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STUDY QUESTION Do publicly funded fertility treatment and single embryo transfer (SET) result in lower hospitalization rates of children of parents with infertility? SUMMARY ANSWER Following the 2010 Quebec law introducing free fertility treatment and SET, neonatal intensive care unit (NICU) admissions decreased among all children born to parents with infertility, but not among singletons, whose risk remained slightly higher than that of children of parents without infertility, even accounting for treatment and maternal age. WHAT IS KNOWN ALREADY Previous studies reported lower NICU admission rates among children conceived with ART after the 2010 law; however, children conceived without ART by parents with infertility were not considered. STUDY DESIGN, SIZE, DURATION Cohort study of children born in 1997–2017 to patients evaluated for infertility (‘exposed’) at an academic fertility center in Montreal (Canada) in 1996–2015. A random sample of births to Montreal residents served as comparison. Outcomes were identified from Quebec administrative databases. PARTICIPANTS/MATERIALS, SETTING, METHODS We compared children’s healthcare utilization before and after the 2010 law in 6273 exposed and 12 583 randomly sampled births (6846 and 12 775 children, respectively). We repeated the analysis among children conceived in the 63 months before and after the law (‘restricted period’), and examined whether differences in twinning, fertility treatment, and maternal age explained the higher risk of NICU admission among children of parents with infertility. MAIN RESULTS AND THE ROLE OF CHANCE In the exposed cohort, the proportion of twin births and of several adverse outcomes declined after the law. NICU admission and duration of NICU stay decreased overall, but not in singletons. Both measures remained higher in exposed children. Except for NICU admission, hospitalization rates were similar in exposed and random sample children. After accounting for fertility treatment and maternal age, exposed singletons were 17% more likely to be admitted to the NICU than children of parents with no medical history of infertility. LIMITATIONS, REASONS FOR CAUTION Sample size was relatively small; infertile patients were from a single center and the random sample from one city. Despite some limitations, administrative databases are likely to accurately reflect healthcare utilization. WIDER IMPLICATIONS OF THE FINDINGS Universal access to treatment and, particularly, SET results in an overall reduction of adverse outcomes among children conceived with treatment; however, children of parents with infertility are at a slightly higher risk, regardless of treatment. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by the Canadian Institutes for Health Research (CIHR, grant no. 123362). No competing interests. TRIAL REGISTRATION NUMBER N/A. more...

STUDY QUESTION Is parents’ age at birth associated with daughters’ fecundability? SUMMARY ANSWER Daughters born to mothers WHAT IS KNOWN ALREADY Two recent studies reported lower fecundability in women born to mothers STUDY DESIGN, SIZE, DURATION A retrospective cohort study of 58 496 pregnancy planners (4290 of whom conceived with treatment) and 14 194 non-planners enrolled in the Norwegian Mother, Father and Child Cohort Study (MoBa) between 2000 and 2008, linked with the Medical Birth Registry of Norway. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants were born in Norway between 1967 and 1990. We estimated fecundability ratios (FRs) and 95% CI as a function of both parents’ (F1) age at the daughter’s (F2) birth among non-treated planners and the relative risk of time to pregnancy (TTP) ≥12 months or treatment among all planners. We explored whether daughters of young mothers were under-represented among planners, compared with the underlying population. Finally, we estimated FRs after adding non-planners, randomly assigned to conceiving in the first cycle with probabilities of 0.60 and 0.70. MAIN RESULTS AND THE ROLE OF CHANCE For both mother and father, the reference category was 25–29 years. Fecundability was slightly lower among daughters of older fathers (FRs (95% CI): 0.95 (0.92, 0.98) for F1 father’s age 35–39 years and 0.93 (0.89, 0.97) for ≥40 years) and daughters of young mothers (0.92 (0.89, 0.96) for F1 mother’s age LIMITATIONS, REASONS FOR CAUTION This was a pregnancy cohort with retrospectively reported information on planning and TTP. Selection bias appears unlikely to fully explain the association with mother’s age WIDER IMPLICATIONS OF THE FINDINGS Daughters of young mothers or older fathers may have slightly lower fecundability. If corroborated, the finding about older paternal age is relevant, given the widespread tendency to delay childbearing. STUDY FUNDING/COMPETING INTEREST(S) This work was partly funded by the Research Council of Norway (project no. 320656), and through its Centres of Excellence funding scheme (project no. 262700). M.C.M. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 947684). No competing interests. TRIAL REGISTRATION NUMBER N/A. more...

Subfertility and infertility treatment can be stressful experiences, but it is unknown whether each predisposes to postpartum mental illness. We sought to evaluate associations between subfertility or infertility treatment and postpartum mental illness.We conducted a population-based cohort study of individuals without pre-existing mental illness who gave birth in Ontario, Canada, from 2006 to 2014, stratified by fertility exposure: subfertility without infertility treatment; noninvasive infertility treatment (intrauterine insemination); invasive infertility treatment (in vitro fertilization); and no reproductive assistance. The primary outcome was mental illness occurring 365 days or sooner after birth (defined as ≥ 2 outpatient visits, an emergency department visit or a hospital admission with a mood, anxiety, psychotic, or substance use disorder, self-harm event or other mental illness). We used multivariable Poisson regression with robust error variance to assess associations between fertility exposure and postpartum mental illness.The study cohort comprised 786 064 births (mean age 30.42 yr, standard deviation 5.30 yr), including 78 283 with subfertility without treatment, 9178 with noninvasive infertility treatment, 9633 with invasive infertility treatment and 688 970 without reproductive assistance. Postpartum mental illness occurred in 60.8 per 1000 births among individuals without reproductive assistance. Relative to individuals without reproductive assistance, those with subfertility had a higher adjusted relative risk of postpartum mental illness (1.14, 95% confidence interval 1.10-1.17), which was similar in noninvasive and invasive infertility treatment groups.Subfertility or infertility treatment conferred a slightly higher risk of postpartum mental illness compared with no reproductive assistance. Further research should elucidate whether the stress of infertility, its treatment or physician selection contributes to this association. more...

SGA (small for gestational age) is widely used to identify high-risk infants, although with inconsistent definitions. Cut points range from 2.5th to 10th percentile of birthweight-for-gestational age. We used receiver operator characteristic curves (ROC) to identify the cut point with maximum sensitivity and specificity (Youden Index), and the area under the curve (AUC), which assesses overall discriminating power. Analysis was conducted on 3,836,034 US births (2015) and 292,279 Norwegian births (2010–14). Birthweight percentiles were calculated using exact birthweights at each week of gestational age, and then summarized across gestational ages. We also conducted a companion analysis of gestational age itself to consider the predictive power of gestational week of birth. Outcomes were neonatal mortality and cerebral palsy, both strongly associated with birthweight. Birthweight percentiles performed poorly in all analyses. The AUC for birthweight percentiles as a discriminator of neonatal mortality was 60% (where 50% is no better than a coin-toss). At such low discrimination, the Youden Index provides no useful SGA cut point. Results in Norway were virtually identical, with an AUC of 58%. The AUC with cerebral palsy as the outcome was even lower, at 54%. In contrast, gestational age had an AUC of 85% as a predictor of neonatal mortality, with more...

Aim: To describe the direct healthcare costs associated with repeated cytotoxic chemotherapy treatments for recurrent high-grade serous cancer (HGSC) of the ovaries. Patients & methods: Retrospective review of 66 women with recurrent stage III/IV HGSC ovarian cancer treated with repeated lines of cytotoxic chemotherapy in a Canadian University Tertiary Center. Results: Mean cost of treatment of first relapse was CAD$52,227 increasing by 38% for two, and 86% for three or more relapses with median overall survival of 36.0, 50.7 and 42.8 months, respectively. In-hospital care accounted for 71% and chemotherapy drugs accounted for 17% of the total costs. Conclusion: After the third relapse of HGSC, cytotoxic chemotherapy did not prolong survival but was associated with substantially increased healthcare costs. more...

BACKGROUND Parental nativity, as well as duration of residence of foreign-born parents in the host country, has been shown to be associated with size at birth. However, most studies have focused on maternal nativity status only and have not accounted for important characteristics of both parents. OBJECTIVE To explore whether maternal and paternal nativity and length of residence (LOR) are independently associated with birthweight for gestational age in a representative sample of infants in Canada. METHODS We compared mean differences in sex- and gestational age-standardised birthweight z-score by nativity status of both parents in a nationally representative sample of 130,532 singleton infants born between May 2004 and May 2006 to mothers residing in Canada. We categorised parental nativity status into four groups (both parents Canada-born, mother only foreign-born, father only foreign-born and both parents foreign-born) and parents' LOR into three (both ≤10 years, only one parent ≤10 years and both >10 years). We estimated mean differences in birthweight z-score and their 95% confidence intervals in linear regression models adjusted for parity, parents' ages, education, ethnicity and marital status of the mother. RESULTS Compared with babies of Canada-born couples, those of two foreign-born parents had on average smaller birthweight z-score, -0.23 (95% CI -0.28, -0.25). However, after adjustment, the mean difference in z-score was -0.02 (95% CI -0.05, 0.00). Infants born to parents who had both resided in Canada for ≤10 years had a unadjusted mean difference in z-score of -0.27 (95% CI -0.29, -0.26), compared infants whose parents were both Canada-born, but the difference became negligible (-0.02, 95% CI -0.04, 0.01) after adjustment. CONCLUSION The birthweight differences by parental nativity or length of residence observed in our study population could be attributed to differences in the distribution of other parental characteristics that affect birthweight. more...

SGA (small for gestational age) is widely used to identify high-risk infants, although with inconsistent definitions. Cut points range from 2.5th to 10th percentile of birthweight-for-gestational age. We used receiver operator characteristic curves (ROC) to identify the cut point with maximum sensitivity and specificity (Youden Index), and the area under the curve (AUC), which assesses overall discriminating power. Analysis was conducted on 3,836,034 US births (2015) and 292,279 Norwegian births (2010-14). Birthweight percentiles were calculated using exact birthweights at each week of gestational age, and then summarized across gestational ages. We also conducted a companion analysis of gestational age itself to consider the predictive power of gestational week of birth. Outcomes were neonatal mortality and cerebral palsy, both strongly associated with birthweight. Birthweight percentiles performed poorly in all analyses. The AUC for birthweight percentiles as a discriminator of neonatal mortality was 60% (where 50% is no better than a coin-toss). At such low discrimination, the Youden Index provides no useful SGA cut point. Results in Norway were virtually identical, with an AUC of 58%. The AUC with cerebral palsy as the outcome was even lower, at 54%. In contrast, gestational age had an AUC of 85% as a predictor of neonatal mortality, with 37 weeks as the optimum cut point. SGA provides surprisingly poor identification of at-risk infants, while gestational age performs well. Similar results in two countries that differ in mean birthweight, percent preterm, and neonatal mortality suggest robustness across populations. more...

STUDY QUESTION Is fecundability associated with miscarriage history and future miscarriage risk? SUMMARY ANSWER Prior miscarriage was associated with lower fecundability, and participants with a history of subfertility (time-to-pregnancy (TTP) ≥12 months) were at a higher risk of subsequent miscarriage. WHAT IS KNOWN ALREADY Although miscarriage and low fecundability share common risk factors, prior studies have reported both lower and higher fecundability after miscarriage. STUDY DESIGN, SIZE, DURATION In this study, we examined two related associations: one, between miscarriage history and subsequent fecundability and, two, between fecundability and miscarriage risk in the subsequent pregnancy. The study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa). In addition, the outcome of the pregnancy after the MoBa index pregnancy was obtained by linking information from three national health registries: the Medical Birth Registry of Norway, the Norwegian Patient Registry and the general practice database. PARTICIPANTS/MATERIALS, SETTING, METHODS We examined the association between number of prior miscarriages and fecundability in 48 537 naturally conceived, planned pregnancies in participants with at least one prior pregnancy. We estimated fecundability ratios (FRs) and 95% CIs using proportional probability regression. We further estimated the relative risk (RR) of miscarriage in the subsequent pregnancy as a function of TTP in the MoBa index pregnancy for 7889 pregnancies using log-binomial regression. Multivariable analyses adjusted for maternal age, pre-pregnancy maternal BMI, smoking status, cycle regularity, income level and highest completed or ongoing education. MAIN RESULTS AND THE ROLE OF CHANCE Fecundability decreased as the number of prior miscarriages increased. The adjusted FRs among women with one, two and three or more prior miscarriages were 0.83 (95% CI: 0.80–0.85), 0.79 (95% CI: 0.74–0.83) and 0.74 (95% CI: 0.67–0.82), respectively, compared with women with no prior miscarriages. Compared to women with a TTP of LIMITATIONS, REASONS FOR CAUTION Information on TTP and prior miscarriages was obtained retrospectively, and TTP was self-reported. MoBa is a pregnancy cohort, and findings may not be generalizable to all women. We were unable to examine the effect of changing partners between pregnancies, as well as other paternal factors such as seminal parameters. We also did not know what proportion of our participants had changed partners between their prior pregnancies and the index pregnancy. Furthermore, it is likely that many early miscarriages are not recognized. WIDER IMPLICATIONS OF THE FINDINGS The association between miscarriage and fecundability may reflect a contribution of occult pregnancy losses to TTP, as well as shared underlying causes for reduced fecundability and miscarriage. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by the Research Council of Norway through its Medical Student Research Program funding scheme (project number 271555/F20), its Centres of Excellence funding scheme (project number 262700) and through the project ‘Women's fertility – an essential component of health and well-being’ (project number 320656). M.C.M. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement number 947684). A.J.W. is supported by the Intramural Program of the National Institute of Environmental Health Sciences at the National Institutes of Health, USA. The authors report no competing interests. TRIAL REGISTRATION NUMBER N/A. more...

Objective: To improve the prediction of maternal end-organ injury or death using routinely-collected variables from the pre-pregnancy and the early pregnancy period. Design: Population-based cohort study using linked administrative health data. Setting: Ontario, Canada, April 1, 2006 to March 31, 2014. Sample: Women aged 18-60 years with a livebirth or stillbirth, of which one birth was randomly selected per woman. Methods and main outcome measures: We constructed a CPM for the primary composite outcome of any maternal end-organ injury or death, arising between 20 weeks’ gestation and 42 days after the birth hospital discharge date. Our CPM included variables collected from 12 months before estimated conception until 19 weeks’ gestation. We developed a separate CPM for parous women to allow for the inclusion of factors from previous pregnancy(ies). Results: Of 634,290 women, 1969 experienced the primary composite outcome (3.1 per 1000). Predictive factors in the main CPM included maternal world region of origin, chronic medical conditions, parity, and obstetrical/perinatal issues – with moderate model discrimination (C-statistic 0.68, 95% CI 0.66-0.69). Among 333,435 parous women, the C-statistic was 0.71 (0.69-0.73) in the model using variables from the current (index) pregnancy as well as pre-pregnancy predictors and variables from any previous pregnancy. Conclusions: A combination of factors ascertained early in pregnancy through a basic medical history help to identify women at risk for severe morbidity, who may benefit from targeted preventive and surveillance strategies including appropriate specialty-based antenatal care pathways. Further refinement of this model would enable clinical use. more...

To describe the association between maternal hypertension (chronic and gestational, MH) and mortality in very preterm singletons and twins, focusing on how estimates depend on gestational age (GA) and size at birth. We estimated relative risks of in-hospital death in 12,320 singletons (MH: 22.4%) and 4381 twins (MH: 10.6%) born at 23–29 weeks in the Italian Neonatal Network (89 hospitals, 2008–2016). Babies with MH had higher GA and were more frequently small-for-gestational age (SGA), especially singletons. In crude analyses, MH was associated with lower mortality in singletons. In multivariable analyses, the effects of GA and size differed between twins and singletons with and without MH. The best-fitting models included continuous birth weight (rather than SGA) and were stratified by GA. In these models, MH was associated with lower mortality in singletons—but not twins—born after week 25. In this cohort of very preterm infants, the association between MH and mortality differed between singletons and twins and across strata of GA at birth. These estimates cannot be interpreted causally, but suggest that, from a descriptive/predictive standpoint, singletons with MH born after week 25 have lower mortality than singletons born to women without MH. more...

BACKGROUND: The extent to which infertility treatment predicts severe maternal morbidity is not well known. We examined the association between infertility treatment and severe maternal morbidity in pregnancy and the postpartum period. METHODS: We conducted a cohort study using population-based registries from Ontario between 2006 and 2012. Pregnancies achieved using infertility treatment (ovulation induction, intrauterine insemination or in vitro fertilization with or without intracytoplasmic sperm injection) were compared with unassisted pregnancies using propensity score matching, based on demographic, reproductive and obstetric factors. The primary outcome was a validated composite of severe maternal morbidity or maternal death from 20 weeks’ gestation to 42 days postpartum. We also calculated the odds ratio of a woman having 1, 2, or 3 or more severe maternal morbidity indicators in relation to invasive (e.g., in vitro fertilization) or noninvasive (e.g., intrauterine insemination) infertility treatment. RESULTS: We matched 11 546 infertility treatment pregnancies with 47 553 untreated pregnancies. Severe maternal morbidity or maternal death occurred in 356 infertility-treated pregnancies (30.8 per 1000 deliveries) versus 1054 untreated pregnancies (22.2 per 1000 deliveries); relative risk 1.39 (95% confidence interval [CI] 1.23–1.56). The likelihood of a woman having 3 or more severe maternal morbidity indicators was increased in women who received invasive infertility treatment (odds ratio [OR] 2.28, 95% CI 1.56–3.33) but not in those who received noninvasive infertility treatment (OR 0.99, 95% CI 0.57–1.72). INTERPRETATION: Women who undergo infertility treatment, particularly in vitro fertilization, are at somewhat higher risk of severe maternal morbidity or death. Efforts are needed to identify patient- and treatment-specific predictors of severe maternal morbidity that may influence the type of treatment a woman is offered. more...

Preterm delivery is one of the strongest predictors of neonatal mortality. A given exposure may increase neonatal mortality directly, or indirectly by increasing the risk of preterm birth. Efforts to assess these direct and indirect effects are complicated by the fact that neonatal mortality arises from two distinct denominators (i.e. two risk sets). One risk set comprises fetuses, susceptible to intrauterine pathologies (such as malformations or infection), which can result in neonatal death. The other risk set comprises live births, who (unlike fetuses) are susceptible to problems of immaturity and complications of delivery. In practice, fetal and neonatal sources of neonatal mortality cannot be separated – not only because of incomplete information, but because risks from both sources can act on the same newborn. We use simulations to assess the repercussions of this structural problem. We first construct a scenario in which fetal and neonatal factors contribute separately to neonatal mortality. We introduce an exposure that increases risk of preterm birth (and thus neonatal mortality) without affecting the two baseline sets of neonatal mortality risk. We then calculate the apparent gestational-age-specific mortality for exposed and unexposed newborns, using as the denominator either fetuses or live births at a given gestational age. If conditioning on gestational age successfully blocked the mediating effect of preterm delivery, then exposure would have no effect on gestational-age-specific risk. Instead, we find apparent exposure effects with either denominator. Except for prediction, neither denominator provides a meaningful way to define gestational-age-specific neonatal mortality. more...

Observational cohort studies represent one of the most powerful designs in epidemiology. They are also the basis of evidence in many areas of obstetric and gynecologic research, given that randomization of women, couples or pregnancies is often impossible or unethical. Indeed, well-conceived cohort studies have led to a better understanding of many important clinical and public health questions over time, including the impact of different exposures on perinatal and pediatric outcomes in pregnant women and their children. In this paper, we describe the main features, challenges, and limitations of cohort studies in the context of obstetric and gynecologic research. As with all epidemiologic studies, cohort studies present numerous challenges and are vulnerable to bias. However, as we describe throughout this review, careful design - from formulating the study question to planning statistical analysis - can reduce the potential for bias. When possible, we also provide examples from the gynecological and obstetrical literature to illustrate the epidemiological challenge and suggest specific readings. more...

Objective Using a simple simulation, we illustrate why associations estimated from studies restricted to preterm births cannot be interpreted causally. Design, Setting, and Population Data simulation involving a hypothetical cohort of fetuses who may be healthy or have one or more of four pathological factors (termed A through D, increasing in severity) with known effects on gestational length and risk of mortality. We focus on babies born ≤32 weeks of gestation. Methods We visually represent the simulated population and compare the association between A (which may represent preeclampsia) and neonatal death. We then repeat the exercise with D (standing in for chorioamnionitis) as the exposure of interest. Main Outcome Measures Odds ratios of neonatal death in the simulated data. Results In most weeks, and for both A and D, the calculated odds ratios are substantially biased and underestimate the true risk of neonatal death associated with each pathology. For example, factor A has a true causal odds ratio of 1.50, yet it appears protective among births ≤32 weeks (estimated crude odds ratio = 0.39; gestational age-adjusted odds ratio = 0.71). Conclusions Among very preterm births, virtually all babies are born with pathologies that increase risk of adverse outcomes. Thus, babies exposed to one factor (e.g., preeclampsia) are compared with babies who have a mix of other pathologies. Such selection bias affects studies carried out among very preterm births (e.g., where preeclampsia appears to reduce risk of neonatal outcomes). Funding JMS is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States National Institutes of Health (grant number R00 HD079658-03). This article is protected by copyright. All rights reserved. more...

Background The longer term cardiovascular effects of fertility therapy are unknown. Objectives The aim of this study was to summarize data linking fertility therapy with subsequent cardiovascular outcomes. Methods We systematically searched published reports for studies addressing the question “does fertility therapy increase the risk of longer term cardiovascular outcomes?” We included: 1) human studies; 2) case control, cohort, or randomized designs with 3) exposure to fertility therapy and 4) cardiovascular outcomes clearly reported; 5) presence of comparison group; 6) minimum 1-year follow-up; and 7) adjustment for age. Two independent reviewers screened abstracts, titles, and full texts, and assessed study quality. We used the DerSimonian and Laird random-effects models to pool hazard ratios (HRs) with 95% confidence intervals (CIs) of the following outcomes: acute cardiac event; stroke; venous thromboembolism; hypertension; and diabetes mellitus, comparing women who received fertility therapy with those who did not. Results Six observational studies met inclusion criteria including 41,910 women who received fertility therapy and 1,400,202 women who did not. There was no increased risk of a cardiac event (pooled HR: 0.91; 95% CI: 0.67 to 1.25; I2 = 36.6%), or diabetes mellitus (pooled HR: 0.93; 95% CI: 0.87 to 1.001; I2 = 0%). Results were not pooled for hypertension (I2 = 95.0%) and venous thromboembolism (I2 = 82.3%). There was a trend toward higher risk of stroke (pooled HR: 1.25; 95% CI: 0.96 to 1.63; I2 = 0%). Conclusions The small number of studies and significant heterogeneity precludes definitive reassurance about the longer term cardiovascular safety of these treatments, particularly stroke. Future studies are needed to address ongoing knowledge gaps in this area. more...

BACKGROUND Whether denominators for postnatal outcomes (ascertained after live birth) with a presumed prenatal origin should consist of fetuses or live births remains controversial. Proponents argue that the extended fetuses-at-risk (FAR) approach (a), provides a justification for medically indicated preterm delivery, (b), avoids paradoxical results, and (c), permits quantification of incidence of fetal-infant phenomena, such as "revealed" small for gestational age (SGA)-which, under FAR, rises with advancing gestation. METHODS This conceptual paper examines the validity of the above arguments. RESULTS As obstetricians induce babies early because of fetal (or maternal) compromise and despite the dangers posed by immaturity, there is no need to modify a paradigm that portrays preterm birth as a powerful risk factor. The FAR approach generally avoids "paradoxical" intersections because FAR rates of postnatal outcomes depend on the birth rate. However, this property, which causes rates of most postnatal outcomes to rise at term, can also lead to risk reversals and other misleading findings. The FAR formulation does not yield the incidence of postnatal conditions but, rather, the incidence of live birth (and survival to diagnosis) of babies with prevalent conditions (and, sometimes, future ones). CONCLUSIONS The proposed arguments do not provide adequate support for extending the FAR approach to postnatal outcomes. As only live births can contribute to the numerator of rates, the usefulness and interpretability of FAR measures in this setting are limited. more...

PURPOSE OF REVIEW: Human reproduction is a common process and one that unfolds over a relatively short time, but pregnancy and birth processes are challenging to study. Selection occurs at every step of this process (e.g., infertility, early pregnancy loss, and stillbirth), adding substantial bias to estimated exposure-outcome associations. Here we focus on selection in perinatal epidemiology, specifically, how it affects research question formulation, feasible study designs, and interpretation of results. RECENT FINDINGS: Approaches have recently been proposed to address selection issues in perinatal epidemiology. One such approach is the ongoing pregnancies denominator for gestation-stratified analyses of infant outcomes. Similarly, bias resulting from left truncation has recently been termed “live birth bias,” and a proposed solution is to control for common causes of selection variables (e.g., fecundity, fetal loss) and birth outcomes. However, these approaches have theoretical shortcomings, conflicting with the foundational epidemiologic concept of populations at risk for a given outcome. SUMMARY: We engage with epidemiologic theory and employ thought experiments to demonstrate the problems of using denominators that include units not “at risk” of the outcome. Fundamental (and commonsense) concerns of outcome definition and analysis (e.g., ensuring that all study participants are at risk for the outcome) should take precedence in formulating questions and analysis approach, as should choosing questions that stakeholders care about. Selection and resulting biases in human reproductive processes complicate estimation of unbiased exposure- outcome associations, but we should not focus solely (or even mostly) on minimizing such biases. more...

Objective To evaluate the change in the proportion of deaths/bronchopulmonary dysplasia (BPD) among premature infants (born Study design We examined 1249 infants (341 born Results Baseline characteristics were similar across sites and epochs. Medical treatment/ligation use remained stable at site 1 but declined progressively to 0% at site 2, indicating adherence to policy. We saw no difference in death/BPD among infants born at 26-29 weeks of gestational age (12%, 95% CI -1% to 24%). However, incidence of death/BPD increased by 31% among infants born Conclusions Adherence to a strict conservative policy did not impact death or BPD among 26 weeks but was associated with a significant rise in infants born more...

Diagnostic testing is recommended in women with “ovarian cancer symptoms.” However, these symptoms are nonspecific. The ongoing Diagnosing Ovarian Cancer Early (DOVE) Study in Montreal, Quebec, Canada, provides diagnostic testing to women aged 50 years or older with symptoms lasting for more than 2 weeks and less than 1 year. The prevalence of ovarian cancer in DOVE is 10 times that of large screening trials, prompting us to estimate the prevalence of these symptoms in this population. We sent a questionnaire to 3,000 randomly sampled women in 2014–2015. Overall, 833 women responded; 81.5% reported at least 1 symptom, and 59.7% reported at least 1 symptom within the duration window specified in DOVE. We explored whether such high prevalence resulted from low survey response by applying inverse probability weighting to correct the estimates. Older women and those from deprived areas were less likely to respond, but only age was associated with symptom reporting. Prevalence was similar in early and late responders. Inverse probability weighting had a minimal impact on estimates, suggesting little evidence of nonresponse bias. This is the first study investigating symptoms that have proven to identify a subset of women with a high prevalence of ovarian cancer. However, the high frequency of symptoms warrants further refinements before symptom-triggered diagnostic testing can be implemented. more...

Immunization of pregnant women against influenza has the potential to reduce adverse fetal outcomes by reducing prenatal exposure to influenza illness. However, as touched on by Fell et al. (Am J Epidemiol. 2016;184(3):163-175) and Vazquez-Benitez et al. (Am J Epidemiol. 2016;184(3):176-186) in this issue of the Journal, observational studies in which the causal effect of maternal influenza illness and influenza immunization on fetal health are evaluated are prone to bias because of the complex temporal nature of influenza illness seasonality, influenza immunization schedules, and gestation itself. Immortal time bias is introduced by an "anytime-in-pregnancy" exposure definition because the shortened pregnancy duration associated with many adverse fetal outcomes limits the opportunity to become exposed, whereas including follow-up time during which pregnancies are no longer at risk of an adverse outcome (e.g., gestational time after 37 weeks in studies of preterm birth) can lead to overestimation of any true benefits of immunization (or harms from influenza illness). We present a framework to avoid time-related biases in the study of influenza illness and immunization in pregnancy and advise that investigations of fetal benefit from maternal influenza immunization should only be undertaken when information is available on the calendar time of influenza virus circulation and the gestational age at which maternal influenza immunization occurred. more...

Background: Earlier studies on the association between antidepressant use and miscarriage have obtained conflicting results after accounting for the role of depression, and none have taken into account the high risk of induced abortions in women using antidepressants. Methods: We identified 41,964 pregnant women delivering between 1998 and 2002 using Quebec’s health administration databases. We compared women prescribed antidepressants in the first trimester and with a recorded diagnosis of depression before pregnancy to (1) women with neither antidepressant use nor a depression diagnosis before or during pregnancy; (2) women with a depression diagnosis before pregnancy, but no antidepressants prescribed in the first trimester; and (3) women prescribed hypothyroid medication in the first trimester, but not antidepressants. We used log binomial regression to assess the adjusted relative risk of miscarriage, corrected for induced abortion risk. Results: The miscarriage risk uncorrected for induced abortions was 16%, 10%, and 9% for depressed women exposed to antidepressants; unexposed depressed women; and unexposed, nondepressed women, respectively. These decreased to 11%, 8%, and 7% after correction for induced abortions. In multivariable analysis, the corrected risk of miscarriage relative to unexposed, nondepressed women was 1.3 (1.1–1.5) for antidepressant-exposed women and 1.1 (1.0–1.2) for unexposed depressed women. The miscarriage relative risk for antidepressant users compared with unexposed depressed women was thus 1.2 (1.0–1.4). Conclusions: Antidepressant use in the first trimester is associated with an increased risk of miscarriage when compared with either nondepressed or depressed unexposed women, even after accounting for induced abortions. more...

Background Some cardiovascular disease risk factors are associated with both risk of preeclampsia and having been born to a younger or older mother. We examined whether mother's age at delivery predicts a primiparous daughter's risk of preeclampsia. Methods The analysis included 39 803 Sister Study participants (designated as "daughters") born between 1930 and 1974. Using log-binomial regression, we estimated relative risks (RR) of preeclampsia in the first pregnancy ending in birth ("primiparous preeclampsia") associated with mother's age at the daughter's birth. Models included: number of older full and maternal half-siblings, income level growing up, daughter's age at delivery, race/ethnicity, and 5-year birth cohort. We examined self-reported relative weight at age 10 (heavier than peers versus not) as a potential effect measure modifier. Results Overall, 6.2% of daughters reported preeclampsia. Compared with those who had been born to 20-24-year old mothers, daughters of teenage mothers had a relative risk of 1.20 (95% confidence interval (CI) 1.01, 1.43) and daughters of mothers ≥25 had a ~10% lower risk. Relative weight at age 10 modified the association, with an inverse association between mother's age at delivery and preeclampsia seen only among daughters with low/normal childhood relative weight. In this subset, results were consistent across strata of daughter's age at menarche and age at first birth. Conclusions These findings, based on self-reported data, require replication. Nevertheless, as women increasingly delay childbearing, they provide some reassurance that having been born to an older mother is not, per se, a risk factor for primiparous preeclampsia. more...

Background The World Health Organization (WHO) recommends that women wait at least 24 months after a livebirth before attempting a subsequent pregnancy to reduce the risk of adverse maternal, perinatal, and infant health outcomes. However, the applicability of the WHO recommendations for women in the United States is unclear, as breast feeding, nutrition, maternal age at first birth, and total fertility rate differs substantially between the United States and the low‐ and middle‐resource countries upon which most of the evidence is based. Methods To inform guideline development for birth spacing specific to women in the United States, the Office of Population Affairs (OPA) convened an expert work group meeting in Washington, DC, on 14‐15 September 2017 among reproductive, perinatal, paediatric, social, and public health epidemiologists; obstetrician‐gynaecologists; biostatisticians; and experts in evidence synthesis related to women's health. Results Presentations and discussion topics included the methodological quality of existing studies, evaluation of the evidence for causal effects of short interpregnancy intervals on adverse perinatal and maternal health outcomes, good practices for future research, and identification of research gaps and priorities for future work. Conclusions This report provides an overview of the presentations, discussions, and conclusions from the expert work group meeting. more...

Background Meta‐analyses of observational studies have shown that women with a shorter interpregnancy interval (the time from delivery to start of a subsequent pregnancy) are more likely to experience adverse pregnancy outcomes, such as preterm delivery or small for gestational age birth, than women who space their births further apart. However, the studies used to inform these estimates have methodological shortcomings. Methods In this commentary, we summarise the discussions of an expert workgroup describing good practices for the design, analysis, and interpretation of observational studies of interpregnancy interval and adverse perinatal health outcomes. Results We argue that inferences drawn from research in this field will be improved by careful attention to elements such as: (a) refining the research question to clarify whether the goal is to estimate a causal effect vs describe patterns of association; (b) using directed acyclic graphs to represent potential causal networks and guide the analytic plan of studies seeking to estimate causal effects; (c) assessing how miscarriages and pregnancy terminations may have influenced interpregnancy interval classifications; (d) specifying how key factors such as previous pregnancy loss, pregnancy intention, and maternal socio‐economic position will be considered; and (e) examining if the association between interpregnancy interval and perinatal outcome differs by factors such as maternal age. Conclusion This commentary outlines the discussions of this recent expert workgroup, and describes several suggested principles for study design and analysis that could mitigate many potential sources of bias. more...

Background Gestational-age-specific rates of postnatal endpoints are sometimes estimated with denominators based on fetuses-at-risk (FAR), rather than live births. However, as infants can only be included in the numerator after they are born alive, interpretation of such rates is problematic. Methods Using simple algebra it can be shown that, at each gestational week, FAR rates of postnatal endpoints are the product of the conventional risk of outcome among live births and the probability of live birth, which increases from near zero early in gestation to close to one in the final weeks. The consequences of such a pattern of live birth on FAR rates are further illustrated in hypothetical scenarios with known conditions. Results FAR rates of postnatal endpoints will generally increase towards the end of pregnancy due to the rising probability of live birth, regardless of the ‘true’ effect of immaturity on risk. In the presence of an exposure that increases the probability of early birth, the same mechanism will cause FAR rates to be higher in the exposed group, even if the exposure has no effect. Conclusions Gestational-age-specific FAR rates of postnatal outcomes strongly depend on the probability of live birth. Thus, they reflect neither the causal effect of gestational length, nor that of a given exposure. Indeed, if an exposure shortens gestation, FAR rates will be higher in exposed infants even when the exposure has no impact on the outcome under study. These intrinsic limitations should be taken into account when applying FAR analyses to postnatal endpoints. more...

The sequelae of preterm births may differ, depending on whether birth follows an acute event or a chronic condition. In a population-based cohort study of 2,711,645 Canadian hospital deliveries from 2003 to 2012, 3,059 women experienced unintentional injury during pregnancy. We assessed the impact of the acute event on pregnancy outcome and on neonatal complications, such as nontraumatic intracranial hemorrhage, respiratory distress syndrome, intubation, and death. We adjusted for maternal age, parity, pregnancy conditions, and (for neonates) gestational age in logistic regression analyses. Injury was significantly associated with fetal mortality and early preterm delivery. For preterm infants born to injured women during the hospitalization for injury versus those born to noninjured women, the adjusted odds ratios were 2.25 (95% confidence interval (CI): 1.23, 4.17) for neonatal death, 2.44 (95% CI: 1.76, 3.37) for respiratory distress, 2.20 (95% CI: 1.26, 3.84) for nontraumatic intracranial hemorrhage, and 2.17 (95% CI: 1.60, 2.96) for intubation, despite more favorable fetal growth in those born to noninjured women (adjusted birth-weight-for-gestational-age z score: 0.154 vs. 0.024, P = 0.041; small-for-gestational-age rate: 4.5% vs. 9.5%, P = 0.001). Our findings suggest that adaptation to the suboptimal intrauterine environment underlying chronic causes of preterm birth may protect preterm infants from adverse sequelae. more...

Background: Preterm birth is a common, costly and dangerous pregnancy complication. Seasonality of risk would suggest modifiable causes. Methods: We examine seasonal effects on preterm birth, using data from the Medical Birth Registry of Norway (2 321 652 births), and show that results based on births are misleading and a fetuses-at-risk approach is essential. In our harmonic-regression Cox proportional hazards model we consider fetal risk of birth between 22 and 37 completed weeks of gestation. We examine effects of both day of year of conception (for early effects) and day of ongoing gestation (for seasonal effects on labour onset) as modifiers of gestational-age-based risk. Results: Naive analysis of preterm rates across days of birth shows compelling evidence for seasonality (P more...

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.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.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).HDP in at least one pregnancy was associated with an increased risk of subsequent CVD or hypertension, irrespective of time of diagnosis. more...

STUDY QUESTION: Is the death of a child associated with higher subsequent fertility?SUMMARY ANSWER: Women who had lost a child had higher fertility both shortly after the loss and throughout the entire follow-up, independent of the child's age at the time of death.WHAT IS KNOWN ALREADY: Women who lose a child in the perinatal period often have another child shortly after. However, to our knowledge no previous study has investigated if the death of an older child affects reproductive behavior.STUDY DESIGN, SIZE, DURATION: The source population for this matched cohort study consisted of all women who gave birth in Denmark from 1978 to 2004 and in Sweden from 1973 to 2002 (N = 1 979 958). Women were followed through to the end of 2008 in Denmark and the end of 2006 in Sweden.PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who had lost a child before the age of 45 years during the study period (exposed group; n = 36 511) were matched with up to five women who were from the same country and of similar age and family characteristics and had not lost a child at the time of matching (unexposed group; n = 182 522).MAIN RESULTS AND THE ROLE OF CHANCE: During follow-up, 74% of exposed and 46% of unexposed women had another birth (live- or stillbirth) after a gestation of 28 weeks or more. Compared with unexposed women, exposed women had a shorter interpregnancy interval and, consequently, a higher rate of conception leading to a birth (HR = 5.5 [95% CI: 5.4-5.6]). Rates for exposed women were higher from the first month following the child's death, but the largest difference was between 2 and 3 months after the event. This pattern was independent of the age of the deceased child. Exposed women had more subsequent children than unexposed, leading to a comparable number of living children at the end of follow-up.LIMITATIONS, REASONS FOR CAUTION: The use of population-based registers allows for the inclusion of virtually all eligible women and nearly complete follow-up; the potential for selection bias is thus negligible. However, only pregnancies that led to a live birth or a stillbirth could be identified, thus fetal losses occurring before week 28 of gestation were missing.WIDER IMPLICATIONS OF THE FINDINGS: Our findings corroborate the previous evidence suggesting that women try to conceive again shortly after a perinatal death, and many succeed. In addition, this is the first study to investigate the reproductive trajectory after losing an older child. The current study indicates that most women who lose a child between the ages of 6 months and 5 years conceive shortly after the loss, and they have a comparable number of living children at the end of the follow-up compared to those who do not lose a child.STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Grant ERC-2010-StG-260242 from the European Research Council, 176673 and 186200 from the Nordic Cancer Union, DFF-6110-00019 from the Danish Council for Independent Research, 904414 and 15199 from TrygFonden, Karen Elise Jensens Fond (2016), and the Program for Clinical Research Infrastructure (PROCRIN) established by the Lundbeck Foundation and the Novo Nordisk Foundation. The authors do not declare any conflicts of interests.TRIAL REGISTRATION NUMBER: N/A. more...

Background: It is well established that singletons born of assisted reproductive technology are at higher risk of preterm birth and other adverse outcomes. What remains unclear is whether the increased risk is attributable to the effects of the treatment alone or whether the underlying causes of infertility also play a role. The aim of this study was to examine whether any of the six categories of causes of infertility were associated with a direct effect on preterm birth using causal mediation analysis. Methods: We assembled a hospital-based cohort of births delivered at a large tertiary care hospital in Montreal, Canada between 2001 and 2007. Causes of infertility were ascertained through a clinical database and medical chart abstraction. We employed marginal structural models (MSM) to estimate the controlled direct effect of each cause of infertility on preterm birth compared with couples without the cause under examination. Results: The final study cohort comprised 18 598 singleton and twin pregnancies, including 1689 in couples with ascertained infertility. MSM results suggested no significant direct effect for any of the six categories of causes. However, power was limited in smaller subgroup analyses, and a possible direct effect for uterine abnormalities (e.g. fibroids and malformations) could not be ruled out. Conclusion: In this cohort, most of the increased risk of preterm birth appeared to be explained by maternal characteristics (such as age, body mass index, and education) and by assisted reproduction. If these findings are corroborated, physicians should consider these risks when counselling patients. more...

Study question Does maternal age at a daughter's birth predict her subsequent probability of lifelong childlessness? Summary answer In this study population, women born to older mothers were more likely to be childless. What is known already Although maternal age at childbearing is increasing in many countries, there is limited evidence on whether being born to older parents may influence offspring fertility. Study design size and duration This analysis included 43 135 women from the US-based Sister Study, a cohort study of 50 884 sisters of women with breast cancer recruited between 2003 and 2009. Participants/materials, setting, methods Participants had no breast cancer at baseline. Women were included in the analytic sample if they were born between 1930 and 1964 and were at least 44 years old at enrolment. Median age when reproductive history was last ascertained was 63.8 years. We estimated relative risks (RR) and 95% CI of lifelong childlessness as a function of maternal age at birth, using multivariable log-binomial models, including total number of siblings, birth order, socioeconomic indicators of the family of origin, race and birth cohort. We examined the association in different subgroups and in a sibling-matched analysis including 802 sister pairs discordant for childlessness. Main results and role of chance Compared with women born to 20-24-year-old mothers, those born to mothers aged 25-29, 30-34 and ≥35 years were more likely to be childless [RR (95% CI): 1.21 (1.14-1.29), 1.30 (1.22-1.39) and 1.40 (1.31-1.50), respectively]. The association was consistent in strata defined by birth cohort, number of siblings, birth order, and participant's educational level, as well as within sister pairs. Overall, we found weak evidence for an independent contribution of paternal age at birth to the daughter's probability of childlessness. Limitations reasons for caution All participants had at least one sister, and all information was self-reported. We had no knowledge of whether childlessness was intentional and found only a modest association between maternal age at birth and self-reported indicators of infertility. Still, the association with childlessness was highly consistent. Wider implications of the finding Given the widespread tendency to delay childbearing, evaluating the influence of maternal age at birth on offspring fertility is a public health priority. Study funding/competing interests This research was supported in part by the Intramural Research Programme of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005). The authors report no conflict of interest. more...

Background Previous studies of maternal influenza illness and preterm birth have yielded inconsistent results. Our objective was to assess the association between 2009 pandemic H1N1 (pH1N1) influenza during pregnancy and preterm birth in a large obstetrical population. Methods We linked a province-wide birth registry with health administrative databases to identify influenza-coded hospitalizations, emergency department visits, or physician visits among pregnant women during the 2009 H1N1 pandemic (our proxy for clinical pH1N1 influenza illness). Using Cox regression, we estimated adjusted hazard ratios (aHR) for preterm birth and spontaneous preterm birth treating influenza as a time-varying exposure. Results Among 192,082 women with a singleton live birth, 2,925 (1.5%) had an influenza-coded health care encounter during the 2009 H1N1 pandemic. Compared with unexposed pregnancy time, there was no association between exposure to the pandemic, with or without clinical influenza illness, and preterm birth (no pH1N1 diagnosis: aHR = 1.0; 95% confidence interval [CI] = 0.98, 1.1; pH1N1 diagnosis: aHR = 1.0; 95% CI = 0.88, 1.2). Among women with preexisting medical conditions, influenza was associated with increased preterm birth (aHR = 1.5; 95% CI = 1.1, 2.2) and spontaneous preterm birth (aHR = 1.7; 95% CI = 1.1, 2.6), and these associations were strongest in the third trimester and when data were analyzed to allow for a transient acute effect of influenza. Conclusions In the general obstetrical population, there was no association between pH1N1 influenza illness and preterm birth, but women with preexisting medical conditions known to increase the risk of influenza-associated morbidity were at elevated risk. more...

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. more...

Background: Preeclampsia (PE) is a dangerous and unpredictable pregnancy complication. A seasonal pattern of risk would suggest that there are potentially preventable environmental contributors, but prior analyses have not adjusted for confounding by PE risk factors that are associated with season of conception. Methods: Seasonal effects were modeled and tested by representing each day of the year as an angle on a unit circle and using trigonometric functions of those angles in predictive models, using “harmonic analysis.” We applied harmonic Cox regression to model confounder-adjusted effects of the estimated day of the year of conception on risk of PE for births from the Medical Birth Registry of Norway for deliveries between 1999 and 2009. We also examined effect measure modification by parity, latitude (region), fetal sex, and smoking. Results: In adjusted models, PE risk was related to season, with higher risk in spring conceptions and lower risk in autumn conceptions, with a risk amplitude (maximum compared with minimum) of about 20%. The pattern replicated across subpopulations defined by parity, latitude (region), fetal sex, and smoking. Conclusions: These results suggest that there is a seasonal driver for PE, with effects that are not modified by parity, latitude, fetal sex, or smoking. https://doi.org/10.1289/EHP963 more...

The longer term cardiovascular effects of fertility therapy are unknown.The aim of this study was to summarize data linking fertility therapy with subsequent cardiovascular outcomes.We systematically searched published reports for studies addressing the question "does fertility therapy increase the risk of longer term cardiovascular outcomes?" We included: 1) human studies; 2) case control, cohort, or randomized designs with 3) exposure to fertility therapy and 4) cardiovascular outcomes clearly reported; 5) presence of comparison group; 6) minimum 1-year follow-up; and 7) adjustment for age. Two independent reviewers screened abstracts, titles, and full texts, and assessed study quality. We used the DerSimonian and Laird random-effects models to pool hazard ratios (HRs) with 95% confidence intervals (CIs) of the following outcomes: acute cardiac event; stroke; venous thromboembolism; hypertension; and diabetes mellitus, comparing women who received fertility therapy with those who did not.Six observational studies met inclusion criteria including 41,910 women who received fertility therapy and 1,400,202 women who did not. There was no increased risk of a cardiac event (pooled HR: 0.91; 95% CI: 0.67 to 1.25; IThe small number of studies and significant heterogeneity precludes definitive reassurance about the longer term cardiovascular safety of these treatments, particularly stroke. Future studies are needed to address ongoing knowledge gaps in this area. more...

Objectives Overweight and obese women may be heavy users of in vitro fertilization (IVF) owing to obesity-related oligo-anovulation. The higher doses of gonadotropins required to achieve pregnancy in obese women may contribute to impaired placentation and the development of preeclampsia. This study was designed to assess the combined effect of high maternal body mass index (BMI) and IVF on risk of preeclampsia and to evaluate for an interaction between the two factors. Methods This is a hospital-based cohort study of 10,013 singleton pregnancies that delivered from 2001 to 2008 at a tertiary hospital in Montreal, Canada. The combined effect of high BMI and IVF on preeclampsia versus no risk factors was estimated in multivariate logistic regression models fitted with an interaction term between high BMI (> 25 or > 30 kg/m2) and IVF. Results IVF pregnancies in obese women had a considerably higher risk of preeclampsia than spontaneous nonobese pregnancies (OR 6.7, 95% CI 3.3-13.8; p interaction 0.03). IVF was not independently associated with preeclampsia (OR 0.6, 95% CI 0.3-1.4). Analyses were similar in subgroup analyses and in analyses correcting for bias. Conclusions High BMI is strongly associated with preeclampsia, and this risk is compounded in IVF pregnancies. more...

OBJECTIVES: To provide an updated US birth weight for gestational age reference corrected for likely errors in last menstrual period (LMP)-based gestational age dating, as well as means and SDs, to enable calculation of continuous and categorical measures of birth weight for gestational age. METHODS: From the 2009–2010 US live birth files, we abstracted singleton births between 22 and 44 weeks of gestation with at least 1 nonmissing estimate of gestational age (ie, LMP or obstetric/clinical) and birth weight. Using an algorithm based on birth weight and the concordance between these gestational age estimates, implausible LMP-based gestational age estimates were either excluded or corrected by using the obstetric/clinical estimate. Gestational age– and sex-specific birth weight means, SDs, and smoothed percentiles (3rd, 5th, 10th, 90th, 95th, 97th) were calculated, and the 10th and 90th percentiles were compared with published population-based references. RESULTS: A total of 7 818 201 (99% of eligible) births were included. The LMP-based estimate of gestational age comprised 85% of the dataset, and the obstetric/clinical estimate comprised the remaining 15%. Cut points derived from the current reference identified ∼10% of births as ≤10th and ≥90th percentiles at all gestational weeks, whereas cut points derived from previous US-based references captured variable proportions of infants at these thresholds within the preterm and postterm gestational age ranges. CONCLUSIONS: This updated US-based birth weight for gestational age reference corrects for likely errors in gestational age dating and allows for the calculation of categorical and continuous measures of birth size. more...