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Background: Children conceived with assisted reproductive technologies (ART) or after a long waiting time have a higher prevalence of congenital malformations, but few studies have examined the contribution of type of infertility., Objectives: To quantify the association between causes of infertility and prevalence of malformations., Methods: We compared the prevalence at birth of all and severe malformations diagnosed up to age 2 between 6656 children born in 1996-2017 to parents who had previously been assessed for infertility a an academic fertility clinic ("exposed") and 10,382 children born in the same period to parents with no recent medical history of infertility ("reference"). We estimated prevalence ratios (PR) and prevalence differences (PD), by infertility status, type of treatment (non-ART, ART), and infertility diagnosis, in all children and among singletons., Results: Compared with children of parents with no infertility, children of parents with infertility had a higher prevalence of malformations (both definitions), particularly following ART conceptions. After accounting for treatment, ovulatory disorders were associated with a higher prevalence of both all (PR 1.49, 95% confidence interval (CI) 1.15, 1.93; PD 3.8, 95% CI 1.0, 6.6) and severe (PR 1.53, 95% CI 1.02, 2.29; PD 1.8, 95% CI -0.2, 3.7) malformations (the estimates refer to exposed children conceived without treatment). Unexplained and male factor infertility were associated with all and severe malformations, respectively. Estimates among singletons were similar. A diagnosis of ovulatory disorders was associated with all malformations also in analyses restricted to exposed children, regardless of treatment (we did not examine severe malformations, due to limited power)., Conclusions: In this study, ovulatory disorders were consistently associated with a higher prevalence of congenital malformations (including severe malformations) among live births, regardless of mode of conception., (© 2023 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: 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., Methods: 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., Results: 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., Interpretation: 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., Competing Interests: Competing interests: Simone Vigod reports receiving royalties from UpToDate for authorship of materials related to depression and pregnancy. No other competing interests were declared., (© 2022 CMA Impact Inc. or its licensors.)

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., Competing Interests: Competing interests: None declared., (© 2019 Joule Inc. or its licensors.)

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., (Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

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., (© 2015 John Wiley & Sons Ltd.)

Objective: To estimate the risk of preterm birth in singleton infants conceived through low-technology assisted reproduction (intrauterine insemination and/or ovulation induction/stimulation)., Design: Hospital-based cohort study., Setting: University-affiliated hospital., Patient(s): Singleton babies born between 2001 and 2007 to 16,712 couples with no reported infertility (reference category), 378 babies conceived with low-technology treatment; 437 conceived with high-technology treatment; and 620 conceived naturally after a period of infertility., Intervention(s): None. Treatment data were obtained from couples undergoing standard infertility investigation and care., Main Outcome Measure(s): Preterm birth, defined at three clinical endpoints: <37, <35, and <32 weeks of completed gestation., Result(s): After adjustment for age, parity, education, smoking, alcohol/drug use, and body mass index, the risk ratios and 95% confidence intervals (CI) of preterm birth for low technology were: 1.49 (CI: 1.12-2.00); 2.02 (CI: 1.30-3.13); and 2.93 (CI: 1.63-5.26) at <37, <35, and <32 weeks gestation, respectively, not dissimilar from the estimates for in vitro fertilization. Restricting the analysis to primiparas strengthened the association between treatment and preterm birth at the lower gestational endpoints. The increased risk persisted when the untreated group was used as the reference category, although the estimates were attenuated., Conclusion(s): In this large hospital-based cohort study, low-technology assisted reproduction appeared to be a moderately strong predictor of preterm birth, with similar associations observed in the high-technology treatment group. After adjusting for confounders, as well as the shared characteristics of infertile couples, associations were attenuated but remained significant, suggesting that part of the risk is likely attributable to the treatment., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Behavioural patterns in children of infertile couples may be influenced by both the underlying causes of infertility and stress in the couples. Treatment procedures, such as culture media and manipulation of gametes and embryos, may also result in developmental problems. We examined behavioural problems in children as a function of infertility and infertility treatment, using data from three population-based birth cohorts in Denmark (Aalborg-Odense Birth Cohort, Aarhus Birth Cohort and Danish National Birth Cohort). Information on time to pregnancy and infertility treatment was collected during pregnancy. Children aged between 7 and 21 years were assessed using the Strengths and Difficulties Questionnaire (SDQ). The SDQ was completed by mothers in all cohorts and, in addition, by teachers in the Aarhus cohort and by children themselves in the Aalborg-Odense cohort. Children born after a time to pregnancy of >12 months and no infertility treatment had a behavioural pattern similar to children of fertile parents. Teachers reported a higher total difficulties score for children born after infertility treatment, but no significant differences were seen on any subscales of the teachers' report, and neither the mothers nor the children reported any differences on the total difficulties score and the prosocial behaviour score. Our results are thus overall reassuring regarding behavioural problems in children born to infertile couples, regardless of infertility treatment., (© 2011 Blackwell Publishing Ltd.)

Background: Children born after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) have been reported to have a higher risk of cerebral palsy (CP), perhaps due to the higher frequency of preterm birth, multiple births or vanishing embryo in the pregnancies. However, it has been suggested that the underlying infertility may be part of the pathway. In this study, we examined whether untreated subfecundity (measured by time to pregnancy) or infertility treatment was associated with an increased risk of CP in the offspring., Methods: Using the Danish National Birth Cohort (1997-2003), we compared children born after 0-2 months of waiting time to pregnancy (n = 35 848) with those born after a time to pregnancy of 3-5 months (n = 15 361), 6-12 months (n = 11 528) and >12 months (n = 7387), as well as those born after IVF/ICSI (n = 3617), ovulation induction with or without intrauterine insemination (n = 3000), and unplanned pregnancies (n = 13 462). CP cases were identified through the Danish CP Register., Results: In total, 165 (0.18%) children were diagnosed with CP in the entire cohort. We found no significant association between time to pregnancy and the risk of CP in children conceived spontaneously. Children born after IVF/ICSI had an increased risk of CP, even after adjustment for preterm birth and multiplicity (hazard ratio 2.30, 95% confidence interval 1.12-4.73)., Conclusions: Subfecundity per se did not appear to be associated with the risk of CP in children, whereas being born after IVF/ICSI conferred an increased risk.

Background: It has previously been reported that children born after infertility treatment had a slight delay in early motor milestones. In this study, we examined whether children of infertile couples with or without infertility treatment had a higher risk of developmental coordination disorder (DCD)., Methods: We used data on parental infertility and DCD among 23 167 singletons from the Danish National Birth Cohort (1996-2002). Data on time to pregnancy (TTP) and infertility treatment were collected early in pregnancy. Data on DCD in children were collected using the Developmental Coordination Disorder Questionnaire, filled in by the mothers during follow-up when the children were 7 years old. We used the recommended cut-off for the age group to classify children., Results: Compared with children born of fertile couples, children conceived after a waiting TTP of longer than 12 months had a slightly higher risk of DCD [odds ratio (OR) 1.35, 95% confidence interval (CI) 1.03-1.77], but the estimated OR was not significant in children born after infertility treatment (OR 1.19, 95% CI 0.86-1.66). None of the individual treatment procedures was significantly associated with a higher risk of DCD. Children of parents who had not planned their pregnancy showed no elevated risk., Conclusions: Our findings are overall reassuring, although it is possible that low fecundity may be associated with a modestly increased risk of DCD.

Background: Mixed-handedness, which may reflect atypical brain laterality, has been linked to a number of medical conditions as well as prenatal stress., Aims: The aim of the study was to examine whether infertility or infertility treatment was associated with an increased risk of mixed-handedness in children. STUDY DESIGN, SUBJECTS AND OUTCOME MEASURES: We used data from three population-based birth cohorts in Denmark: the Aalborg-Odense Birth Cohort (1984-1987), the Aarhus Birth Cohort (1990-1992) and the Danish National Birth Cohort (1996-2002) (N=7728, 5720 and 29486, respectively). Data on time to pregnancy and infertility treatment were collected during pregnancy. Handedness was reported in a follow-up questionnaire when the children were at least 7years old. Children were categorized as mixed-handed if their mothers reported that they used both hands equally., Results: Children born after infertility treatment, particularly intrauterine insemination, had a higher risk of being mixed-handed compared to children of fertile couples with a time to pregnancy

Babies born of infertile couples, regardless of treatment, have a higher risk of preterm birth and low birthweight, conditions associated with delayed development. We examined developmental milestones in singletons as a function of parental infertility [time to pregnancy (TTP) > 12 months] and infertility treatment. From the Danish National Birth Cohort (1997-2003), we identified 37 897 singletons born of fertile couples (TTP < or = 12 months), 4351 born of infertile couples conceiving naturally (TTP > 12 months), and 3309 born after infertility treatment. When the children were about 18 months old, mothers reported 12 developmental milestones by responding to structured questions. We defined a failure to achieve the assessed milestone or the minimal numbers of milestones in a summary (motor, or cognitive/language skills) as delay. Naturally conceived children born of infertile couples had a pattern of psychomotor development similar to that of children born of fertile couples, but increasing TTP correlated with a modest delay. When the analysis was restricted to infertile couples (treated and untreated), children born after treatment showed a slight delay in cognitive/language development (odds ratio 1.24, [95% confidence interval 1.01, 1.53]) for not meeting at least three out of six cognitive/language milestones); children born after intracytoplasmic sperm injection (ICSI) had the highest estimated relative risk of delay for most milestones, especially motor milestones. These results suggest that a long TTP may be associated with a modest developmental delay. Infertility treatment, especially ICSI, may be associated with a slight delay for some of these early milestones.

Background: The reproductive health of children born of infertile couples may be affected by infertility treatment or factors associated with infertility. We examined sexual maturation in children of parents with infertility., Methods: We used data from a follow-up of 3382 girls and 2810 boys born between 1984 and 1987 in the Aalborg-Odense Birth Cohort. We had mothers' report of time to pregnancy (TTP) and infertility treatment (at the time, mostly hormonal) from the pregnancy questionnaire administered in 1984-1987, and the children's report of their own sexual maturation from the follow-up questionnaire administered in 2005, when they were between 18 and 21 years old. Many reported age only in year when they had the events related to sexual maturation, and for each event, we imputed the month based on the median month at each year of age among those reporting both years and months., Results: In girls, the mean age at menarche was 13.3 years and, in boys, the mean age at appearance of acne, voice break, regular shaving and first nocturnal emission were 14.5, 14.5, 17.2 and 14.7 years, respectively. We saw no significant differences in age at these events among children born of either fertile (with TTP of 0-12 months and no treatment), untreated infertile (with TTP of more than 12 months and no treatment) or treated infertile couples (with a history of examination or treatment for infertility)., Conclusions: Our data suggest no significant association between parental infertility or hormonal treatment and timing of sexual maturation in the offspring.

Background: We have previously observed that an increasing time to pregnancy (TTP) is associated with a reduced frequency of twin deliveries in couples not receiving infertility treatment. By using updated information, we assessed the frequencies of dizygotic (DZ) and monozygotic (MZ) twin deliveries as a function of infertility (TTP > 12 months), as well as infertility treatment., Methods: From the Danish National Birth Cohort (1997-2003), we identified 51 730 fertile couples with TTP 12 months and 5163 infertile couples who conceived after treatment. Information on zygosity, available for part of the cohort (1997-2000), was based on standardized questions on the similarities between the twins at the age of 3-5 years., Results: Compared with fertile couples, the frequency of DZ twin deliveries was lower for infertile couples conceiving naturally (odds ratio 0.4, 95% confidence interval 0.2-0.7) and was much higher for infertile couples conceiving after treatment (17.3, 14.4-20.7). The frequency of DZ twin deliveries decreased with TTP in untreated couples, whereas the frequency of MZ twin deliveries remained constant., Conclusions: The frequency of DZ twin deliveries decreased with TTP and substantially increased with infertility treatment, whereas MZ twin deliveries remained substantially unchanged.

Objectives: To examine whether infertile couples (with a time to pregnancy of > 12 months), who conceive naturally or after treatment, give birth to children with an increased prevalence of congenital malformations., Design: Longitudinal study., Setting: Danish national birth cohort., Participants: Three groups of liveborn children and their mothers: 50,897 singletons and 1366 twins born of fertile couples (time to pregnancy < or = 12 months), 5764 singletons and 100 twins born of infertile couples who conceived naturally (time to pregnancy > 12 months), and 4588 singletons and 1690 twins born after infertility treatment., Main Outcome Measures: Prevalence of congenital malformations determined from hospital discharge diagnoses., Results: Compared with singletons born of fertile couples, singletons born of infertile couples who conceived naturally or after treatment had a higher prevalence of congenital malformations-hazard ratios 1.20 (95% confidence interval 1.07 to 1.35) and 1.39 (1.23 to 1.57). The overall prevalence of congenital malformations increased with increasing time to pregnancy. When the analysis was restricted to singletons born of infertile couples, babies born after treatment had an increased prevalence of genital organ malformations (hazard ratio 2.32, 1.24 to 4.35) compared with babies conceived naturally. No significant differences existed in the overall prevalence of congenital malformations among twins., Conclusions: Hormonal treatment for infertility may be related to the occurrence of malformations of genital organs, but our results suggest that the reported increased prevalence of congenital malformations seen in singletons born after assisted reproductive technology is partly due to the underlying infertility or its determinants. The association between untreated infertility and congenital malformations warrants further examination.

Subfecundity is a frequent and serious problem that may sometimes be preventable, but we need to know more about its determinants. Different epidemiologic designs are available. The best of these use prospectively collected data from the population, but they are time consuming, expensive and often hampered by low-participation rates. Most patients undergoing infertility treatment are closely monitored for clinical reasons, making it feasible to use secondary data to study the period from conception to implantation and pregnancy. In spite that infertility patients are highly selected, there are specific exposure-effect relations that can be studied in cohorts of infertility patients. These patients offer a potentially useful setting for studying exposures that operate late in fertilization, whereas the designs may be inadequate to identify exposures that cause reduced sperm counts, anovulation and total occlusion. The clinical sampling and the treatment set limitations for what can be studied. In certain situations, infertile patients can, however, provide useful epidemiologic evidence for learning about the causes of subfecundity.

Many reproductive failures tend to repeat themselves within the same couple. Whether fecundability (the probability of conceiving in a given number of menstrual cycles) follows the same pattern is studied using data from the European Studies on Infertility and Subfecundity (ESIS): 6630 women were interviewed on 'time to pregnancy' (TTP) and other aspects of their pregnancy history. Surveys were conducted between 1991 and 1994 in seven regions from five European countries. Furthermore, the pattern of fecundability in this population was compared with results from computer simulations based upon a population with fixed fecundability parameters. Results from ESIS speak in favour of the stability of fecundability in the relatively short reproductive life of a couple. However, a substantial proportion of couples with up to two events of subfecundability (TTP >9.5 months) became pregnant shortly after trying again. This finding calls for reservation in starting expensive and/ or unpleasant diagnostic procedures at an early stage when a couple tries to become pregnant again.

Shift work has been associated with various unfavorable pregnancy outcomes (ie, pregnancy loss, spontaneous abortion, low birth weight, etc). The suggested underlying mechanism is the interference of shift work with the circadian regulation of human metabolism and, in particular, with the temporal pattern of endocrine function. To analyze the effect of shift work on fecundity, the Time of Unprotected Intercourses (TUI) has been measured in couples recruited in the European Studies on Infertility and Subfecundity, which were undertaken in seven European countries. A low (odds ratio < 2.0) but consistent excess risk of subfecundity (TUI > or = 9.4 months) has been observed both in a representative sample of the general population of women in reproductive age and in a sample of pregnant women or women who had just given birth. The excess risk was also consistently evident both in the subsample of the first pregnancies and in the subsample of the most recent pregnancies. Only the exposure of women to shift work seemed to affect a couple's fecundity; men working shift work did not modify the fecundity pattern of their own couples. No specific job title among shift workers concentrated the risk of subfecundity. No association of menstrual disorders with shift work was identified. Even though residual confounding could partly account for the results and the fact that a plausible biological explanation of the claimed effect is still lacking, data from this study are in favor of an association between shift work and prolonged waiting time to pregnancy.

Study Question: Is maternal stress following the death of a close relative before or during pregnancy associated with the risk of infertility in daughters?Summary Answer: Compared with unexposed women, women whose mothers had experienced bereavement stress during, or in the year before, pregnancy had a similar risk of infertility overall, but those exposed to maternal bereavement during the first trimester had a higher risk of infertility.What Is Known Already: Animal studies have shown that prenatal maternal stress results in reduced offspring fertility. In humans, there is evidence that girls who have been prenatally exposed to stress have a more masculine behaviour and a slight delay in having their first child.Study Design, Size and Duration: This population-based cohort study, included 660 099 females born in Denmark between 1 January 1973 and 31 December 1993 to mothers of Danish origin and with at least one living relative in the exposure window, and followed the women through 31 December 2011.Participants/materials, Setting, Methods: Overall, 13 334 women (2.0%) were considered prenatally exposed to stress because their mother had lost a spouse/partner, a child, a parent, or a sibling during pregnancy or in the year before conception. Infertility was defined as any record of infertility treatment or diagnosis of female infertility. We considered the date of onset as the date of the first appearance of any such record. The association between exposure and outcome was examined using hazard ratios (HR) with 95% confidence intervals (CI).Main Results and the Role Of Chance: Based on our definition, 40 052 (6.5%) women were infertile in the follow-up period (median age at the end of follow-up: 26.7 years, maximum age: 39 years). Overall, prenatal exposure to maternal stress was not associated with risk of infertility (adjusted HR = 1.04 [CI: 0.95-1.14]). However, women prenatally exposed during the first trimester had a higher estimated risk (adjusted HR = 1.40 [CI: 1.05-1.86]). These findings were consistent in subgroups defined by the relationship of the mother to the deceased and in several sensitivity analyses, including a sibling-matched analysis, and in analyses restricted to women who were married or cohabitating with a man, or to women born at term.Limitations, Reasons For Caution: We did not have a direct measure of stress, but bereavement due to death of a close relative is likely to be very stressful. We based the timing of exposure on the date of the death of the family member, although the stress may well have started earlier. Infertility was also defined indirectly, and many women in the cohort were too young at the end of the follow-up to have been diagnosed. However, misclassification of the outcome was most likely non-differential, and the similar results from all sensitivity analyses suggest that it is unlikely that the effect observed in first trimester exposure would be due to chance.Wider Implications Of the Findings: Prenatal exposure to maternal stress in the first trimester may affect the later fecundity of daughters.Study Funding/competing Interests: This study was supported by a grant from the European Research Council (ERC-2010-StG-260242-PROGEURO) to the ProgEuro project (http://progeuro.au.dk). O.P.-R. is partly supported by a fellowship from Aarhus University and a travel grant from Oticon Fonden. The authors report no conflict of interests. [ABSTRACT FROM AUTHOR]