently of maternal smoking, with the risk of childhood overweight. Population strategies should focus on parental smoking prevention before or at the start, rather than during, pregnancy.

Maternal hypertensive disorders and subtypes of hypospadias: A Dutch case-control study.

BACKGROUND: Hypospadias is a frequently occurring congenital anomaly in male infants, in which the opening of the urethra is located along the ventral side of the penis. Although various studies attempted to identify its causes, the aetiology of the majority of hypospadias cases remains poorly understood. Maternal hypertensive disorders are believed to be associated with hypospadias, but the results of previous studies are not consistent, especially for subtypes of hypospadias. OBJECTIVES: To investigate the associations between maternal hypertensive disorders, stratified by pharmacological treatment, and the occurrence of hypospadias divided into subtypes in a large population-based case-control study. METHODS: We included 887 hypospadias cases and 1005 male controls from the AGORA data- and biobank. Cases and controls were born in the periods 1975-2016 and 1990-2011, respectively. All data were collected in the period 2004-2018. Maternal questionnaires were used to obtain information on hypertensive disorders during pregnancy, antihypertensive medication treatment, and potential confounders. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) for the associations between hypertensive disorders and hypospadias were estimated using logistic regression. RESULTS: Hypertensive disorders were reported by 15.3% of the women in this study. Maternal hypertensive disorders in general, chronic hypertension, and gestational hypertension were not associated with hypospadias or its subtypes. Preeclampsia was associated with posterior hypospadias (aOR 3.09, 95% CI 1.49, 6.43), whether it was untreated (aOR 2.81, 95% CI 1.24, 6.38) or pharmacologically treated preeclampsia (aOR 4.96, 95% CI 1.08, 22.80). CONCLUSIONS: Our findings indicate that preeclampsia is associated with posterior hypospadias, irrespective of pharmacological treatment. This result supports the hypothesis of aetiological heterogeneity among the subtypes of hypospadias, with pregnancy-related risk factors being associated with the more severe types of hypospadias.

Data From Web-Based Questionnaires Were Valid for Gestational Diabetes and Preeclampsia, but Not Gestational Hypertension.

OBJECTIVES: We aimed to validate Web-based questionnaires for the common pregnancy complications gestational diabetes, gestational hypertension, and preeclampsia. STUDY DESIGN AND SETTING: We included 1,809 women participating in the PRegnancy and Infant DEvelopment (PRIDE) Study who delivered in 2012-2017, for whom relevant data were complete. Sensitivity, specificity, and positive and negative predictive values of self-reported diagnoses of gestational diabetes, gestational hypertension, and preeclampsia were determined using obstetric records as reference standard. Furthermore, we assessed whether maternal characteristics affected disagreement between questionnaires and obstetric record. RESULTS: For gestational diabetes and preeclampsia, we observed very few false-positive and false-negative reports, yielding sensitivities of 93% (95% confidence interval [CI] 86-100) and 88% (95% CI 79-98), respectively, and specificities of 100%. Depending on the definition of gestational hypertension, sensitivity and positive predictive values ranged from 62% to 89% and 53% to 64%, respectively. Disagreement on gestational hypertension was associated with prepregnancy overweight and multiparity. CONCLUSION: Self-reports of gestational diabetes and preeclampsia in Web-based questionnaires were valid, but the validity of gestational hypertension seemed to be lower because of relatively high numbers of false-positive reports. However, it is questionable whether an appropriate reference standard exists to validate this pregnancy complication.