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Eyal Cohen,1– 3 Péter Szentkúti,4 Erzsébet Horváth-Puhó,4 Hilary K Brown,3,5 Sonia M Grandi,2 Henrik Toft Sørensen,4,6 Joel G Ray2,3,7 1Department of Pediatrics and Edwin S.H. Leong Centre for Healthy Children, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; 2Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada; 3Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 5Department of Health & Society, University of Toronto Scarborough; 6Clinical Excellence Research Center, Stanford University, Stanford, CA, USA; 7St.Michael’s Hospital Department of Medicine, University of Toronto, Toronto, Ontario, CanadaCorrespondence: Eyal Cohen, Department of Pediatrics and Edwin S.H. Leong Centre for Healthy Children, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada, Tel +1 416-813-7654, Email eyal.cohen@sickkids.caBackground: The mother of an infant with a major congenital anomaly is at a higher risk of premature cardiometabolic disease, possibly from chronic caregiver stress and distraction from self-care, including maintaining a healthy lifestyle and body weight.Objective: To compare the interpregnancy weight gain in women whose first infant had a major congenital anomaly vs those without an affected child.Methods: Multivariable linear regression compared women whose infant had an anomaly vs those whose infant did not, adjusting for interpregnancy time interval, demographics, smoking and health status at the first pregnancy.Results: Of the 199,536 women who had two consecutive singleton births, 4035 (2.0%) had a child with an anomaly at the first birth. The mean (SD) maternal BMI at the start of the first pregnancy was 24.1 (4.7) and 23.7 (4.4) kg/m2 in women with, and without, an anomaly-affected newborn. By the start of the second pregnancy, 3 years later, they had gained a mean (SD) of 2.2 (5.5) and 1.8 (5.2) kg, respectively – an adjusted absolute higher gain of 0.26 kg (95% CI 0.10 to 0.42) in women with an anomaly-affected first-born infant compared to those with an unaffected pregnancy. The adjusted interpregnancy weight gain difference was greatest in women whose first-born infant had a multi-organ anomaly at 0.59 kg (95% CI 0.02 to 1.16). The adjusted odds ratio of moving from a normal BMI category of 18.5– 24.9 kg/m2 in the first pregnancy, to an overweight or obese BMI category of 25+ kg/m2 in the second, was 1.18 (95% CI 1.06 to 1.32) comparing mothers with vs without an anomaly-affected child in the first pregnancy.Conclusion: Mothers of an infant with a major congenital anomaly have a modestly higher interpregnancy weight gain and tend to climb to a higher BMI category. The long-term implications of this greater weight trajectory require further study.Keywords: weight gain, congenital anomaly, inter-pregnancy, body mass index

Background and Objectives: The widespread adoption of virtual care during the pandemic may not have been uniform across populations, including among paediatric immigrants and refugees. We sought to examine the association between virtual mental healthcare utilisation and immigration factors., Methods: This population-based cohort study of immigrants and refugees (3-17 years) used linked health administrative databases in Ontario, Canada (March 2020 to December 2021). Exposures included self-reported Canadian language ability (CLA) at arrival and immigration category (economic class, family class and refugee). The primary outcome was the visit modality (inperson/virtual) measured as a rate of physician-based mental healthcare visits. Modified Poisson regression model estimated adjusted rate ratios (aRRs) with 95% CIs., Results: Among 22 420 immigrants, 12 135 (54%) did not have CLA (economic class: 6310, family class: 2207, refugees: 3618) and 10 285 did (economic class; 6293, family class: 1469, refugees: 2529). The cohort's mean age (SD) was 12.0 (4.0) years and half (50.3%) were female. Of 71 375 mental health visits, 47 989 (67.2%) were delivered virtually. Compared with economic class immigrants with CLA (referent), refugees with and without CLA had a lower risk of virtual care utilisation (CLA: aRR 0.89, 95% CI 0.86 to 0.93; non-CLA: aRR 0.80, 95% CI 0.77 to 0.83), as did family class immigrants with CLA (aRR 0.96, 95% CI 0.92 to 0.99). No differences in virtual care utilisation were observed among economic class immigrants with CLA and other immigrant groups., Conclusions: Language ability at arrival and immigration category are associated with virtual mental healthcare utilisation. Whether findings reflect user preference or inequities in accessibility, particularly for refugees and those without CLA at arrival, warrants further study., Competing Interests: Competing interests: NRS reported receiving personal fees from the BMJ Group Archives of Disease in Childhood, grants from the Canadian Institutes for Health Research and the Ontario Ministry of Health, grants from the Centre for Addiction and Mental Health, and grants from The Hospital for Sick Children outside the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Preterm birth (PTB) is a leading cause of neonatal mortality. However, evidence on mortality beyond the neonatal period is limited, especially in North America., Objective: To examine associations of PTB with all-cause and cause-specific mortality from birth through 23 to 36 years of age., Design, Setting, and Participants: This population-based matched cohort study of live births in Canada included individuals born between January 1, 1983, and December 31, 1996, and followed up until December 31, 2019. Data were analyzed from June 1, 2023, to April 30, 2024., Exposure: PTBs, between 24 and 37 weeks' gestation (with gestational age [GA]-specific subcategories of 24 to 27 weeks, 28 to 31 weeks, 32 to 33 weeks, and 34 to 36 weeks) compared with term births (37-41 weeks' gestation)., Main Outcomes and Measures: All-cause mortality and cause-specific mortality were the main outcomes. Risk differences (RDs) and risk ratios (RRs) were estimated for all-cause mortality using log-binomial regressions and hazard ratios were estimated for cause-specific mortality using Cox proportional hazards regression models (censoring individuals who died from other causes) within prespecified age intervals (ages 0-11 months and ages 1-5, 6-12, 13-17, 18-28, and 29-36 years). Observed confounding was accounted for using coarsened exact matching on baseline characteristics., Results: Of 4 998 560 births (54.2% male), 6.9% were born preterm (with GA-specific subcategories of 0.3% born at 24-27 weeks, 0.6% at 28-31 weeks, 0.8% at 32-33 weeks, and 5.1% at 34-36 weeks). During a median of 29 years of follow-up, 72 662 individuals died (14 312 born preterm and 58 350 at term). PTB was associated with an increased risk of death in all age intervals, with the highest RDs and RRs from birth through infancy (ages 0-11 months) (RD, 2.29% [95% CI, 2.23%-2.35%]; RR, 11.61 [95% CI, 11.09-12.15]) and in early childhood (ages 1-5 years) (RD, 0.34% [95% CI, 0.31%-0.36%]; RR, 2.79 [95% CI, 2.61-2.98]) and the lowest RDs and RRs among those between ages 18 and 28 years (RD, 0.07% [95% CI, 0.04%-0.10%]; RR, 1.13 [95% CI, 1.07-1.19]). We identified increased risks of mortality associated with several causes, including respiratory, circulatory, and digestive system disorders; nervous system, endocrine, and infectious diseases; cancers; congenital malformations; and conditions originating in the perinatal period. No associations were found for external causes of deaths. Associations by GA categories suggested lower risks with higher GA., Conclusions and Relevance: The findings of this population-based matched cohort study suggest that individuals born preterm were at an increased risk of death from birth until their third and fourth decades of life, with higher risks as GA decreased. Some of these associations may have been partly due to underlying health determinants that affected PTB and mortality. These findings suggest that PTB should be recognized as a risk factor for mortality and could inform preventive strategies.

Background: Pregnancy complications have been recognized as a window to future health. Though cesarean delivery is common, it is unknown whether labor duration and mode of delivery are associated with maternal long-term mortality., Objective: To examine whether labor duration and mode of delivery were associated with all-cause and cause-specific mortality., Study Design: Participants were mothers from the multisite Collaborative Perinatal Project (CPP) cohort (1959-1966; n=43,646, limited to last CPP delivery). We ascertained all-cause and specific causes of death as of 2016 via linkage to the National Death Index and Social Security Death Master File. Hazard ratios (HR) testing mode of delivery and labor duration were estimated using Cox proportional hazards models adjusted for demographic and clinical characteristics. We further stratified analyses by parity., Results: Among participants with a recorded delivery mode, 5.9% (2486/42,335) had a cesarean delivery. Participants who had a cesarean were older (26.9 vs 24.3 years), with higher body mass index (24.0 vs 22.7 kg/m 2 ), were less likely to be nulliparous (21% vs 30%), and more likely to have a household income of at least $6000 (22% vs 17%), to smoke ≥1 pack/d (18% vs 15%), to have diabetes mellitus (12% vs 1%) and to have a prior medical condition (47% vs 34%), compared to participants with a vaginal delivery. Delivery mode was similar by race/ethnicity, marital status, and education. Median labor duration was 395 minutes among participants who had an intrapartum cesarean delivery and 350 minutes among participants delivered vaginally. By 2016, 52.2% of participants with a cesarean delivery and 38.5% of participants with a vaginal delivery had died. Cesarean vs vaginal delivery was significantly associated with increased risk for all-cause mortality (HR=1.16 (95% confidence interval [CI]: 1.09, 1.23); in nulliparas, HR=1.27 (95% CI: 1.09, 1.47); in multiparas, HR=1.13 (95% CI: 1.06, 1.21) as well as increased risk of death from cardiovascular disease, diabetes, respiratory disease, infection, and kidney disease. Associations with death from cardiovascular disease, infection, and kidney disease were stronger for multiparas than nulliparas, though the association with death from diabetes was stronger among nulliparas. Labor duration was not significantly related to overall mortality., Conclusion: In a historic United States cohort with a low cesarean delivery rate, cesarean delivery was an indicator for subsequent increased mortality risk, particularly related to cardiovascular disease and diabetes. Future studies with long-term follow-up are warranted given the current high prevalence of cesarean delivery., (Published by Elsevier Inc.)

Importance: The incidence of severe maternal morbidity (SMM)-and particularly cardiovascular SMM (cvSMM), the first cause of pregnancy-related mortality-has been rising in North America. Although hypertensive disorders of pregnancy (HDP) are common, their association with cvSMM specifically remains unclear., Objective: To assess the association between individual subtypes of HDP and cvSMM, in addition to overall SMM, in a large, nationally representative sample., Design, Setting, and Participants: A population-based cohort study using the United States National Inpatient Sample was conducted. Individuals with obstetric deliveries between 2015 and 2019 were included. Data analysis was performed from October 2023 to February 2024., Exposure: HDP subtypes included gestational hypertension, chronic hypertension, preeclampsia without severe features, severe preeclampsia, and HELLP (hemolysis, elevated liver enzymes, and low platelet) syndrome., Main Outcomes and Measures: The primary outcome was a composite of cvSMM (including conditions such as pulmonary edema, stroke, and acute myocardial infarction) and the secondary outcome was a composite of overall SMM (including cvSMM and other conditions such as respiratory failure, severe postpartum hemorrhage, and sepsis). Adjusted risk ratios (aRRs) for the association between HDP subtypes and the outcomes were estimated using modified Poisson regression models adjusted for demographic and clinical characteristics., Results: Among 15 714 940 obstetric deliveries, 2 045 089 (13.02%) had HDP, 23 445 (0.15%) were affected by cvSMM, and 282 160 (1.80%) were affected by SMM. The mean (SD) age of the cohort was of 29 (6) years. The incidence of cvSMM was higher in participants with HDP than those without HDP (0.48% [9770 of 2 045 089] vs 0.10% [13 680 of 13 669 851]; P < .001). Participants with HELLP syndrome had the highest risk for cvSMM (aRR, 17.55 [95% CI, 14.67-21.01]), followed by severe preeclampsia (aRR, 9.11 [95% CI, 8.26-10.04]), and chronic hypertension (aRR, 3.57 [95% CI, 3.15-4.05]). Although HDP subtypes were also associated with overall SMM, the association with HELLP syndrome (aRR, 9.94 [95% CI, 9.44-10.45]), severe preeclampsia (aRR, 3.66 [95% CI, 3.55-3.78]), and chronic hypertension (aRR, 1.96 [95% CI, 1.88-2.03]) was attenuated compared with cvSMM., Conclusions and Relevance: In this cohort study, a graded relationship by severity characterized the association between HDP and cvSMM. Although all HDP subtypes were associated with an increased risk of overall SMM, the risk was more pronounced for cvSMM.

Background: Individuals with disabilities may require specific medications in pregnancy. The prevalence and patterns of medication use, overall and for medications with known teratogenic risks, are largely unknown. Methods: This population-based cohort study in Ontario, Canada, 2004-2021, comprised all recognized pregnancies among individuals eligible for public drug plan coverage. Included were those with a physical ( n = 44,136), sensory ( n = 13,633), intellectual or developmental ( n = 2,446) disability, or multiple disabilities ( n = 5,064), compared with those without a disability ( n = 299,944). Prescription medication use in pregnancy, overall and by type, was described. Modified Poisson regression generated relative risks (aRR) for the use of medications with known teratogenic risks and use of ≥2 and ≥5 medications concurrently in pregnancy, comparing those with versus without a disability, adjusting for sociodemographic and clinical factors. Results: Medication use in pregnancy was more common in people with intellectual or developmental (82.1%), multiple (80.4%), physical (73.9%), and sensory (71.9%) disabilities, than in those with no known disability (67.4%). Compared with those without a disability (5.7%), teratogenic medication use in pregnancy was especially higher in people with multiple disabilities (14.2%; aRR 2.03, 95% confidence interval [CI]: 1.88-2.20). Furthermore, compared with people without a disability (3.2%), the use of ≥5 medications concurrently was more common in those with multiple disabilities (13.4%; aRR 2.21, 95% CI: 2.02-2.41) and an intellectual or developmental disability (9.3%; aRR 2.13, 95% CI: 1.86-2.45). Interpretation: Among people with disabilities, medication use in pregnancy is prevalent, especially for potentially teratogenic medications and polypharmacy, highlighting the need for preconception counseling/monitoring to reduce medication-related harm in pregnancy.

Background: Autoimmune diseases disproportionately impact women and female-specific aspects of reproduction are thought to play a role. We investigated the time-varying association between pregnancy complications and new-onset autoimmune disease in females during the reproductive and midlife years., Methods: We conducted a population-based cohort study of 1 704 553 singleton births to 1 072 445 females in Ontario, Canada (2002-17) with no pre-existing autoimmune disease. Pregnancy complications were preeclampsia, stillbirth, spontaneous preterm birth and severe small for gestational age (SGA). Royston-Parmar models were used to estimate the time-varying association between pregnancy complications and a composite of 25 autoimmune diseases from date of delivery to date of autoimmune disease diagnosis or censoring at death, loss of health insurance, or 31 March 2021. Models were adjusted for baseline socio-demographics, parity and comorbidities., Results: At 19 years (median = 10.9 years of follow-up), cumulative incidence of autoimmune disease was 3.1% in those with a pregnancy complication and 2.6% in those without complications. Adjusted hazard ratio (AHR) curves as a function of time since birth were generally L-shaped. Universally, risks were most elevated within the first 3 years after birth [at 1 year: preeclampsia AHR 1.22, 95% confidence interval (CI) 1.09-1.36; stillbirth AHR 1.36, 95% CI 0.99-1.85; spontaneous preterm birth AHR 1.30, 95% CI 1.18-1.44; severe SGA AHR 1.14, 95% CI 0.99-1.31] and plateaued but remained elevated thereafter., Conclusions: Prior history of pregnancy complications may be an important female-specific risk factor to consider during clinical assessment of females for possible autoimmune disease to facilitate timely detection and treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: While the benefits of levothyroxine are well-established for overt hypothyroidism, they are unclear for subclinical hypothyroidism (SCH) among pregnant women., Objective: To estimate the effect of initiation of levothyroxine on pregnancy loss among women with SCH with an emulated target trial using observational data., Methods: We emulated a target trial using the United Kingdom's Clinical Practice Research Datalink to account for the staggered timing of diagnosis and treatment of SCH and the time of entry of women into prenatal care. We emulated multiple nested trials (at each gestational week) and used an intention-to-treat approach to define levothyroxine use (≥1 prescription in the 7 days prior to trial entry), with eligible users matched to non-users (1:4) on time of diagnosis, gestational week of the first eligible trial and high-dimensional propensity score. Pregnancy losses included spontaneous abortion and stillbirth. A pooled logistic regression model with bootstrap resampling was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI)., Results: Based on 159,177 eligible person-trials (5781 women), the matched cohort included 181 initiators and 640 non-initiators of levothyroxine, with 57 pregnancy losses occurring during follow-up. Overall, the mean age of women was 32.2 years (SD 5.4), 25% were obese, 8% had type 2 diabetes and about 50% were nulliparous. After matching, women who initiated levothyroxine versus not had higher thyroid-stimulating levels during pregnancy and were more likely to have a history of hypothyroidism. The cumulative incidence of pregnancy loss was lower in initiators versus non-initiators of levothyroxine. The adjusted HR for pregnancy loss was 0.87 (95% CI 0.22, 1.56)., Conclusions: Although our assessment of the effect of initiation of levothyroxine for SCH in pregnancy precludes any definitive conclusions due to wide confidence intervals, this study illustrates the feasibility of using the target trial emulation framework to examine the effectiveness of medication use in pregnancy., (© 2023 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Study Question: What is the association between reproductive health history (e.g. age at menarche, menopause, reproductive lifespan) with abdominal adiposity in postmenopausal women?, Summary Answer: Higher visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) tissue levels were observed among women with earlier menarche, earlier menopause, and greater parity., What Is Known Already: Postmenopausal women are predisposed to accumulation of VAT and SAT. Reproductive health variables are known predictors of overall obesity status in women, defined by BMI., Study Design, Size, Duration: This study is a secondary analysis of data collected from the baseline visit of the Women's Health Initiative (WHI). The WHI is a large prospective study of postmenopausal women, including both a randomized trial and observational study. There were 10 184 women included in this analysis., Participants/materials, Setting, Methods: Data were collected from a reproductive health history questionnaire, dual-energy x-ray absorptiometry scans, and anthropometric measures at WHI baseline. Reproductive history was measured via self-report, and included age at menarche, variables related to pregnancy, and age at menopause. Reproductive lifespan was calculated as age at menopause minus age at menarche. Statistical analyses included descriptive analyses and multivariable linear regression models to examine the association between reproductive history with VAT, SAT, total body fat, and BMI., Main Results and the Role of Chance: Women who reported early menarche (<10 years) or early menopause (<40 years) had the highest levels of VAT. Adjusted multivariable linear regression results demonstrate women who experienced menarche >15 years had 23 cm2 less VAT (95% CI: -31.4, -14.4) and 47 cm2 less SAT (95% CI: -61.8, -33.4) than women who experienced menarche at age 10 years or earlier. A similar pattern was observed for age at menopause: compared to women who experienced menopause <40 years, menopause at 50-55 years was associated with 19.3 cm2 (95% CI: -25.4, -13.3) less VAT and 27.4 cm2 (-29.6, 10.3) less SAT. High parity (>3 pregnancies) was also associated with VAT and SAT. For example, adjusted beta coefficients for VAT were 8.36 (4.33, 12.4) and 17.9 (12.6, 23.2) comparing three to four pregnancies with the referent, one to two pregnancies., Limitations, Reasons for Caution: The WHI reproductive health history questionnaire may be subject to poor recall owing to a long look-back window. Residual confounding may be present given lack of data on early life characteristics, such as maternal and pre-menarche characteristics., Wider Implications of the Findings: This study contributes to our understanding of reproductive lifespan, including menarche and menopause, as an important predictor of late-life adiposity in women. Reproductive health has also been recognized as a sentinel marker for chronic disease in late life. Given established links between adiposity and cardiometabolic outcomes, this research has implications for future research, clinical practice, and public health policy that makes use of reproductive health history as an opportunity for chronic disease prevention., Study Funding/competing Interest(s): HRB and AOO are supported by the National Institute of Health National Institute of Aging (R01AG055018-04). JWB reports royalties from 'ACSM'S Body Composition Assessment Book' and consulting fees from the WHI. The remaining authors have no competing interests to declare., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Introduction: As the fetus relies on maternal thyroid hormones in early pregnancy, maternal hypothyroidism plays an important role in fetal development. However, the association between maternal hypothyroidism and metabolic disease in offspring is unclear., Objective: To examine the association between maternal hypothyroidism in pregnancy and metabolic outcomes (obesity, hypertension, type 2 diabetes mellitus, and dyslipidemia) in children < 18 years., Methods: We systematically searched 5 databases from inception to May 2023. Eligible studies included cohort, case-control, and randomized controlled trials involving children born to mothers with or without hypothyroidism in pregnancy. Data were pooled across studies using random-effects models for outcomes reported in at least three studies. Quality assessment was performed using the ROBINS-E tool for observational studies and the Cochrane Risk of Bias tool for trials., Results: The search identified 3221 articles, of which 7 studies were included (1 trial, 6 observational). All studies were conducted outside of North America and ranged in size from 250 to > 1 million children. The follow-up time ranged from 6 to 20 years. Included studies support an increased risk of hypertension and glucose dysregulation in offspring exposed to maternal hypothyroidism (hypertension: OR 1.08, 95% CI 0.75, 1.57 and HR 1.81, 95% CI 1.21, 2.69; diabetes: RR 2.7, 95% CI 0.7, 10). In the pooled analysis, maternal hypothyroidism was not associated with obesity in offspring (OR 1.04, 95% CI 0.64, 1.70)., Conclusion: This study found inconsistent evidence on the association between maternal hypothyroidism in pregnancy and metabolic outcomes in offspring, though associations with hypertension and glucose dysregulation are possible., (© 2024. The Author(s).)

Background: Low-dose aspirin prophylaxis is recommended for women at risk of preeclampsia. Capturing aspirin prophylaxis within administrative databases can be challenging since it is an over-the-counter medication. The Better Outcome Registry and Network (BORN) database, a perinatal health registry in Ontario, Canada, includes a formal variable that captures aspirin prophylaxis for preeclampsia. This variable has not been formally validated., Objectives: To assess the accuracy of the aspirin prophylaxis variable in the BORN database against an electronic medical record (EMR)., Methods: This validation study comprised 200 randomly selected women who had a livebirth at St. Michael's Hospital (SMH) in Toronto, Ontario, from January 2018 to July 2022. Recorded aspirin prophylaxis in pregnancy and maternal sociodemographic characteristics were independently extracted by two abstractors. Accuracy of aspirin prophylaxis use in the BORN database was compared to that in the SMH EMR, expressed as sensitivity, specificity, positive (PPV) and negative predictive values (NPV), Cohen's kappa (κ), and overall percent agreement, with 95% confidence intervals (CI). Sensitivity analyses were performed to account for missing or unclear aspirin prophylaxis use., Results: Among 200 women, 24 (12.0%) received aspirin prophylaxis - 12.5% within the SMH EMR and 8.0% in the BORN database. Women using aspirin were older (37.0 vs 33.0 years) and had higher median gravidity (3 vs. 2). Sensitivity and specificity of the BORN aspirin prophylaxis variable were 62.5% (95% CI 40.6, 81.2) and 100.0% (95% CI 97.3, 100.0), respectively. The corresponding positive and negative predictive values were 100.0% (95% CI 78.2, 100.0), and 93.8% (95% CI 88.6, 97.1), respectively. Cohen's κ was 0.74 (95% CI 0.58, 0.90), and overall percent agreement was 94.4% (95% CI 87.1, 100.0)., Conclusions: Aspirin use within the BORN database, based on a standard variable field, appears accurate enough for the potential use in epidemiological studies of aspirin prophylaxis for preeclampsia or as a covariate in related studies., (© 2023 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Background: During pregnancy, various maternal IgG antibodies are transferred to the developing fetus, some of which may protect the newborn against infection. If a mother and her fetus have different A, B or O (ABO) blood groups, then transferred maternal antibodies may plausibly protect the infant against infection., Aim: To determine if maternal-newborn ABO blood group incongruence vs. congruence is associated with a lower risk of serious infection in the infant., Design: Retrospective population-based cohort., Methods: We used linked patient-level datasets for all singleton hospital livebirths from 2008 to 2022 in Ontario, Canada, with known maternal and newborn ABO blood groups. We used a dichotomous exposure state, either ABO blood group congruent (N = 114 507) or incongruent (N = 43 074). The main outcome of interest was the risk of serious infant infection within 27 days, and from 28 to 365 days, after birth. Cox proportional hazard models generated hazard ratios and 95% confidence intervals, and were adjusted for maternal age, world region of origin, residential income quintile and gestational age at birth., Results: Relative to maternal-newborn congruency, incongruent ABO blood group was associated with an adjusted hazard ratio of 0.88 (95% CI: 0.80-0.97) for serious neonatal infection within 27 days of birth, and 0.93 (95% CI: 0.90-0.96) for serious infection between 28 and 365 days after birth., Conclusions: Maternal-newborn ABO incongruence may be associated with a lower relative risk of a serious infant infection within 27 days, and from 28 to 365 days, after birth., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To define major congenital anomaly (CA) subgroups and assess outcome variability based on defined subgroups., Study Design: This population-based cohort study used registries in Denmark for children born with a major CA between January 1997 and December 2016, with follow-up until December 2018. We performed a latent class analysis (LCA) using child and family clinical and sociodemographic characteristics present at birth, incorporating additional variables occurring until age of 24 months. Cox proportional hazards regression models estimated hazard ratios (HRs) of pediatric mortality and intensive care unit (ICU) admissions for identified LCA classes., Results: The study included 27 192 children born with a major CA. Twelve variables led to a 4-class solution (entropy = 0.74): (1) children born with higher income and fewer comorbidities (55.4%), (2) children born to young mothers with lower income (24.8%), (3) children born prematurely (10.0%), and (4) children with multiorgan involvement and developmental disability (9.8%). Compared with those in Class 1, mortality and ICU admissions were highest in Class 4 (HR = 8.9, 95% CI = 6.4-12.6 and HR = 4.1, 95% CI = 3.6-4.7, respectively). More modest increases were observed among the other classes for mortality and ICU admissions (Class 2: HR = 1.7, 95% CI = 1.1-2.5 and HR = 1.3, 95% CI = 1.1-1.4, respectively; Class 3: HR = 2.5, 95% CI = 1.5-4.2 and HR = 1.5, 95% CI = 1.3-1.9, respectively)., Conclusions: Children with a major CA can be categorized into meaningful subgroups with good discriminative ability. These groupings may be useful for risk-stratification in outcome studies., Competing Interests: Declaration of Competing Interest We declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To describe the mental health trajectories of caregivers of children with medical complexity (CMC) and explore child characteristics associated with below-average caregiver mental health., Design: A secondary analysis of prospectively collected data from 123 caregivers of children aged <16 years with medical complexity from a multicentre randomised trial conducted from December 2016 to June 2021., Main Outcome Measure: The Patient-Reported Outcomes Measurement Information System Global Mental Health Scale was used to measure caregivers' self-reported mental health well-being. Group-based trajectory analysis was used to identify clusters of caregivers with similar changes in mental health across 24 months. Logistic regression was used to identify child-related predictors of mental health among caregivers., Results: A final model with three distinct groups was selected, corresponding to caregivers with average (n=39), moderately below-average (n=65) and severely below-average (n=19) mental health scores, all with stable trajectories and high posterior probabilities (>90%). Moderately and severely below-average caregiver mental health groups, merged into one group, were associated with a greater number of child medical technology devices (adjusted OR (aOR) 1.44, 95% CI 1.01 to 2.04), gross motor difficulties (aOR 3.51, 95% CI 1.02 to 12.05) and worse child emotional (aOR 0.93, 95% CI 0.87 to 0.99) and psychological well-being (aOR 0.93, 95% CI 0.88 to 0.99)., Conclusion: Most caregivers of CMC reported persistently below-average mental health. The intensity of caregiving, as indicated by medical technology and child functional needs, is a potential risk factor for below-average caregiver mental health. Future design and evaluation of interventions focused on support for caregivers of CMC are warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Mothers whose newborn experiences adversity may neglect their own health to care for their affected infant or following a perinatal death. Weight gain after pregnancy is one measure of maternal self-care. We measured interpregnancy weight gain among women whose child had an adverse perinatal event., Methods: This population-based observational study included 192 154 primigravid women with two consecutive singleton births in Ontario, Canada. Outcomes included net weight gain, and adjusted odds ratios (aOR) of moving to a higher body mass index (BMI) category between pregnancies, comparing women whose child did versus did not experience either a perinatal death, prematurity, severe neonatal morbidity, major congenital anomaly, or severe neurologic impairment., Results: Perinatal death was associated with a +3.5 kg (95% confidence interval [CI]: 2.1-4.9) net higher maternal weight gain in the subsequent pregnancy. Relative to term births, preterm birth <32 weeks (+3.2 kg, 95% CI: 1.9-4.6), 32-33 weeks (+1.8 kg, 95% CI: 0.7-2.8) and 34-36 weeks (+0.9 kg, 95% CI: 0.6-1.3) were associated with higher net weight gain. Having an infant with severe neonatal morbidity was associated with a +1.2 kg (95% CI: 0.3-2.1) weight gain. Likewise, the aOR of moving to a higher BMI category was 1.27 (95% CI, 1.14-1.42) following a perinatal death, 1.21 (95% CI: 1.04-1.41) after a preterm birth <32 weeks, and 1.11 (95% CI: 1.02-1.22) with severe neonatal morbidity., Conclusion: Greater interpregnancy weight gain, and movement to a higher BMI category, are each more likely in a woman whose first-born was affected by certain major adverse perinatal events., (© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Importance: Unintentional injury, suicide, and homicide are leading causes of death among young females. Teen pregnancy may be a marker of adverse life experiences., Objective: To evaluate the risk of premature mortality from 12 years of age onward in association with number of teen pregnancies and age at pregnancy., Design, Setting, and Participants: This population-based cohort study was conducted among all females alive at 12 years of age from April 1, 1991, to March 31, 2021, in Ontario, Canada (the most populous province, which has universal health care and data collection). The study period ended March 31, 2022., Exposures: The main exposure was number of teen pregnancies between 12 and 19 years of age (0, 1, or ≥2). Secondary exposures included how the teen pregnancy ended (birth or miscarriage vs induced abortion) and age at first teen pregnancy., Main Outcomes and Measures: The main outcome was all-cause mortality starting at 12 years of age. Hazard ratios (HRs) were adjusted for year of birth, comorbidities at 9 to 11 years of age, and area-level education, income level, and rurality., Results: Of 2 242 929 teenagers, 163 124 (7.3%) experienced a pregnancy at a median age of 18 years (IQR, 17-19 years). Of those with a teen pregnancy, 60 037 (36.8%) ended in a birth (of which 59 485 [99.1%] were live births), and 106 135 (65.1%) ended in induced abortion. The median age at the end of follow-up was 25 years (IQR, 18-32 years) for those without a teen pregnancy and 31 years (IQR, 25-36 years) for those with a teen pregnancy. There were 6030 deaths (1.9 per 10 000 person-years [95% CI, 1.9-2.0 per 10 000 person-years]) among those without a teen pregnancy, 701 deaths (4.1 per 10 000 person-years [95% CI, 3.8-4.5 per 10 000 person-years]) among those with 1 teen pregnancy, and 345 deaths (6.1 per 10 000 person-years [95% CI, 5.5-6.8 per 10 000 person-years]) among those with 2 or more teen pregnancies; adjusted HRs (AHRs) were 1.51 (95% CI, 1.39-1.63) for those with 1 pregnancy and 2.14 (95% CI, 1.92-2.39) for those with 2 or more pregnancies. Comparing those with vs without a teen pregnancy, the AHR for premature death was 1.25 (95% CI, 1.12-1.40) from noninjury, 2.06 (95% CI, 1.75-2.43) from unintentional injury, and 2.02 (95% CI, 1.54-2.65) from intentional injury., Conclusions and Relevance: In this population-based cohort study of 2.2 million female teenagers, teen pregnancy was associated with future premature mortality. It should be assessed whether supports for female teenagers who experience a pregnancy can enhance the prevention of subsequent premature mortality in young and middle adulthood.

Background: Multifetal gestation could be associated with higher long-term maternal mortality because it increases the risk of pregnancy complications such as preeclampsia and preterm birth, which are in turn linked to postpartum cardiovascular risk., Objectives: We examined whether spontaneously conceived multifetal versus singleton gestation was associated with long-term maternal mortality in a racially diverse U.S., Methods: We ascertained vital status as of 2016 via linkage to the National Death Index and Social Security Death Master File of 44,174 mothers from the Collaborative Perinatal Project (CPP; 1959-1966). Cox proportional hazards models with maternal age as the time scale assessed associations between history of spontaneous multifetal gestation (in the last CPP observed pregnancy or prior pregnancy) and all-cause and cardiovascular mortality, adjusted for demographics, smoking status, and preexisting medical conditions. We calculated hazard ratios (HR) for all-cause and cause-specific mortality over the study period and until age 50, 60, and 70 years (premature mortality)., Results: Of eligible participants, 1672 (3.8%) had a history of multifetal gestation. Participants with versus without a history of multifetal gestation were older, more likely to have a preexisting condition, and more likely to smoke. By 2016, 51% of participants with and 38% of participants without a history of multifetal gestation had died (unadjusted all-cause HR 1.14, 95% confidence interval [CI] 1.07, 1.23). After adjustment for smoking and preexisting conditions, a history of multifetal gestation was not associated with all-cause (adjusted HR 1.00, 95% CI 0.93, 1.08) or cardiovascular mortality (adjusted HR 0.99, 95% CI 0.87, 1.11) over the study period. However, history of multifetal gestation was associated with an 11% lower risk of premature all-cause mortality (adjusted HR 0.89, 95% CI 0.82, 0.96)., Conclusions: In a cohort with over 50 years of follow-up, history of multifetal gestation was not associated with all-cause mortality, but may be associated with a lower risk of premature mortality., (© 2023 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Adults with multiple chronic conditions (MCC) are a heterogeneous population with elevated risk of future adverse health outcomes. Yet, despite the increasing prevalence of MCC globally, data about MCC in pregnancy are scarce., Objectives: To estimate the population prevalence of MCC in pregnancy and determine whether certain types of chronic conditions cluster together among pregnant women with MCC., Methods: We conducted a population-based cohort study in Ontario, Canada, of all 15-55-year-old women with a recognised pregnancy, from 2007 to 2020. MCC was assessed from a list of 22 conditions, identified using validated algorithms. We estimated the prevalence of MCC. Next, we used latent class analysis to identify classes of co-occurring chronic conditions in women with MCC, with model selection based on parsimony, clinical interpretability and statistical fit., Results: Among 2,014,508 pregnancies, 324,735 had MCC (161.2 per 1000, 95% confidence interval [CI] 160.6, 161.8). Latent class analysis resulted in a five-class solution. In four classes, mood and anxiety disorders were prominent and clustered with one additional condition, as follows: Class 1 (22.4% of women with MCC), osteoarthritis; Class 2 (23.7%), obesity; Class 3 (15.8%), substance use disorders; and Class 4 (22.1%), asthma. In Class 5 (16.1%), four physical conditions clustered together: obesity, asthma, chronic hypertension and diabetes mellitus., Conclusions: MCC is common in pregnancy, with sub-types dominated by co-occurring mental and physical health conditions. These data show the importance of preconception and perinatal interventions, particularly integrated care strategies, to optimise treatment and stabilisation of chronic conditions in women with MCC., (© 2023 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Background: High weight gain in pregnancy is associated with greater postpartum weight retention, yet long-term implications remain unknown. We aimed to assess whether gestational weight change was associated with mortality more than 50 years later., Methods: The Collaborative Perinatal Project (CPP) was a prospective US pregnancy cohort (1959-65). The CPP Mortality Linkage Study linked CPP participants to the National Death Index and Social Security Death Master File for vital status to 2016. Adjusted hazard ratios (HRs) with 95% CIs estimated associations between gestational weight gain and loss according to the 2009 National Academy of Medicine recommendations and mortality by pre-pregnancy BMI. The primary endpoint was all-cause mortality. Secondary endpoints included cardiovascular and diabetes underlying causes of mortality., Findings: Among 46 042 participants, 20 839 (45·3%) self-identified as Black and 21 287 (46·2%) as White. Median follow-up time was 52 years (IQR 45-54) and 17 901 (38·9%) participants died. For those who were underweight before pregnancy (BMI <18·5 kg/m 2 ; 3809 [9·4%] of 40 689 before imputation for missing data]), weight change above recommendations was associated with increased cardiovascular mortality (HR 1·84 [95% CI 1·08-3·12]) but not all-cause mortality (1·14 [0·86-1·51]) or diabetes-related mortality (0·90 [0·13-6·35]). For those with a normal pre-pregnancy weight (BMI 18·5-24·9 kg/m 2 ; 27 921 [68·6%]), weight change above recommendations was associated with increased all-cause (HR 1·09 [1·01-1·18]) and cardiovascular (1·20 [1·04-1·37]) mortality, but not diabetes-related mortality (0·95 [0·61-1·47]). For those who were overweight pre-pregnancy (BMI 25·0-29·9 kg/m 2 ; 6251 [15·4%]), weight change above recommendations was associated with elevated all-cause (1·12 [1·01-1·24]) and diabetes-related (1·77 [1·23-2·54]) mortality, but not cardiovascular (1·12 [0·94-1·33]) mortality. For those with pre-pregnancy obesity (≥30·0 kg/m 2 ; 2708 [6·7%]), all associations between gestational weight change and mortality had wide CIs and no meaningful relationships could be drawn. Weight change below recommended levels was associated only with a reduced diabetes-related mortality (0·62 [0·48-0·79]) in people with normal pre-pregnancy weight., Interpretation: This study's novel findings support the importance of achieving healthy gestational weight gain within recommendations, adding that the implications might extend beyond the pregnancy window to long-term health, including cardiovascular and diabetes-related mortality., Funding: National Institutes of Health., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Persons with non-O and Rh-positive blood types are purported to be more susceptible to infection, including SARS-CoV-2, but there remains uncertainty about the degree to which this is so for both non-viral and viral infections., Methods: We systematically reviewed Embase and PubMed from January 1 st 1960 to May 31 st 2022. English-language publications were selected that separately investigated the relation between ABO and/or Rh blood group and risk of SARS-CoV-2 and non-SARS-CoV-2 infection. Pooled odds ratios (OR p ) and 95% confidence intervals (CI) were then generated for each., Results: Non-O blood groups had a higher OR p for SARS-CoV-2 than O blood groups, both within 22 case-control studies (2.13, 95% CI 1.49- 3.04) and 15 cohort studies (1.89, 95% CI 1.56- 2.29). For non-SARS-CoV-2 viral infections, the respective OR p were 1.98 (95% CI 1.49-2.65; 4 case-control studies) and 1.87 (95% CI 1.53-2.29; 12 cohort studies). For non-viral infections, the OR p were 1.56 (95% CI 0.98-2.46; 13 case-control studies) and 2.11 (95% CI 1.67-6.67; 4 cohort studies). Rh-positive status had a higher OR p for SARS-CoV-2 infection within 6 case-control studies (13.83, 95% CI 6.18-30.96) and 6 cohort studies (19.04, 95% CI 11.63-31.17), compared to Rh-negative persons. For Rh status, non-SARS-CoV-2 infections, the OR p were 23.45 (95% CI 16.28-33.76) among 7 case-control studies, and 9.25 (95% CI 2.72-31.48) within 4 cohort studies. High measures of heterogeneity were notably observed for all analyses., Conclusions: Non-O and Rh-positive blood status are each associated with a higher risk of SARS-CoV-2 infection, in addition to other viral and non-viral infections., (© 2023. The Author(s).)

Severe maternal morbidity (SMM) refers to any unexpected outcome directly related to pregnancy and childbirth that results in both short-term delivery complications and long-term consequences to a women's health. This affects about 60,000 women annually in the United States. Cardiovascular contributions to SMM including cardiac arrest, arrhythmia, and acute myocardial infarction are on the rise, probably driven by changing demographics of the pregnant population including more women of extreme maternal age and an increased prevalence of cardiometabolic and structural heart disease. The utilization of SMM prediction tools and risk scores specific to cardiovascular disease in pregnancy has helped with risk stratification. Furthermore, health system data monitoring and reporting to identify and assess etiologies of cardiovascular complications has led to improvement in outcomes and greater standardization of care for mothers with cardiovascular disease. Improving cardiovascular disease-related SMM relies on a multipronged approach comprised of patient-level identification of risk factors, individualized review of SMM cases, and validation of risk stratification tools and system-wide improvements in quality of care. In this article, we review the epidemiology and cardiac causes of SMM, we provide a framework of risk prediction clinical tools, and we highlight need for organization of care to improve outcomes.

Background: Maternal adaptations may vary by foetal sex. Whether male infants influence long-term mortality in mothers remains uncertain., Objective: The objective of the study was to examine whether male infants increase the risk of maternal mortality., Methods: This study included pregnant women enrolled at 12 US sites from 1959 to 1966 in the Collaborative Perinatal Project (CPP). Collaborative Perinatal Project records were linked to the National Death Index and the Social Security Master Death File to ascertain deaths until 2016. Foetal sex was determined by infant sex at birth, defined as the total number of male or female infants in pregnancies prior to or during enrolment in the CPP. In secondary analyses, exposure was defined as infant sex at the last CPP delivery. Outcomes included all-cause and underlying causes of mortality. We used Cox proportional hazards models weighted by the number of prior live births and stratified our models by parity and race/ethnicity., Results: Among 48,188 women, 50.8% had a male infant at their last registered CPP pregnancy and 39.0% had a recorded death after a mean follow-up of 47.8 years (SD 10.5 years). No linear association was found between the number of liveborn males and all-cause mortality (primipara women: HR 1.02, 95% CI 0.95, 1.09, multipara women, 1 prior live birth: HR 0.96, 95% CI 0.89, 1.03, multipara women, ≥2 prior live births: HR 0.97, 95% CI 0.85, 1.11). A similar trend was noted for cardiovascular- and cancer-related mortality. At the last delivery, women with a male infant did not have an increased risk of all-cause or cause-specific mortality compared to women with a female infant. These findings were consistent across racial/ethnic groups., Conclusions: Women who give birth to male infants, regardless of number, are not at increased risk of all-cause and cause-specific mortality. These findings suggest that giving birth to male infants may not independently influence the long-term health of women., (© 2023 John Wiley & Sons Ltd.)

Background: Pregnant and postpartum women have been historically excluded from clinical trials, with data on the safety of drugs relying on observational research. Methodological concerns regarding the timing and dosing of medications, data sources, study designs, and methods used for estimating associations are still problematic in observational studies. Answering causal questions is even more complex. Despite the increased interest in emulating target trials using observational data, little is known about this approach in perinatal pharmacoepidemiology. Objective: This scoping review protocol aims to describe the methodology for assessing the available literature concerning emulating target trials for studying outcomes in women exposed to medications in the preconception, perinatal, or postpartum periods. Methods and Analysis: We will follow the methods detailed in the Joanna Briggs Institute reviewer's manual. We will adopt the six-stage framework recommended by Arksey and O'Malley and Levac and others. Web scraping techniques will be used for identifying relevant studies. Two authors will select articles based on the title and abstract, with discrepancies resolved by consensus, by a third reviewer. Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews flow diagram will be presented to reflect the search process. We will use existing statements to identify quality gaps in the current literature. Variables related to the content for perinatal pharmacoepidemiologic research will be included. The Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) will guide the assessment of the target trial emulation (i.e., treatment strategies compared, assignment procedures, follow-up period, outcome, and causal contrasts). Discussion: Data regarding the safety of drugs taken, prior to and during pregnancy and while lactating are lacking and it is necessary to understand how we can answer these questions using rigorous methods in observational research. Through this scoping review, we intend to understand to what extent the target trial approach is being used in perinatal pharmacoepidemiology and provide recommendations to improve its use in this field. Ethics and Dissemination: Secondary data from published scientific articles will be used, not requiring approval by the Research Ethics Committee with human beings. Findings will be submitted to a peer-reviewed journal., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Leal, Grandi, Mota, Ferreira, Gore and Platt.)

Pregnancy loss is a common reproductive complication, but its association with long-term mortality and whether this varies by maternal race/ethnicity is not well understood. Data from a racially diverse cohort of pregnant women enrolled in the Collaborative Perinatal Project (CPP) from 1959 to 1966 were used for this study. CPP records were linked to the National Death Index and the Social Security Death Master File to identify deaths and underlying cause (until 2016). Pregnancy loss comprised self-reported losses, including abortions, stillbirths, and ectopic pregnancies. Among 48,188 women (46.0% White, 45.8% Black, 8.2% other race/ethnicity), 25.6% reported at least 1 pregnancy loss and 39% died. Pregnancy loss was associated with a higher absolute risk of all-cause mortality (risk difference, 4.0 per 100 women, 95% confidence interval: 1.4, 6.5) and cardiovascular mortality (risk difference, 2.2 per 100 women, 95% confidence interval: 0.8, 3.5). Stratified by race/ethnicity, a higher risk of mortality persisted in White, but not Black, women. Women with recurrent losses are at increased risk of death, both overall and across all race/ethnicity groups. Pregnancy loss is associated with death; however, it does not confer an excess risk above the observed baseline risk in Black women. These findings support the need to assess reproductive history as part of routine screening in women., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Our study aimed to describe levothyroxine prescription patterns and trends over time among pregnant women with subclinical hypothyroidism (SCH) in the United Kingdom. We used data from the Clinical Practice Research Datalink linked to its Pregnancy Register and the Hospital Episode Statistics database from 1998 to 2017. The study population included women with a diagnosis of SCH or an abnormal thyroid-simulated hormone (TSH) level one year prior to or during pregnancy. We compared characteristics between women who received a prescription for levothyroxine during pregnancy and those who did not. We further described the timing, dose, duration, and temporal trends of levothyroxine prescriptions. Our cohort included 6,757 pregnancies from 6,287 women with SCH, of whom 10% received levothyroxine during pregnancy. Among women who received levothyroxine, most received their first prescription during the first trimester (median gestational age: 7 weeks; interquartile range [IQR]: 0, 16) with a median daily dosage of 50 mcg (IQR: 50, 73). Levothyroxine prescription varied over time, decreasing from 23% of pregnant women in 1998 to 7.5% in 2003, remaining stable until 2014, and increasing to 12.5% in 2016. Smoking, diabetes, polycystic ovary syndrome, infertility, timing of SCH diagnosis, age, TSH level at diagnosis, and general practice regions were associated with prescription. Few women with SCH received levothyroxine during pregnancy, and treatment varied by patient characteristics and geographical regions. These results highlight the need to increase awareness among healthcare providers and will guide future studies that explore barriers to initiating levothyroxine treatment for women with SCH during pregnancy., (© 2021 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Background: In perinatal epidemiology, the development of risk prediction models is complicated by parity; how repeat pregnancies influence the predictive accuracy of models that include obstetrical history is unclear., Methods: To assess the influence of repeat pregnancies on the association between predictors and the outcomes, as well as the influence of ignoring the nonindependence between pregnancies, we created four analytical cohorts using the Clinical Practice Research Datalink. The cohorts included (1) first deliveries, (2) a random sample of one delivery per woman, (3) all eligible deliveries per woman, and (4) all eligible deliveries and censoring of follow-up at subsequent pregnancies. Using Plasmode simulations, we varied the predictor-outcome association across cohorts., Results: We found minimal differences in the relative contribution of predictors to the overall predictions and the discriminative accuracy of models in the cohort of randomly sampled deliveries versus the all deliveries cohort (C-statistic: 0.62 vs. 0.63; Nagelkerke's R2: 0.03 for both). Accounting for clustering and censoring upon subsequent pregnancies also had negligible influence on model performance. We found important differences in model performance between the models developed in the cohort of first deliveries and the random sample of deliveries., Conclusions: In our study, a model including first deliveries had the best predictive accuracy but was not generalizable to women of varying parities. Moreover, including repeat pregnancies did not improve the predictive accuracy of the models. Multiple models may be needed to improve the transportability and accuracy of prediction models when the outcome of interest is influenced by parity., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Levothyroxine replacement therapy may decrease the risk of adverse pregnancy outcomes among women with subclinical hypothyroidism (SCH). The aim of this study is to conduct a systematic review and meta-analysis to examine the risk of adverse pregnancy, perinatal, and early childhood outcomes among women with SCH treated with levothyroxine., Methods: A systematic literature search was conducted using Ovid-Medline, Ovid-EMBASE, Pubmed (non-Medline), Ebsco-CINAHL Plus with full text and Cochrane Library databases. Randomized controlled studies (RCTs) and observational studies examining the association between treatment of SCH during pregnancy and our outcomes of interest were included. Studies that compared levothyroxine treatment versus no treatment were eligible for inclusion. Data from included studies were extracted and quality assessment was performed by two independent reviewers., Results: Seven RCTs and six observational studies met our inclusion criteria. A total of 7342 individuals were included in these studies. RCTs demonstrated several sources of bias, with lack of blinding of the participants or research personnel; only one study was fully blinded. In the observational studies, there was moderate to serious risk of bias due to lack of adjustment for certain confounding variables, participant selection, and selective reporting of results. Pooled analyses showed decreased risk of pregnancy loss (RR: 0.79; 95% CI: 0.67 to 0.93) and neonatal death (RR: 0.35; 95% CI: 0.17 to 0.72) associated with levothyroxine treatment during pregnancy among women with SCH. There were no associations between levothyroxine treatment and outcomes during labour and delivery, or cognitive status in children at 3 or 5 years of age., Conclusion: Treatment of SCH with levothyroxine during pregnancy is associated with decreased risks of pregnancy loss and neonatal death. Given the paucity of available data and heterogeneity of included studies, additional studies are needed to address the benefits of levothyroxine use among pregnant women with SCH.

Hypertensive disorders of pregnancy account for approximately 22% of all maternal deaths in Latin America and the Caribbean. Pharmacotherapies play an important role in preventing and reducing the occurrence of adverse outcomes. However, the patterns of medications used for treating women with hypertensive disorders of pregnancy (HDP) living in this country is unclear. A population-based birth cohort study including 4262 women was conducted to describe the pattern of use of cardiovascular agents and acetylsalicylic acid between women with and without HDP in the 2015 Pelotas (Brazil) Birth Cohort. The prevalence of maternal and perinatal outcomes in this population was also assessed. HDP were classified according to Ministry of Health recommendations. Medications were defined using the Anatomical Therapeutic Chemical Classification System and the substance name. In this cohort, 1336 (31.3%) of women had HDP. Gestational hypertension was present in 636 (47.6%) women, 409 (30.6%) had chronic hypertension, 191 (14.3%) pre-eclampsia, and 89 (6.7%) pre-eclampsia superimposed on chronic hypertension. Approximately 70% of women with HDP reported not using any cardiovascular medications. Methyldopa in monotherapy was the most frequent treatment (16%), regardless of the type of HDP. Omega-3 was the medication most frequently reported by women without HDP. Preterm delivery, caesarean section, low birth weight, and neonatal intensive care admissions were more prevalent in women with HDP. Patterns of use of methyldopa were in-line with the Brazilian guidelines as the first-line therapy for HDP. However, the large number of women with HDP not using medications to manage HDP requires further investigation.

Background: Women with a history of certain pregnancy complications are at higher risk for cardiovascular (CVD) disease. However, most clinical guidelines only recommend postpartum follow-up of those with a history of preeclampsia, gestational diabetes mellitus, or preterm birth. This systematic review was undertaken to determine if there is an association between a broader array of pregnancy complications and the future risk of CVD., Methods: We systematically searched PubMed, MEDLINE and EMBASE (via Ovid), CINAHL, and the Cochrane Library from inception to September 22, 2017, for observational studies of the association between the hypertensive disorders of pregnancy, placental abruption, preterm birth, gestational diabetes mellitus, low birth weight, small-for-gestational-age birth, stillbirth, and miscarriage and subsequent CVD. Likelihood ratio meta-analyses were performed to generate pooled odds ratios (OR) and 95% intrinsic confidence intervals (ICI)., Results: Our systematic review included 84 studies (28 993 438 patients). Sample sizes varied from 250 to 2 000 000, with a median follow-up of 7.5 years postpartum. The risk of CVD was highest in women with gestational hypertension (OR 1.7; 95% ICI, 1.3-2.2), preeclampsia (OR 2.7; 95% ICI, 2.5-3.0), placental abruption (OR 1.8; 95% ICI, 1.4-2.3), preterm birth (OR 1.6; 95% ICI, 1.4-1.9), gestational diabetes mellitus (OR 1.7; 95% ICI, 1.1-2.5), and stillbirth (OR 1.5; 95% ICI, 1.1-2.1). A consistent trend was seen for low birth weight and small-for-gestational-age birth weight but not for miscarriage., Conclusions: Women with a broader array of pregnancy complications, including placental abruption and stillbirth, are at increased risk of future CVD. The findings support the need for assessment and risk factor management beyond the postpartum period.

Background: Previous studies suggest that women with hypertensive disorders of pregnancy (HDP) are at increased risk of subsequent cardiovascular disease (CVD). However, it is unclear whether this association differs by timing of onset of HDP., Methods: A population-based cohort of 146,748 women, aged 15-45 years, with a first recorded pregnancy were identified in the Clinical Practice Research Datalink. HDP were defined between 18 weeks gestation and 6 weeks postpartum and further sub-classified as early- (<34 weeks) and late-onset HDP (≥34 weeks). The primary outcome was incident CVD, and the secondary outcome was incident hypertension. We used marginal structural Cox models to account for time-varying exposure and confounding., Results: Compared with women with no HDP, those with early-onset HDP had a higher risk of developing incident CVD (HR 2.6, 95% CI 1.5, 4.3) and hypertension (HR 4.3, 95% CI 3.6, 5.0). Wide CIs precluded any conclusions regarding a difference in the risk of incident CVD and hypertension in women with early- vs late-onset HDP (HR 0.90, 95% CI 0.50, 1.62 and HR 1.06, 95% CI 0.87, 1.28, respectively)., Conclusion: HDP in at least one pregnancy was associated with an increased risk of subsequent CVD or hypertension, irrespective of time of diagnosis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Hypertensive disorders in pregnancy (HDP) have been shown to predict later risk of cardiovascular disease (CVD). However, previous studies have not accounted for subsequent pregnancies and their complications, which are potential confounders and intermediates of this association., Methods: A cohort of 146 748 women with a first pregnancy was constructed using the Clinical Practice Research Datalink. HDP was defined using diagnostic codes, elevated blood pressure readings, or new use of an anti-hypertensive drug between 18 weeks' gestation and 6 weeks post-partum. The study outcomes were incident CVD and hypertension. Marginal structural Cox models (MSM) were used to account for time-varying confounders and intermediates. Time-fixed exposure defined at the first pregnancy was used in secondary analyses., Results: A total of 997 women were diagnosed with incident CVD, and 6812 women were diagnosed with hypertension or received a new anti-hypertensive medication during the follow-up period. Compared with women without HDP, those with HDP had a substantially higher rate of CVD (hazard ratio (HR) 2.2, 95% confidence interval (CI) 1.7, 2.7). In women with HDP, the rate of hypertension was five times that of women without a HDP (HR 5.6, 95% CI 5.1, 6.3). With overlapping 95% CIs, the time-fixed analysis and the MSM produced consistent results for both outcomes., Conclusions: Women with HDP are at increased risk of developing subsequent CVD and hypertension. Similar estimates obtained with the MSM and the time-fixed analysis suggests that subsequent pregnancies do not confound a first episode of HDP and later CVD., (© 2017 John Wiley & Sons Ltd.)

Background: Previous trials examining the use of bupropion for smoking cessation therapy after myocardial infarction (MI) have been inconclusive. To understand better the observed lack of effectiveness of bupropion in this population, we examined abstinence rates by level of adherence across treatment groups., Methods: We used data from a randomized, double-blind, placebo-controlled trial of bupropion in smokers (n = 388) hospitalized with MI to study the association of interest. Patients were classified as being fully adherent if they reported taking 2 pills/d; partially adherent if they reported 0, 1, and/or 2 pills/d; and nonadherent if they reported 0 and/or 1 pill/d throughout the 9-week treatment period. Abstinence was assessed by 7-day biochemically validated self-report at 4 and 9 weeks and 6 and 12 months., Results: A total of 156 patients were fully adherent to the study medication (66 bupropion and 90 placebo), 149 were partially adherent (76 and 73, respectively), and 83 were nonadherent (46 and 37, respectively). Regardless of treatment group, patients who were fully or partially adherent reported greater abstinence than did nonadherent patients. Among partially adherent patients, bupropion conferred an important benefit at 12 months (% difference 13.3, 95% CI 1.3-25.3). At 12 months, patients who were fully adherent were more likely to be abstinent compared with those who were nonadherent (adjusted odds ratio 7.6, 95% CI 3.2-17.6)., Conclusions: Adherence to study medication, regardless of assigned treatment, is associated with a substantial increase in abstinence. Patients who are motivated to quit smoking should be targeted for smoking cessation treatment after MI., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Current guidelines recommend smoking cessation and weight management for secondary prevention in patients post-myocardial infarction. However, little is known about the effects of smoking cessation on weight change post-myocardial infarction., Methods: We examined patterns of weight change and its effects on blood pressure and glycemic control using data from a randomized trial investigating the effect of bupropion on smoking cessation in patients post-myocardial infarction. Weight change was compared among 3 groups of patients: those who were completely abstinent (n = 92), those who smoked intermittently (n = 49), and those who smoked persistently (n = 38) during the 12-month follow-up. Analyses were restricted to patients who attended all follow-up visits., Results: The median weight at baseline was 77.1 kg (interquartile range [IQR], 66.0, 87.5), and 64.3% of patients were overweight/obese (body mass index ≥25.0 kg/m(2)). The median weight gain at 12 months was 4.0 kg (IQR, 0-7.0), with more than one third gaining >5 kg. The proportion of patients who were overweight/obese increased by approximately 10%, and 23.2% of patients moved up a body mass index category. Abstainers gained a median of 4.8 kg (IQR, 1.0, 8.6), intermittent smokers gained a median of 2.0 kg (IQR, -2.0, 5.0), and persistent smokers gained a median of 3.0 kg (IQR, -0.8, 6.0). Weight gain was associated with an increase in blood pressure and requirements for hypoglycemic medications at 12 months., Conclusions: The majority of patients attempting to quit smoking gain weight 12 months post-myocardial infarction, with abstainers gaining more weight than those who return to smoking. Weight gain was associated with an increased prevalence of hypertension and diabetes., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Limited data exist regarding the management of patients with acute coronary syndrome (ACS) in high-income countries compared with low/middle-income countries. We aimed to compare in-hospital trends of revascularization and prescription of medications at discharge in patients with ACS from high-income (Canada and United States) and low/middle-income (India, Iran, Pakistan, and Tunisia) countries. Data from a double-blind, placebo-controlled, randomized trial investigating the effect of bupropion on smoking cessation in patients after an enzyme-positive ACS was used for our study. A total of 392 patients, 265 and 127 from high-income and from low/middle-income countries, respectively, were enrolled. Patients from high-income countries were older, and were more likely to have diagnosed hypertension and dyslipidemia. During the index hospitalization, patients from high-income countries were more likely to be treated by percutaneous coronary intervention (odds ratio [OR] 19.7, 95% confidence interval [CI] 10.5 to 37.0). Patients with ST elevation myocardial infarction from high-income countries were more often treated by primary percutaneous coronary intervention (OR 16.3, 95% CI 6.3 to 42.3) in contrast with thrombolytic therapy (OR 0.24, 95% CI 0.14 to 0.41). Patients from high-income countries were also more likely to receive evidence-based medications at discharge (OR 2.32, 95% CI 1.19 to 4.52, a composite of aspirin, clopidogrel, and statin). In conclusion, patients with ACS in low/middle-income countries were less likely to be revascularized and to receive evidence-based medications at discharge. Further studies are needed to understand the underutilization of procedures and evidence-based medications in low/middle-income countries., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The use of bupropion, a smoking cessation aid, has been associated with improved health-related quality of life (HRQOL) in the general population of smokers; but, its effect on HRQOL in post-myocardial infarction (MI) patients remains unknown., Objectives: To examine the effect of bupropion on HRQOL in post-MI patients who are attempting to quit smoking., Methods: To accomplish this objective, we used data from a randomized, double-blind, placebo-controlled trial in 392 hospitalized post-MI patients. Treatment duration was 9 weeks, and follow-up was 12 months. HRQOL was assessed via the EuroQol-5D (EQ-5D) questionnaire, which includes 5 dimensions (mobility, self-care, daily activities, pain/discomfort, and anxiety/depression). Analyses were restricted to patients (n=225) who completed the EQ-5D at baseline, 6 months, and 12 months., Results: Patients randomized to bupropion (n=109) and those randomized to placebo (n=116) experienced similar improvements in HRQOL during follow-up (difference in change in EQ-5D index from baseline to 6 months = 0.02, 95% confidence interval [CI] = -0.04, 0.08; from baseline to 12 months = 0.02, 95% CI = -0.04, 0.08). No between-group differences were observed in any of the 5 dimensions. Similar improvements in HRQOL were observed between patients who remained abstinent and those who relapsed. Lower baseline HRQOL, defined as having a HRQOL that was less than the median value, was associated with decreased smoking abstinence at 12 months follow-up (odds ratio OR =0.39, 95% CI = 0.22, 0.68)., Conclusions: Bupropion does not improve HRQOL among patients attempting to quit smoking post-MI.