Parental fecundability and neurodevelopmental delays and difficulties in offspring

Background: Impaired neurodevelopment is reported among children conceived by assisted reproductive technologies (ART). However, this might be explained by conditions underlying parental subfecundity, rather than the ART procedure. Methods: We examined associations of parental time-to-pregnancy (TTP) and conception by ART with neurodevelopmental traits up to 8 years of age, including motor and language skills, social delays and difficulties, and inattention-hyperactivity, among 92 142 singletons participating in the Norwegian Mother, Father and Child Cohort Study (MoBa). Mothers reported TTP and neurodevelopmental traits through questionnaires. Mean differences in standardized neurodevelopmental traits were estimated using linear regression, adjusting for maternal age, parity, educational level, body mass index and smoking, and paternal age. Results: A longer TTP was associated with decreased language skills and motor skills at 6, 18 and 36 months (P-values for trend ≤0.01), prosocial skills delay at 36 months (P-values for trend ≤0.001) and increased scores for inattention-hyperactivity traits at all ages up to 8 years (P-values for trend from 0.06 to 0.01). Effect sizes were small, ranging between 0.03 and 0.05 difference in the standardized neurodevelopmental scores. Estimates for ART were imprecise, but there were no differences between children conceived by ART and naturally conceived children of subfecund parents (TTP ≥12 months). Conclusions: Longer parental TTP is modestly but robustly associated with offspring neurodevelopmental delays and difficulties, with no added impact of ART. Future studies should investigate the underlying causes of—or aspects related to—parental subfecundity which might explain the association with offspring neurodevelopmental delays and difficulties

Investigating causal relations between sleep duration and risks of adverse pregnancy and perinatal outcomes:linear and nonlinear Mendelian randomization analyses

BACKGROUND: Observational studies have reported maternal short/long sleep duration to be associated with adverse pregnancy and perinatal outcomes. However, it remains unclear whether there are nonlinear causal effects. Our aim was to use Mendelian randomization (MR) and multivariable regression to examine nonlinear effects of sleep duration on stillbirth (MR only), miscarriage (MR only), gestational diabetes, hypertensive disorders of pregnancy, perinatal depression, preterm birth and low/high offspring birthweight. METHODS: We used data from European women in UK Biobank (N=176,897), FinnGen (N=~123,579), Avon Longitudinal Study of Parents and Children (N=6826), Born in Bradford (N=2940) and Norwegian Mother, Father and Child Cohort Study (MoBa, N=14,584). We used 78 previously identified genetic variants as instruments for sleep duration and investigated its effects using two-sample, and one-sample nonlinear (UK Biobank only), MR. We compared MR findings with multivariable regression in MoBa (N=76,669), where maternal sleep duration was measured at 30 weeks. RESULTS: In UK Biobank, MR provided evidence of nonlinear effects of sleep duration on stillbirth, perinatal depression and low offspring birthweight. Shorter and longer duration increased stillbirth and low offspring birthweight; shorter duration increased perinatal depression. For example, longer sleep duration was related to lower risk of low offspring birthweight (odds ratio 0.79 per 1 h/day (95% confidence interval: 0.67, 0.93)) in the shortest duration group and higher risk (odds ratio 1.40 (95% confidence interval: 1.06, 1.84)) in the longest duration group, suggesting shorter and longer duration increased the risk. These were supported by the lack of evidence of a linear effect of sleep duration on any outcome using two-sample MR. In multivariable regression, risks of all outcomes were higher in the women reporting <5 and ≥10 h/day sleep compared with the reference category of 8–9 h/day, despite some wide confidence intervals. Nonlinear models fitted the data better than linear models for most outcomes (likelihood ratio P-value=0.02 to 3.2×10(−52)), except for gestational diabetes. CONCLUSIONS: Our results show shorter and longer sleep duration potentially causing higher risks of stillbirth, perinatal depression and low offspring birthweight. Larger studies with more cases are needed to detect potential nonlinear effects on hypertensive disorders of pregnancy, preterm birth and high offspring birthweight. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02494-y

Pregnancy outcome among HIV-infected women on different antiretroviral therapies in Ethiopia:a cohort study

Objective: The objective of the study was to compare pregnancy outcomes according to maternal antiretroviral treatment (ART) regimens. Design: A retrospective cohort study. Participants and settings: Clinical data was extracted from ART exposed pregnancies of HIV-infected Ethiopian women attending antenatal care follow-up in public health facilities in Addis Ababa between February 2010 and October 2016. Outcomes: The primary outcomes evaluated were preterm birth, low birth weight and small-for-gestational-age. Results: A total 1663 of pregnancies exposed to ART were included in the analyses. Of these pregnancies, 17% resulted in a preterm birth, 19% in low birth weight and 32% in a small-for-gestational-age baby. Compared with highly active antiretroviral therapy (HAART) initiated during pregnancy, zidovudine monotherapy was less likely to result in preterm birth (adjusted OR 0.35, 95% CI 0.19 to 0.64) and low birth weight (adjusted OR 0.48, 95% CI 0.24 to 0.94). We observed no differential risk of preterm birth, low birth weight and small-for-gestational-age, when comparing women who initiated HAART during pregnancy to women who initiated HAART before conception. The risk for preterm birth was higher in pregnancies exposed to nevirapine-based HAART (adjusted OR 1.44, 95% CI 1.06 to 1.96) compared with pregnancies exposed to efavirenz-based HAART. Comparing nevirapine-based HAART with efavirenz-based HAART indicated no strong evidence of increased risk of low birth weight or small-for-gestational-age. Conclusions: We observed a higher risk of preterm birth among women who initiated HAART during pregnancy compared with zidovudine monotherapy. Pregnancies exposed to nevirapine-based HAART also had a greater risk of preterm births compared with efavirenz-based HAART

The association between constipation and lower urinary tract symptoms in parous middle-aged women:a prospective cohort study

Objective: To examine the prospective association between constipation and risk of developing lower urinary tract symptoms (LUTS) in parous middle-aged women. Materials and Methods: The study uses data from 3,729 women from the Avon Longitudinal Study of Parents and Children who provided self-reports of medication intake for constipation at two time points (Baseline): 2001–2003 and 2003–2005. Women with LUTS at baseline were excluded. After 10 years of follow-up, women provided self-reports of LUTS using an adapted version of the International Consultation on Incontinence Questionnaire on Female LUTS. LUTS were categorized according to International Continence Society definitions as stress urinary incontinence (UI), urgency UI, mixed UI, nocturia, increased daytime frequency, urgency, hesitancy, and intermittency. LUTS were considered present if symptoms were reported to occur at least “sometimes” for all subtypes, except for increased daytime frequency (≥9 times) and nocturia (≥2 times nightly). Results: At follow-up, the prevalence of any LUTS was 40%. Women (mean age 43.3 years, standard deviation 0.5), who took medication for constipation at either time point had increased risks of urgency (adjusted relative risks [RRs] = 1.35; 95% confidence interval [CI] 1.04–1.95) and hesitancy (adjusted RR = 1.72; 95% CI 1.04–3.01) compared with women who reported not using medication for constipation at either time point. The risk of urgency (adjusted RR = 1.94; 95% CI 1.15–3.29) and hesitancy (adjusted RR = 1.78; 95% CI 1.03–4.19) was greater for women who reported taking medication for constipation at both time points. There was no evidence that constipation was associated with stress UI, urgency UI, mixed UI, nocturia, increased daytime frequency, and intermittency. Conclusion: Constipation is prospectively associated with an increased risk of urgency and hesitancy among parous middle-aged women. If further research finds evidence that this association is causal, this implies that women should seek treatment to alleviate constipation to reduce their consequent risk of developing these LUTS

Associations between insomnia and pregnancy and perinatal outcomes: Evidence from Mendelian randomization and multivariable regression analyses

BACKGROUND: Insomnia is common and associated with adverse pregnancy and perinatal outcomes in observational studies. However, those associations could be vulnerable to residual confounding or reverse causality. Our aim was to estimate the association of insomnia with stillbirth, miscarriage, gestational diabetes (GD), hypertensive disorders of pregnancy (HDP), perinatal depression, preterm birth (PTB), and low/high offspring birthweight (LBW/HBW). METHODS AND FINDINGS: We used 2-sample mendelian randomization (MR) with 81 single-nucleotide polymorphisms (SNPs) instrumenting for a lifelong predisposition to insomnia. Our outcomes included ever experiencing stillbirth, ever experiencing miscarriage, GD, HDP, perinatal depression, PTB (gestational age 4,500 grams). We used data from women of European descent (N = 356,069, mean ages at delivery 25.5 to 30.0 years) from UK Biobank (UKB), FinnGen, Avon Longitudinal Study of Parents and Children (ALSPAC), Born in Bradford (BiB), and the Norwegian Mother, Father and Child Cohort (MoBa). Main MR analyses used inverse variance weighting (IVW), with weighted median and MR-Egger as sensitivity analyses. We compared MR estimates with multivariable regression of insomnia in pregnancy on outcomes in ALSPAC (N = 11,745). IVW showed evidence of an association of genetic susceptibility to insomnia with miscarriage (odds ratio (OR): 1.60, 95% confidence interval (CI): 1.18, 2.17, p = 0.002), perinatal depression (OR 3.56, 95% CI: 1.49, 8.54, p = 0.004), and LBW (OR 3.17, 95% CI: 1.69, 5.96, p < 0.001). IVW results did not support associations of insomnia with stillbirth, GD, HDP, PTB, and HBW, with wide CIs including the null. Associations of genetic susceptibility to insomnia with miscarriage, perinatal depression, and LBW were not observed in weighted median or MR-Egger analyses. Results from these sensitivity analyses were directionally consistent with IVW results for all outcomes, with the exception of GD, perinatal depression, and PTB in MR-Egger. Multivariable regression showed associations of insomnia at 18 weeks of gestation with perinatal depression (OR 2.96, 95% CI: 2.42, 3.63, p < 0.001), but not with LBW (OR 0.92, 95% CI: 0.69, 1.24, p = 0.60). Multivariable regression with miscarriage and stillbirth was not possible due to small numbers in index pregnancies. Key limitations are potential horizontal pleiotropy (particularly for perinatal depression) and low statistical power in MR, and residual confounding in multivariable regression. CONCLUSIONS: In this study, we observed some evidence in support of a possible causal relationship between genetically predicted insomnia and miscarriage, perinatal depression, and LBW. Our study also found observational evidence in support of an association between insomnia in pregnancy and perinatal depression, with no clear multivariable evidence of an association with LBW. Our findings highlight the importance of healthy sleep in women of reproductive age, though replication in larger studies, including with genetic instruments specific to insomnia in pregnancy are important

Risk of miscarriage in women with chronic diseases in Norway:A registry linkage study

BACKGROUND: Increased risk of miscarriage has been reported for women with specific chronic health conditions. A broader investigation of chronic diseases and miscarriage risk may uncover patterns across categories of illness. The objective of this study was to study the risk of miscarriage according to various preexisting chronic diseases. METHODS AND FINDINGS: We conducted a registry-based study. Registered pregnancies (n = 593,009) in Norway between 2010 and 2016 were identified through 3 national health registries (birth register, general practitioner data, and patient registries). Six broad categories of illness were identified, comprising 25 chronic diseases defined by diagnostic codes used in general practitioner and patient registries. We required that the diseases were diagnosed before the pregnancy of interest. Miscarriage risk according to underlying chronic diseases was estimated as odds ratios (ORs) using generalized estimating equations adjusting for woman’s age. The mean age of women at the start of pregnancy was 29.7 years (SD 5.6 years). We observed an increased risk of miscarriage among women with cardiometabolic diseases (OR 1.25, 95% CI 1.20 to 1.31; p-value <0.001). Within this category, risks were elevated for all conditions: atherosclerosis (2.22; 1.42 to 3.49; p-value <0.001), hypertensive disorders (1.19; 1.13 to 1.26; p-value <0.001), and type 2 diabetes (1.38; 1.26 to 1.51; p-value <0.001). Among other categories of disease, risks were elevated for hypoparathyroidism (2.58; 1.35 to 4.92; p-value 0.004), Cushing syndrome (1.97; 1.06 to 3.65; p-value 0.03), Crohn’s disease (OR 1.31; 95% CI: 1.18 to 1.45; p-value 0.001), and endometriosis (1.22; 1.15 to 1.29; p-value <0.001). Findings were largely unchanged after mutual adjustment. Limitations of this study include our inability to adjust for measures of socioeconomic position or lifestyle characteristics, in addition to the rareness of some of the conditions providing limited power. CONCLUSIONS: In this registry study, we found that, although risk of miscarriage was largely unaffected by maternal chronic diseases, risk of miscarriage was associated with conditions related to cardiometabolic health. This finding is consistent with emerging evidence linking cardiovascular risk factors to pregnancy complications