Severe Maternal and Neonatal Morbidity Among Gestational Carriers : A Cohort Study.

BACKGROUND: Use of a gestational ("surrogate") carrier is increasingly common. Risk for maternal and neonatal adversity is largely unknown in this birthing population. OBJECTIVE: To determine the risk for severe maternal morbidity (SMM) and severe neonatal morbidity (SNM) in gestational carriers. DESIGN: Population-based cohort study. SETTING: All of Ontario, Canada. PARTICIPANTS: All singleton births at more than 20 weeks' gestation, from 2012 to 2021. MEASUREMENTS: Exposure was type of conception, namely, gestational carriage (main exposure), unassisted conception (comparison group 1), and in vitro fertilization (IVF) (comparison group 2). Main composite outcomes were SMM and SNM. Modified Poisson regression models generated weighted relative risks (wRRs) using propensity score-based overlap weighting. Secondary outcomes included hypertensive disorders of pregnancy, cesarean delivery, preterm birth, and postpartum hemorrhage. RESULTS: Of all eligible singleton births, 846 124 (97.6%) were by unassisted conception, 16 087 (1.8%) by IVF, and 806 (0.1%) by gestational carriage. Respective risks for SMM were 2.3%, 4.3%, and 7.8%. The wRRs were 3.30 (95% CI, 2.59 to 4.20) comparing gestational carriage with unassisted conception and 1.86 (CI, 1.36 to 2.55) comparing gestational carriage with IVF. Respective risks for SNM were 5.9%, 8.9%, and 6.6%, generating wRRs of 1.20 (CI, 0.92 to 1.55) for gestational carriage versus unassisted conception and 0.81 (CI, 0.61 to 1.08) for gestational carriage versus IVF. Hypertensive disorders, postpartum hemorrhage, and preterm birth at less than 37 weeks were also significantly higher contrasting gestational carriers to either comparison group. LIMITATION: Absence of information about indications for choosing a gestational carrier, and oocyte or sperm donor source. CONCLUSION: Among singleton births of more than 20 weeks' gestation, a higher risk for SMM and adverse pregnancy outcomes was seen among gestational carriers compared with women who conceived with and without assistance. Although gestational carriage was associated with preterm birth, there was less clear evidence of severe neonatal morbidity. Potential mechanisms for higher maternal morbidity among gestational carriers require elucidation, alongside developing special care plans for gestational carriers. PRIMARY FUNDING SOURCE: The Canadian Institutes of Health Research.

Endometriosis and mental health: a population-based cohort study.

BACKGROUND: Endometriosis is a chronic gynecologic disorder that leads to considerable pain and a reduced quality of life. Although its physiological manifestations have been explored, its impact on mental health is less well defined. Existing studies of endometriosis and mental health were conducted within diverse healthcare landscapes with varying access to care and with a primary focus on surgically diagnosed endometriosis. A single-payer healthcare system offers a unique environment to investigate this association with fewer barriers to access care while considering the mode of endometriosis diagnosis. OBJECTIVE: Our objective was to assess the association between endometriosis and the risk for mental health conditions and to evaluate differences between patients diagnosed medically and those diagnosed surgically. STUDY DESIGN: A matched, population-based retrospective cohort study was conducted in Ontario and included patients aged 18 to 50 years with a first-time endometriosis diagnosis between January 1, 2010, and July 1, 2020. Endometriosis exposure was determined through either medical or surgical diagnostic criteria. A medical diagnosis was defined by the use of the corresponding International Classification of Disease diagnostic codes from outpatient and in-hospital visits, whereas a surgical diagnosis was identified through inpatient or same-day surgeries. Individuals with endometriosis were matched 1:2 on age, sex, and geography to unexposed individuals without a history of endometriosis. The primary outcome was the first occurrence of any mental health condition after an endometriosis diagnosis. Individuals with a mental health diagnosis in the 2 years before study entry were excluded. Cox regression models were used to generate hazard ratios with adjustment for hysterectomy, salpingo-oophorectomy, infertility, pregnancy history, qualifying surgery for study inclusion, immigration status, history of asthma, abnormal uterine bleeding, diabetes, fibroids, hypertension, irritable bowel disorder, migraines, and nulliparity. RESULTS: A total of 107,832 individuals were included, 35,944 with a diagnosis of endometriosis (29.5% medically diagnosed, 60.5% surgically diagnosed, and 10.0% medically diagnosed with surgical confirmation) and 71,888 unexposed individuals. Over the study period, the incidence rate was 105.3 mental health events per 1000 person-years in the endometriosis group and 66.5 mental health events per 1000 person-year among unexposed individuals. Relative to the unexposed individuals, the adjusted hazard ratio for a mental health diagnosis was 1.28 (95% confidence interval, 1.24-1.33) among patients with medically diagnosed endometriosis, 1.33 (95% confidence interval, 1.16-1.52) among surgically diagnosed patients, and 1.36 (95% confidence interval, 1.2-1.6) among those diagnosed medically with subsequent surgical confirmation. The risk for receiving a mental health diagnosis was highest in the first year after an endometriosis diagnosis and declined in subsequent years. The cumulative incidence of a severe mental health condition requiring hospital visits was 7.0% among patients with endometriosis and 4.6% among unexposed individuals (hazard ratio, 1.56; 95% confidence interval, 1.53-1.59). CONCLUSION: Endometriosis, regardless of mode of diagnosis, is associated with a marginally increased risk for mental health conditions. The elevated risk, particularly evident in the years immediately following the diagnosis, underscores the need for proactive mental health screening among those newly diagnosed with endometriosis. Future research should investigate the potential benefits of mental health interventions for people with endometriosis with the aim of enhancing their overall quality of life.

Miscarriage after SARS-CoV-2 vaccination: A population-based cohort study.

OBJECTIVE: To evaluate the risk of miscarriage following SARS-CoV-2 vaccination, while accounting for the competing risk of induced abortion. DESIGN: Population-based cohort study. SETTING: Ontario, Canada. PARTICIPANTS: Women aged 15-50 years with a confirmed pregnancy at ≤19 completed weeks' gestation. METHODS: Exposure to first SARS-CoV-2 vaccination, handled in a time-varying manner, was defined as (i) unvaccinated, (ii) remotely vaccinated >28 days before the estimated conception date or (iii) recently vaccinated ≤28 days before conception and up to 120 days after conception. MAIN OUTCOME MEASURES: The outcome was miscarriage, occurring between the estimated date of conception and up to 19 completed weeks of pregnancy. Fine-Grey hazard models, accounting for the competing risk of induced abortion, generated hazard ratios (aHR), adjusted for socio-demographic factors, comorbidities, and biweekly periods. RESULTS: Included were 246 259 pregnant women, of whom 34% received a first SARS-CoV-2 vaccination. Miscarriage occurred at a rate of 3.6 per 10 000 person-days among remotely vaccinated women and 3.2 per 10 000 person-days among those recently vaccinated, in contrast to a rate of 1.9 per 10 000 person-days among unvaccinated women, with corresponding aHR of 0.98 (95% confidence interval [CI] 0.91-1.07) and 1.00 (95% CI 0.93-1.08). CONCLUSIONS: SARS-CoV-2 vaccination was not associated with miscarriage while accounting for the competing risk of induced abortion. This study reiterates the importance of including pregnant women in new vaccine clinical trials and registries, and the rapid dissemination of vaccine safety data.

Maternal exposure to metals and time-to-pregnancy: The MIREC cohort study.

OBJECTIVE: To study the association between maternal exposure to arsenic, cadmium, lead, manganese and mercury, time-to-pregnancy (TTP) and infertility. DESIGN: Pregnancy-based retrospective TTP cohort study. SETTING: Hospitals and clinics from ten cities across Canada. POPULATION: A total of 1784 pregnant women. METHODS: Concentrations of arsenic, cadmium, lead, manganese and mercury were measured in maternal whole blood during the first trimester of pregnancy as a proxy of preconception exposure. Discrete-time Cox proportional hazards models generated fecundability odds ratios (FOR) for the association between metals and TTP. Logistic regression generated odds ratios (OR) for the association between metals and infertility. Models were adjusted for maternal age, pre-pregnancy body mass index, education, income, recruitment site and plasma lipids. MAIN OUTCOME MEASURES: TTP was self-reported as the number of months of unprotected intercourse to become pregnant. Infertility was defined as TTP longer than 12 months. RESULTS: A total of 1784 women were eligible for the analysis. Mean ± SD maternal age and gestational age at interview were 32.2 ± 5.0 years, and 11.6 ± 1.6 weeks, respectively. Exposure to arsenic, cadmium, manganese or mercury was not associated with TTP or infertility. Increments of one standard deviation of lead concentrations resulted in a shorter TTP (adjusted FOR 1.09, 95% CI 1.02-1.16); however, the association was not linear when exposure was modelled in tertiles. CONCLUSION: Blood concentrations of metals at typical levels of exposure among Canadian pregnant women were not associated with TTP or infertility. Further studies are needed to assess the role of lead, if any, on TTP.

The varying estimation of infertility in Ethiopia: the need for a comprehensive definition.

BACKGROUND: Infertility is a marginalized sexual and reproductive health issue in low-resource settings. Globally, millions are affected by infertility, but the lack of a universal definition makes it difficult to estimate the prevalence of infertility at the population level. Estimating the prevalence of infertility may inform targeted and accessible intervention, especially for a resource-limited country like Ethiopia. This study aims to estimate the prevalence of female infertility in Ethiopia using the Demographic and Health Survey (DHS) through two approaches: (i) the demographic approach and (ii) the current duration approach. METHODS: Data from 15,683 women were obtained through the 2016 Ethiopian DHS. The demographic approach estimates infertility among women who had been married/in a union for at least five years, had never used contraceptives, and had a fertility desire. The current duration approach includes women at risk of pregnancy at the time of the survey and determines their current length of time-at-risk of pregnancy at 12, 24, and 36 months. Logistic regression analysis estimated the prevalence of infertility and factors associated using the demographic approach. Parametric survival analysis estimated the prevalence of infertility using the current duration approach. All estimates used sampling weights to account for the DHS sampling design. STATA 14 and R were used to perform the statistical analysis. RESULTS: Using the demographic definition, the prevalence of infertility was 7.6% (95% CI 6.6-8.8). When stratified as primary and secondary infertility, the prevalence was 1.4% (95% CI 1.0-1.9) and 8.7% (95% CI 7.5-10.1), respectively. Using the current duration approach definition, the prevalence of overall infertility was 24.1% (95% CI 18.8-34.0) at 12-months, 13.4% (95% CI 10.1-18.6) at 24-months, and 8.8% (95% CI 6.5-12.3) at 36-months. CONCLUSION: The demographic definition of infertility resulted in a lower estimate of infertility. The current duration approach definition could be more appropriate for the early detection and management of infertility in Ethiopia. The findings also highlight the need for a comprehensive definition of and emphasis on infertility. Future population-based surveys should incorporate direct questions related to infertility to facilitate epidemiological surveillance.

Polycystic Ovary Syndrome, Gestational Diabetes Mellitus, and the Mediating Role of Obesity: A Population-Based Cohort Study.

This population-based cohort study in Ontario, Canada evaluated the association between polycystic ovary syndrome (PCOS) and gestational diabetes mellitus, and the mediating effect of obesity. The study included 1 268 901 pregnancies between 2006 and 2018; 387 748 with maternal PCOS and 881 153 without PCOS. Modified Poisson regression generated relative risks adjusted for maternal covariates. Causal mediation analyses accounted for the indirect effect of obesity. Relative to individuals without PCOS, those with PCOS had a slightly higher rate (6.0% vs. 4.9%) and adjusted relative risk (1.05; 95% CI 1.03-1.06) of gestational diabetes mellitus. Obesity mediated a significant proportion (90%) of this association. Preconception counselling and future research should include strategies to support weight optimization in patients with PCOS.

Pregnancy Outcomes in Survivors of Adolescent and Young Adult Breast Cancer: A Population-Based Cohort Study.

OBJECTIVES: To evaluate the association between adolescent and young adult (AYA) breast cancer (BC) and the adverse pregnancy outcomes of preterm birth, small for gestational age birth, cesarean delivery, and preeclampsia, and the effect of fertility treatment on this association. METHODS: Population-based cohort study with universal coverage health data for Ontario, Canada. BC was identified from the Ontario Cancer Registry. All births >220 weeks gestation between April 2006 to March 2018 were included. Modified Poisson regression generated risk ratios between AYA BC and adverse pregnancy outcomes, adjusted for maternal characteristics. Models were stratified by fertility treatment. RESULTS: Among 1 189 980 deliveries, 474 mothers had AYA BC history (exposed), while 1 189 506 had no cancer history (unexposed). AYA BC was associated with cesarean delivery (adjusted risk ratio [aRR] 1.26; 95% CI 1.14-1.39). There was no association between AYA BC and other adverse outcomes. Modelling cesarean delivery subtypes, AYA BC was associated with increased risk of planned (aRR 1.27; 95% CI 1.08-1.49) and unplanned cesarean delivery (aRR 1.41; 95% CI 1.20-1.66). An increased risk of cesarean delivery in exposed persisted among singleton pregnancies (aRR 1.27; 95% CI 1.15-1.41), but not in models stratified by mode of conception (fertility treatment: aRR 1.07; 95% CI 0.84-1.36; unassisted conception: aRR 1.30; 95% CI 1.16-1.46). CONCLUSIONS: A history of AYA BC did not confer an elevated risk of adverse pregnancy outcomes, except for planned and unplanned cesarean delivery. The risk of adverse pregnancy outcomes does not appear to be an indication for delayed pregnancy after AYA BC diagnosis.

Endometriosis, Severe Maternal Morbidity, and the Effect of Infertility: Population-Based Cohort Study.

This population-based cohort evaluated the association between endometriosis and severe maternal morbidity (SMM), and the mediating effect of infertility and fertility treatment. Included were all singleton deliveries in Ontario between 2006 and 2014. Modified Poisson regression generated adjusted relative risks. Mediation analysis estimated the direct effect of endometriosis and indirect effect through infertility and mode of conception. 787 449 deliveries were included (19 099, 2.4% with endometriosis). SMM occurred in 29.0 per 1000 deliveries among women with endometriosis, in contrast to 18.2 per 1000 deliveries among those without endometriosis-corresponding to an adjusted relative risk of SMM of 1.43 (95% CI 1.31-1.56). Mediation analysis demonstrated that the effect of endometriosis on SMM was independent of infertility or fertility treatment. We conclude that SMM in women with endometriosis appears to be due to the disease itself and not to infertility or related treatments.

The contributions of fertility during adolescence to disability across the life-course: hypothesized causal pathways, research gaps, and future directions.

CONTEXT: Robust associations have been identified between fertility during adolescence and the disablement process, including pathologies, impairments, functional limitations and disability. Limited theoretical or empirical research considers how and why such relationships exist generally or with the individual associated components of disablement. OBJECTIVE: To consolidate and critically evaluate literature to describe testable, theory-based hypotheses to guide future research on the mechanisms by which fertility during adolescence contributes to disablement. METHODS: Targeted literature review of research from diverse global settings contextualised in two well-accepted theoretical frameworks in life-course epidemiology: the cumulative risk model and the critical period approach. RESULTS: Five hypothesised causal pathways linking adolescent fertility to disablement in later life are described: 1) Causal relationship initiated by fertility during adolescence; 2) Common cause(s) for both, such as adverse childhood experiences; 3) Contributing cause(s) to adolescent fertility; 4) Interaction between adolescent fertility and other risk factors; and 5) Critical period effects unique to adolescence. Most research on the topic is on pathologies versus functional limitations and disability. CONCLUSION: We highlight promising research avenues to inform future research and interventions on adolescent fertility and the disablement process. This work provides theoretical clarity, identifies research gaps, and offers hypotheses-testing opportunities for future research.

Cohort profile update: The Canadian Maternal-Infant Research on Environmental Chemicals Child Development study (MIREC-CD PLUS).

BACKGROUND: The pan-Canadian Maternal-Infant Research on Environmental Chemicals (MIREC) study was established to determine whether maternal environmental chemical exposures were associated with adverse pregnancy outcomes in 2001 pregnant women. OBJECTIVES: The MIREC-Child Development (CD PLUS) study followed this cohort with the goal of assessing the potential effects of prenatal exposures on anthropometry and neurodevelopment in early childhood. POPULATION: MIREC families with children between the ages of 15 months and 5 years who had agreed to be contacted for future research (n = 1459) were invited to participate in MIREC-CD PLUS which combines data collected from an online Maternal Self-Administered Questionnaire with biomonitoring and neurodevelopment data collected from two in-person visits. PRELIMINARY RESULTS: Between April 2013 and March 2015, 803 children participated in the Biomonitoring visit where we collected anthropometric measures, blood, and urine from the children. The Behavioural Assessment System for Children-2, Behaviour Rating Inventory of Executive Function, MacArthur-Bates Communicative Development Inventories and the Communication subscale of the Adaptive Behaviour Scale from the Bayley Scales of Infant and Toddler Development-III are available on close to 900 children. There were 610 singleton children who completed in-person visits for neurodevelopment assessments including the Social Responsiveness Scale, Wechsler Preschool Primary Scale of Intelligence-III and NEuroPSYchological assessments (NEPSY). Currently, we are following the cohort into early adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC-ENDO). CONCLUSIONS: Data collection for the MIREC-CD PLUS study is complete and analysis of the data continues. We are now extending the follow-up of the cohort into adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC-ENDO). MIREC-CD PLUS is limited by loss to follow-up and the fact that mothers are predominately of higher socioeconomic status and 'White' ethnicity, which limits our generalizability. However, the depth of biomonitoring and clinical measures in MIREC provides a platform to examine associations of prenatal, infancy and childhood exposures with child growth and development.

Accuracy of Serum Human Chorionic Gonadotrophin for Estimating Gestational Age in the First Trimester of Pregnancy: Population-Based Study.

This study determined the accuracy of first-trimester serum human chorionic gonadotrophin (hCG) for estimating gestational age (GA). We included 273 584 singleton live births that had a first-trimester ultrasound and measured serum hCG at 4-12 weeks gestation in Ontario from 2012 to 2018. We estimated hCG accuracy compared to known GA, within a boundary of ± 1 week. Between 4 to 8 weeks gestation, sensitivity of hCG was over 88% and specificity over 51%. However, at 9-12 weeks gestation, sensitivity declined from 72% to 0%, and specificity rose from 86% to 100%. At all GA, the positive predictive value was consistently under 42%, while negative predictive values were over 96%. Within epidemiological studies in which GA is otherwise unknown, first-trimester serum hCG may aid somewhat in estimating GA between 4 to 6 weeks gestation, but much less so thereafter. Thus, there remains an ongoing need for an accurate method for estimating missing GA within large datasets.

Premature ovarian insufficiency in female adolescent and young adult survivors of non-gynecological cancers: a population-based cohort study.

BACKGROUND: The risk of premature ovarian insufficiency (POI) is increased in adolescent and young adult (AYA) cancer survivors, with the prevalence depending on cancer diagnosis, treatment, and patient factors. Prior studies are limited by sample size and type of cancer included. The objective of this study was to assess the risk of POI in female AYA survivors of non-gynecologic cancers, using a population-based approach. METHODS: This population-based retrospective cohort study comprises 21,666 females, 15-39 years old, diagnosed with a single non-gynecologic cancer in Ontario, Canada from 1995 to 2015. Through health administrative data linkage, participants were followed until their 40th birthday, December 31, 2018, bilateral oophorectomy, loss of health insurance eligibility or death. Each cancer survivor was matched to 5 females who were not diagnosed with cancer (unexposed, n = 108,330). Women with bilateral oophorectomy or a prior menopause diagnosis were excluded. POI was identified through use of the ICD-9 code for menopause (ICD9-627). Modified Poisson regression models were used to calculate the adjusted relative risk (aRR) of POI for AYA cancer survivors compared to unexposed individuals, adjusted for income, parity, age, and immigration status. RESULTS: The occurrence of POI was higher in survivors of AYA cancer versus unexposed patients (5.4% vs. 2.2%). Survivors of AYA cancer had an increased risk of POI relative to unexposed patients (aRR 2.49; 95% CI 2.32-2.67). Risk varied by type of cancer: breast (4.32; 3.84-4.86), non-Hodgkin's lymphoma (3.77; 2.88-4.94), Hodgkin's lymphoma (2.37; 1.91-2.96), leukemia (14.64; 10.50-20.42), thyroid (1.26; 1.09-1.46) and melanoma (1.04; 0.82-1.32). Risk varied by age at time of cancer diagnosis, with a higher risk among females diagnosed at age 30-39 years (3.07; 2.80-3.35) than aged 15-29 years (1.75; 1.55-1.98). CONCLUSIONS: AYA survivors of non-gynecologic cancers are at an increased risk of POI, particularly survivors of lymphomas, leukemia, breast, and thyroid cancer. The risk of POI is increased for those diagnosed with cancer at an older age. These results should inform reproductive counseling of female AYAs diagnosed with cancer.

Premature ovarian insufficiency is the onset of premature menopause in individuals less than 40-years-old. Previous research has shown that there is a higher risk of premature ovarian insufficiency in adolescent and young adult cancer survivors, due to the toxicity of cancer treatments on reproductive organs. Prior research was limited in its applicability by having small sample sizes, only including childhood cancer, excluding young adults, and studying fewer types of cancer. This study was conducted using a large population-based approach, on all females aged 15­39 years old with cancer in Ontario, Canada from 1995 to 2015. We found that there was nearly a 2.5 times greater risk of premature ovarian insufficiency in cancer survivors compared patients without cancer. Compared to patients without cancer, this risk was highest for survivors of leukemia (14 times higher risk), followed by breast cancer (4 times higher risk), lymphomas (2­4 times higher risk), and thyroid cancer (1.2 times higher risk). There is no increased risk in melanoma survivors. The risk was higher in individuals diagnosed with cancer at a later age (30­39 years), with a risk 3 times higher than the population without cancer, while a younger age of diagnosis (15­29 years) carries a risk only 1.75 times higher than the population without cancer. These results should help improve healthcare provider and patient understanding of the risk of premature ovarian insuficiency in young cancer survivors, and guide counseling at the time of cancer diagnosis and during survivorship on future reproductive function.

Attention-deficit hyperactivity disorder in children born to mothers with infertility: a population-based cohort study.

STUDY QUESTION: Is the risk of attention-deficit hyperactivity disorder (ADHD) increased in children born to mothers with infertility, or after receipt of fertility treatment, compared to mothers with unassisted conception? SUMMARY ANSWER: Infertility itself may be associated with ADHD in the offspring, which is not amplified by the use of fertility treatment. WHAT IS KNOWN ALREADY: Infertility, and use of fertility treatment, is common. The long-term neurodevelopmental outcome of a child born to a mother with infertility, including the risk of ADHD, remains unclear. STUDY DESIGN, SIZE, DURATION: This population-based cohort study comprised all singleton and multiple hospital births in Ontario, Canada, 2006-2014. Outcomes were assessed up to June 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Linked administrative datasets were used to capture all hospital births in Ontario, maternal health and pregnancy measures, fertility treatment and child outcomes. Included were all children born at ≥24 weeks gestation between 2006 and 2014, and who were alive at age 4 years. The main exposure was mode of conception, namely (i) unassisted conception (reference group), (ii) infertility without fertility treatment (history of an infertility consultation with a physician within 2 years prior to conception but no fertility treatment), (iii) ovulation induction (OI) or intrauterine insemination (IUI) and (iv) IVF or intracytoplasmic sperm injection (ICSI). The main outcome was a diagnosis of ADHD after age 4 years and assessed up to June 2020. Hazard ratios (HRs) were adjusted for maternal age, income quintile, rurality, immigration status, smoking, obesity, parity, any drug or alcohol use, maternal history of mental illness including ADHD, pre-pregnancy diabetes mellitus or chronic hypertension and infant sex. In addition, we performed pre-planned stratified analyses by mode of delivery (vaginal or caesarean delivery), infant sex, multiplicity (singleton or multiple), timing of birth (term or preterm <37 weeks) and neonatal adverse morbidity (absent or present). MAIN RESULTS AND THE ROLE OF CHANCE: The study included 925 488 children born to 663 144 mothers, of whom 805 748 (87%) were from an unassisted conception, 94 206 (10.2%) followed infertility but no fertility treatment, 11 777 (1.3%) followed OI/IUI and 13 757 (1.5%) followed IVF/ICSI. Starting at age 4 years, children were followed for a median (interquartile range) of 6 (4-8) years. ADHD occurred among 7.0% of offspring in the unassisted conception group, 7.5% in the infertility without fertility treatment group, 6.8% in the OI/IUI group and 6.3% in the IVF/ICSI group. The incidence rate (per 1000 person-years) of ADHD was 12.0 among children in the unassisted conception group, 12.8 in the infertility without fertility treatment group, 12.9 in the OI/IUI group and 12.2 in the IVF/ICSI group. Relative to the unassisted conception group, the adjusted HR for ADHD was 1.19 (95% CI 1.16-1.22) in the infertility without fertility treatment group, 1.09 (95% CI 1.01-1.17) in the OI/IUI group and 1.12 (95% CI 1.04-1.20) in the IVF/ICSI group. In the stratified analyses, these patterns of risk for ADHD were largely preserved. An exception was seen in the sex-stratified analyses, wherein females had lower absolute rates of ADHD but relatively higher HRs compared with that seen among males. LIMITATIONS, REASONS FOR CAUTION: Some mothers in the isolated infertility group may have received undocumented OI oral therapy, thereby leading to possible misclassification of their exposure status. Parenting behaviour, schooling and paternal mental health measures were not known, leading to potential residual confounding. WIDER IMPLICATIONS OF THE FINDINGS: Infertility, even without treatment, is a modest risk factor for the development of ADHD in childhood. The reason underlying this finding warrants further study. STUDY FUNDING/COMPETING INTEREST(S): This study was made possible with funding from the Canadian Institutes of Health Research, Grant number PJT 165840. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Prescribed opioid analgesics in early pregnancy and the risk of congenital anomalies: a population-based cohort study.

BACKGROUND: Recent data suggest an increased risk of congenital anomalies with prenatal exposure to opioid analgesics. We sought to further quantify the risk of anomalies after opioid analgesic exposure during the first trimester in a population-based cohort study. METHODS: Using administrative health data from Ontario, we followed 599 579 gestational parent-infant pairs from singleton pregnancies without opioid use disorder. We identified opioid analgesics dispensed in the first trimester and congenital anomalies diagnosed during the first year of life. We estimated propensity score-adjusted risk ratios (RRs) between first trimester exposure (any opioid analgesic and specific agents) and congenital anomalies (any anomaly, organ system anomalies, major or minor anomalies and specific anomalies). RESULTS: The prevalence of congenital anomalies was 2.8% in exposed infants and 2.0% in unexposed infants. Relative to unexposed infants, we observed elevated risks among those who were exposed for some anomaly groups, including gastrointestinal anomalies (any opioid analgesic: adjusted RR 1.46, 95% confidence interval [CI] 1.15-1.85; codeine: adjusted RR 1.53, 95% CI 1.12-2.09; tramadol: adjusted RR 2.69, 95% CI 1.34-5.38) and several specific anomalies, including ankyloglossia (any opioid: adjusted RR 1.88, 95% CI 1.30-2.72; codeine: adjusted RR 2.14, 95% CI 1.35-3.40). These findings persisted in sensitivity analyses. INTERPRETATION: Although the absolute risk of congenital anomalies was low, our findings add to accumulating data that suggest a small increased risk of some organ system anomalies and specific anomalies with first trimester exposure to opioid analgesics. These findings further quantify the potential risks associated with prenatal exposure to opioid analgesics to inform treatment choices for pain in pregnancy.

Severe Maternal Morbidity and Maternal Mortality Associated with Assisted Reproductive Technology.

OBJECTIVE: To assess the association between use of assisted reproductive technologies (ART) and severe maternal morbidity and maternal mortality (SMM). METHODS: We carried out a cohort study that included all hospital deliveries at ≥20 weeks gestation in Canada (excluding Québec) between April 2009 and March 2018. Outcomes of interest included composite SMM and SMM types (e.g., severe preeclampsia, HELLP syndrome, and eclampsia; severe hemorrhage; acute renal failure). Multivariable regression was used to estimate crude and adjusted rate ratios (RR and aRR) and 95% confidence intervals (CI). RESULTS: The study included 2 535 056 women, of whom 72 023 (2.8%) delivered following the use of ART. The composite SMM rate for women who used ART was 34.7 per 1000 deliveries (95% CI 33.0-36.0) versus 11.5 per 1000 deliveries (95% CI 11.4-11.6) for women who did not use ART (RR 3.01; 95% CI 2.89-3.14). ART use was associated with SMM types such as severe preeclampsia, HELLP syndrome, and eclampsia (RR 3.50; 95% CI 3.27-3.73), severe hemorrhage (RR 3.58, 95% CI 3.27-3.92), and acute renal failure (RR 6.79; 95% CI 5.78-7.98). Associations between ART and composite SMM were attenuated but remained elevated after adjusting for maternal characteristics (aRR 2.34; 95% CI 2.24-2.45). Women who used ART and had a multi-fetal pregnancy had a 4.7 times higher rate of composite SMM compared with women who did not use ART and delivered singletons. CONCLUSION: Women who deliver following the use of ART have increased risks of SMM and require counselling that includes mention of the lower risks of SMM associated with ART-conceived singleton pregnancy.

Outcomes of Pregnant Women With Cirrhosis and Their Infants in a Population-Based Study.

BACKGROUND & AIMS: The incidence of cirrhosis is increasing among women of childbearing age. Contemporary outcomes of pregnant women with cirrhosis and their infants, as well as liver-related complications, have not been described in North America, to our knowledge. We investigated the association between cirrhosis and perinatal outcomes and evaluated perinatal liver-related events. METHODS: We performed a retrospective cohort study using population-based administrative health care data from Ontario, Canada (2000-2017). We identified pregnant women with compensated cirrhosis (n = 2022) using validated case definitions and routine mother-infant linkage; the women were matched to 10,110 pregnant women in the general population (1:5) based on birth year and socioeconomic status. Maternal and infant outcomes up to 6 weeks postpartum and liver-related complications up to 1 year postpartum were evaluated by using multivariate log-binomial regression. RESULTS: After we adjusted for demographic and metabolic risk factors, cirrhosis was independently associated with intrahepatic cholestasis of pregnancy (relative risk [RR], 10.64; 95% confidence interval [CI], 7.49-15.12), induction of labor (RR, 1.15; 95% CI, 1.03-1.28), puerperal infections (RR, 1.32; 95% CI, 1.02-1.70), preterm birth (RR, 1.60; 95% CI, 1.35-1.89), infants who were large for gestational age (RR, 1.24; 95% CI, 1.05-1.46), and neonatal respiratory distress (RR, 1.20; 95% CI, 1.02-1.42). Fewer than 2% of pregnant women with cirrhosis had liver-related complications, but these occurred in a significantly higher proportion of women with a history of hepatic decompensation (13%) than women with compensated cirrhosis (1.2%) (P < .001). CONCLUSIONS: In a population-based study, we found that cirrhosis is an independent risk factor for adverse perinatal outcomes. However, liver-related complications are rare. Multidisciplinary teams are needed to coordinate care for pregnant women with cirrhosis during pregnancy and postpartum to optimize outcomes.

Prenatal Opioid Analgesics and the Risk of Adverse Birth Outcomes.

BACKGROUND: It is unclear whether confounding accounts for the increased risk of preterm birth and small for gestational age (SGA) birth in opioid analgesic exposed pregnancies. METHODS: Using universal coverage health data for Ontario, we assembled a cohort of mother-infant pairs without opioid use disorder (627,172 pregnancies and 509,522 women). We estimated risk ratios (RRs) between opioid analgesics and preterm birth, SGA birth, and stillbirth; neonatal abstinence syndrome was a secondary outcome. We used high-dimensional propensity scores and sensitivity analyses for confounding adjustment. RESULTS: 4% of pairs were exposed, mainly to codeine (2%), morphine (1%), and oxycodone (1%). Compared with unexposed, the adjusted risk of preterm birth was higher with any (1.3, 95% confidence interval [CI] = 1.2, 1.3), first- (RR: 1.2, 95% CI = 1.2, 1.3), and second-trimester (RR: 1.3, 95% CI = 1.2, 1.4) opioid analgesic exposure. Preterm birth risk was higher for first- and second-trimester codeine, morphine, and oxycodone exposure, and for third-trimester morphine. There was a small increase in SGA with first-trimester exposure to any opioid analgesic or to codeine. Exposed pregnancies had an elevated stillbirth risk with any (RR: 1.6, 95% CI = 1.4, 1.8), first- and second-trimester exposure. Few infants had neonatal abstinence syndrome (N = 143); the risk was higher in exposed (RR: 3.6, 95% CI = 2.1, 6.0). In sensitivity analyses of unmeasured confounding, an elevated risk in exposed pregnancies persisted for preterm birth but not SGA. CONCLUSIONS: Opioid analgesic-exposed pregnancies had a small increased risk of preterm birth and possibly stillbirth after accounting for confounding by indication and sociodemographic factors.

Long-term follow-up of endometriosis surgery in Ontario: a population-based cohort study.

BACKGROUND: Endometriosis is a chronic gynecological disease affecting approximately 10% of reproductive aged females and leads to decreased quality of life and productivity. Despite effective medical options, many women do require surgery for endometriosis. There is limited literature examining long term outcomes of endometriosis surgery. OBJECTIVE: This study aimed to characterize the long-term outcomes, including recurrence of symptoms, fertility outcomes, and need for reoperation, of patients who underwent surgical management for endometriosis. STUDY DESIGN: This was a population-based cohort study in which the universal coverage health database for the province of Ontario, Canada, was used to identify women aged 18 to 50 years who underwent surgery for endometriosis from April 1, 2002, through March 31, 2018. Surgery was classified as diagnostic laparoscopy, conservative or uterine preserving (minor or major, with and without ovarian preservation), or hysterectomy (with and without ovarian preservation). The outcomes were evaluated from 30 days after the index surgery to the end of the study period or at censoring. Cox proportional hazard regression models were used to estimate the hazard ratios between exposures and outcomes following adjustment for confounders. RESULTS: A total of 84,885 women 2,718 (3.2%) diagnostic laparoscopy, 21,594 (25.4%) minor conservative surgery, 28,484 (33.6%); major conservative with ovarian preservation, 2,102 (2.5%) major conservative without ovarian preservation, 21,609 (25.5%) hysterectomy with ovarian preservation, and 8,378 (9.9%) hysterectomy without ovarian preservation) were included in the cohort and followed for a median of 10 years (interquartile range, 6-13 years). In the first postoperative year, women who underwent diagnostic laparoscopy were significantly more likely to require repeat surgery (adjusted hazard ratio, 1.68; 95% confidence interval, 1.51-1.87), whereas those who underwent major conservative surgery were significantly less likely to require repeat surgery (with ovarian preservation: adjusted hazard ratio, 0.44; 95% confidence interval, 0.41-0.48; without ovarian preservation: adjusted hazard ratio, 0.05; 95% confidence interval, 0.03-0.09). Among women who did not receive repeat surgery in the first year, those who underwent a diagnostic laparoscopy (adjusted hazard ratio, 0.85; 95% confidence interval, 0.76-0.95) and major conservative surgery without ovarian preservation were less likely to undergo repeat surgery (adjusted hazard ratio, 0.12; 95% confidence interval, 0.09-0.18) than those who initially had minor surgery. Compared with those who initially underwent minor surgery, patients who underwent other treatment modalities were less likely to undergo a hysterectomy (diagnostic laparoscopy: adjusted hazard ratio, 0.85; 95% confidence interval, 0.75-0.96; major surgery with ovarian preservation: adjusted hazard ratio, 0.60; 95% confidence interval, 0.57-0.64; major surgery without ovarian preservation: adjusted hazard ratio, 0.05; 95% confidence interval, 0.03-0.08). Following minor and major conservative with ovarian preservation surgery, 8,331 (38.6%) and 9,498 (33.3%) of patients sought an infertility consult within 1 year, respectively. By 5 years after the index surgery, 5,290 (29.4%) of patients who had minor conservative surgery and 4,528 (20.7%) of those who had major conservative with ovarian preservation surgery had given birth at least once. CONCLUSION: Our study suggests that only a few endometriosis patients who undergo hysterectomy surgery require repeat surgery; however, up to 1 in 4 who undergo minor surgery and 1 in 5 who undergo major conservative surgery with ovarian preservation require additional endometriosis surgery. Up to 1 in 3 patients who had uterine sparing endometriosis surgery subsequently sought an infertility assessment. These findings may inform preoperative counseling in terms of recurrence of symptoms, fertility outcomes, and need for reoperation of women seeking surgical management for endometriosis. Future studies should consider the outcomes of patient satisfaction and quality of life based on the current practices for management of endometriosis.

Assisted reproductive technology and hypertensive disorders of pregnancy: systematic review and meta-analyses.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) is one of the most common pregnancy complications and causes of maternal morbidity and mortality. Assisted reproductive technology (ART) has been associated with adverse pregnancy outcomes, including HDP. However, the impact of multiple pregnancies, oocyte donation, as well as fresh and frozen embryo transfer needs to be further studied. We conducted a systematic review and meta-analyses to evaluate the association between ART and HDP or preeclampsia relative to spontaneous conception (SC). METHODS: We identified studies from EMBASE, MEDLINE, and Cochrane Library (up to April 8, 2020) and manually using structured search strategies. Cohort studies that included pregnancies after in vitro fertilization (IVF) with or without intracytoplasmic sperm fertilization (ICSI) relative to SC with HDP or preeclampsia as the outcome of interest were included. The control group was women who conceived spontaneously without ART or fertility medications. The pooled results were reported in odds ratios (OR) with 95% confidence intervals based on random effects models. Numbers needed to harm (NNH) were calculated based on absolute risk differences between exposure and control groups. RESULTS: Eighty-five studies were included after a screening of 1879 abstracts and 283 full text articles. Compared to SC, IVF/ICSI singleton pregnancies (OR 1.70; 95% CI 1.60-1.80; I2 = 80%) and multiple pregnancies (OR 1.34; 95% CI 1.20-1.50; I2 = 76%) were both associated with higher odds of HDP. Singleton pregnancies with oocyte donation had the highest odds of HDP out of all groups analyzed (OR 4.42; 95% CI 3.00-6.51; I2 = 83%). Frozen embryo transfer resulted in higher odds of HDP (OR 1.74; 95% CI 1.58-1.92; I2 = 55%) than fresh embryo transfer (OR 1.43; 95% CI 1.33-1.53; I2 = 72%). The associations between IVF/ICSI pregnancies and SC were similar for preeclampsia. Most interventions had an NNH of 40 to 100, while singleton and multiple oocyte donation pregnancies had particularly low NNH for HDP (16 and 10, respectively). CONCLUSIONS: Our meta-analysis confirmed that IVF/ICSI pregnancies are at higher odds of HDP and preeclampsia than SC, irrespective of the plurality. The odds were especially high in frozen embryo transfer and oocyte donation pregnancies.

Short-term outcomes of endometriosis surgery in Ontario: A population-based cohort study.

INTRODUCTION: Our objective was to compare the short-term outcomes by type of surgical management of endometriosis in Ontario, Canada and to characterize the population of women undergoing surgical management of endometriosis. MATERIAL AND METHODS: We conducted a population-based cohort study including women aged 18-50 years undergoing same-day or inpatient surgery for endometriosis from 1 April 2002 through 31 March 2018. Surgery was classified as minimally invasive hysterectomy (MIH), total abdominal hysterectomy (TAH) or minor or major conservative (uterus-preserving) surgery. Outcomes examined included length of stay, intraoperative complications, postoperative complications, emergency department visits, ambulatory care visits, and readmission. We estimated the relative risk of these outcomes in minor, major conservative surgery and TAH vs MIH adjusted for age, income quintile, parity, and comorbidities. RESULTS: A total of 85 605 patients underwent surgery, 12.9% MIH, 22.1% TAH, 36.3% major conservative, and 28.6% minor conservative. The mean age at index surgery was 37.6 ± 7.7 years. Before surgery, 70.6% of patients had visited a physician for pain at least once (64.7% MIH, 69.5% TAH, 71.1% major conservative and 73.4% minor conservative) and 23.5% of patients had sought infertility consultation (5.7% MIH, 6.6% TAH, 29.3% major conservative and 37.1% minor conservative). The overall risk of intraoperative and postoperative complications was 1.5% and 4.7%, respectively. In adjusted models, compared with those undergoing minor conservative surgery, those having major conservative surgery were 1.77 (95% CI 1.49-2.11) times as likely to experience an intraoperative complication, those having MIH and TAH were 2.55 (95% CI 2.08-3.13) and 2.34 (95% CI 1.93-2.82) times as likely to do so, respectively. Similarly, compared with those undergoing minor conservative surgery, those having major conservative surgery were 2.60 (95% CI 2.30, 2.93) times as likely to experience any postoperative complication, and those having MIH and TAH were 4.69 (95% CI 4.11-5.36) and 5.38 (95% CI 4.76-6.09) times as likely to do so, respectively. CONCLUSIONS: Approximately one-third of patients undergoing surgical management for endometriosis in Ontario between 2002 and 2018 had a hysterectomy. Overall, complications following surgery were low, and dependent on extent of surgery. These results should help to inform preoperative counseling for patients and health policy development for providers.