Evaluation of the association between patent ductus arteriosus approach and neurodevelopment in extremely preterm infants.

OBJECTIVE: Assess if unit-level PDA management correlates with neurodevelopmental impairment (NDI) at 18-24 months corrected postnatal age (CPA) in extremely preterm infants. STUDY DESIGN: Retrospective analysis of infants born at <29 weeks (2014-2017) across two units having distinct PDA strategies. Site 1 utilized an echocardiography-based treatment strategy aiming for accelerated closure (control). Site 2 followed a conservative approach. PRIMARY ENDPOINT: NDI, characterized by cerebral palsy, any Bayley-III composite score <85, sensorineural/mixed hearing loss, or at least unilateral visual impairment. RESULTS: 377 infants were evaluated. PDA treatment rates remained unchanged in Site 1 but eventually reached 0% in Site 2. Comparable rates of any/significant NDI were seen across both sites (any NDI: 38% vs 36%; significant NDI: 13% vs 10% for Site 1 and 2, respectively). After adjustments, NDI rates remained similar. CONCLUSION: PDA management strategies in extremely preterm newborns showed no significant impact on neurodevelopment outcomes at 18-24 months CPA.

The association between miscarriage and fecundability: the Norwegian Mother, Father and Child Cohort Study.

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 <3 months, the adjusted RR of miscarriage in the subsequent pregnancy was 1.16 (0.99-1.35) with TTP of 3-6 months, 1.18 (0.93-1.49) with TTP of 7-11 months and 1.43 (1.13-1.81) with TTP of 12 or more months. 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.

Outcomes of Extremely Premature Infants Comparing Patent Ductus Arteriosus Management Approaches.

OBJECTIVE: To evaluate the change in the proportion of deaths/bronchopulmonary dysplasia (BPD) among premature infants (born <26 and 26-29 weeks of gestational age) following a policy change to a strict nonintervention approach, compared with standard treatment. STUDY DESIGN: We examined 1249 infants (341 born <26 weeks of gestational age) at 2 comparable sites. Site 1 (control) continued medical treatment/ligation, and site 2 (exposed) changed to a nonintervention policy in late 2013. Using the difference-in-differences approach, which accounts for time-invariant differences between sites and secular trends, we assessed changes in death or BPD separately among infants born 26-29 weeks and <26 weeks of gestational age in 2 epochs (epoch 1: 2011-2013; epoch 2: 2014-2017). 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 <26 weeks of gestational age (95% CI 10%-51%) in site 2, whereas there was no change in outcomes in site 1. The Score for Neonatal Acute Physiology-Version II, used as a control outcome, did not change in either site, suggesting that our findings were not due to changes in patients' severity. 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 <26 weeks.

Maternal age at birth and daughter's fecundability.

STUDY QUESTION: Do daughters of older mothers have lower fecundability? SUMMARY ANSWER: In this cohort study of North American pregnancy planners, there was virtually no association between maternal age ≥35 years and daughters' fecundability. WHAT IS KNOWN ALREADY: Despite suggestive evidence that daughters of older mothers may have lower fertility, only three retrospective studies have examined the association between maternal age and daughter's fecundability. STUDY DESIGN, SIZE, DURATION: Prospective cohort study of 6689 pregnancy planners enrolled between March 2016 and January 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Pregnancy Study Online (PRESTO) is an ongoing pre-conception cohort study of pregnancy planners (age, 21-45 years) from the USA and Canada. We estimated fecundability ratios (FR) for maternal age at the participant's birth using multivariable proportional probabilities regression models. MAIN RESULTS AND THE ROLE OF CHANCE: Daughters of mothers ≥30 years were less likely to have previous pregnancies (or pregnancy attempts) or risk factors for infertility, although they were more likely to report that their mother had experienced problems conceiving. The proportion of participants with prior unplanned pregnancies, a birth before age 21, ≥3 cycles of attempt at study entry or no follow-up was greater among daughters of mothers <25 years. Compared with maternal age 25-29 years, FRs (95% CI) for maternal age <20, 20-24, 30-34, and ≥35 were 0.72 (0.61, 0.84), 0.92 (0.85, 1.00), 1.08 (1.00, 1.17), and 1.00 (0.89, 1.12), respectively. LIMITATIONS, REASONS FOR CAUTION: Although the examined covariates did not meaningfully affect the associations, we had limited information on the participants' mother. Differences by maternal age in reproductive history, infertility risk factors and loss to follow-up suggest that selection bias may partly explain our results. WIDER IMPLICATIONS OF THE FINDINGS: Our finding that maternal age 35 years or older was not associated with daughter's fecundability is reassuring, considering the trend towards delayed childbirth. However, having been born to a young mother may be a marker of low fecundability among pregnancy planners. STUDY FUNDING/COMPETING INTEREST(S): PRESTO was funded by NICHD Grants (R21-HD072326 and R01-HD086742) and has received in-kind donations from Swiss Precision Diagnostics, FertilityFriend.com, Kindara.com, and Sandstone Diagnostics. Dr Wise is a fibroid consultant for AbbVie, Inc. TRIAL REGISTRATION NUMBER: n/a.

Real-world direct healthcare costs of treating recurrent high-grade serous ovarian cancer with cytotoxic chemotherapy.

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.

Recruitment challenges in clinical research: Survey of potential participants in a diagnostic study of ovarian cancer.

OBJECTIVE: Recruiting participants in clinical research is challenging. Certain groups, such as older adults, rural residents, and individuals with lower socio-economic status, are typically underrepresented. Here, we explore perceived motivators and barriers among potential participants in a diagnostic study of ovarian cancer. METHODS: Women aged 50 and older who answered a mail survey in Montreal, Canada, were asked to assess their eligibility to participate in the ongoing Diagnosing Ovarian cancer Early (DOvE) Study. If 'eligible', they were asked whether they planned to participate in DOvE. Using modified Poisson regression, we examined responders' self-assessment of eligibility, intention to participate, and reasons for why or why not, as a function of socio-demographic and health indicators. RESULTS: Of 826 responders, 33.1% misclassified themselves with respect to eligibility. Among 532 self-assessed eligible women, 56.4% planned to participate in the study. The majority of women not planning to participate preferred to be assessed by their physicians (a reason more commonly reported by those with lower education or income) or believed they were not at risk of ovarian cancer (despite having no fewer risk factors). "Inconvenience" was also a commonly reported reason, especially among rural residents. Women who planned to participate often perceived a benefit (e.g. to rule out ovarian cancer, or to receive a quick check-up). CONCLUSIONS: Recruitment, particularly of underrepresented groups, in clinical studies may be enhanced by involving primary care providers, facilitating access to study sites, and providing clear information about the disease under study (including risk factors) and eligibility criteria.

Season of Conception, Smoking, and Preeclampsia in Norway.

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.

Reproductive function in the sons of women who experienced stress due to bereavement before and during pregnancy: a nationwide population-based cohort study.

OBJECTIVE: To estimate the association between prenatal exposure to maternal stress and reproductive disorders in Danish men, where prenatal stress exposure was defined as the mother's loss of a close relative during pregnancy or in the 12 months before conception. DESIGN: Population-based cohort study. SETTING: Not applicable. PATIENT(S): All males born in Denmark between 1973 and 2008 (n = 1,217,576) and observed for up to 39 years. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Male reproductive function, defined using a composite outcome including congenital malformations of genital organs, testicular cancer, diagnosis of male infertility, or assisted conception use due to male factor infertility. RESULT(S): In total, 28,986 men (2.4%) had been exposed to prenatal stress, and 62,929 (5.2%) experienced the composite outcome during the follow-up period. Prenatal exposure to stress was associated with an elevated risk of reproductive problems (hazard ratio [HR] 1.09; 95% CI, 1.04-1.15). The association was stronger when the exposure occurred during the first trimester of pregnancy, and for congenital malformations of genital organs. When focusing on infertility alone, we saw no evidence of increased risk (HR 0.90; 95% CI, 0.77-1.06). In addition, the probability of marrying a woman was lower for exposed men (HR 0.93; 95% CI, 0.89-0.98). CONCLUSION(S): Prenatal stress in the form of the mother's bereavement during the first trimester of pregnancy is associated with a higher risk of reproductive disorders from congenital malformations of the genital organs in the male offspring. The lack of an association between maternal bereavement and later infertility in the exposed male offspring may be due in part to the men's lower probability of attempting to have children.

Estimating the Prevalence of Ovarian Cancer Symptoms in Women Aged 50 Years or Older: Problems and Possibilities.

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.

Maternal Antioxidant Levels in Pregnancy and Risk of Preeclampsia and Small for Gestational Age Birth: A Systematic Review and Meta-Analysis.

BACKGROUND: Oxidative stress in preeclampsia and small for gestational age (SGA) birth suggests antioxidant supplementation could prevent these conditions. However, it remains unclear whether maternal antioxidant levels are systematically lower in these pregnancies. OBJECTIVE: To conduct a systematic review of the association between maternal antioxidant levels during pregnancy and preeclampsia or SGA. METHODS: We searched PubMed, Embase, and several other databases from 1970-2013 for observational studies that measured maternal blood levels of non-enzymatic antioxidants (vitamins A, C, E, and carotenoids) during pregnancy or within 72 hours of delivery. The entire review process was done in duplicate. Study quality was assessed using the Newcastle-Ottawa Scale and additional questions. We pooled the standardized mean difference (SMD) across studies, stratified by outcome and pregnancy trimester, and investigated heterogeneity using meta-regression. RESULTS: We reviewed 1,882 unique citations and 64 studies were included. Most studies were small with important risk of bias. Among studies that addressed preeclampsia (n = 58) and SGA (n = 9), 16% and 66%, respectively, measured levels prior to diagnosis. The SMDs for vitamins A, C, and E were significantly negative for overall preeclampsia, but not for mild or severe preeclampsia subtypes. Significant heterogeneity was observed in all meta-analyses and most could not be explained. Evidence for lower carotenoid antioxidants in preeclampsia and SGA was limited and inconclusive. Publication bias appears likely. CONCLUSIONS: Small, low-quality studies limit conclusions that can be drawn from the available literature. Observational studies inconsistently show that vitamins C and E or other antioxidants are lower in women who develop preeclampsia or SGA. Reverse causality remains a possible explanation for associations observed. New clinical trials are not warranted in light of this evidence; however, additional rigorous observational studies measuring antioxidant levels before clinical detection of preeclampsia and SGA may clarify whether levels are altered at a causally-relevant time of pregnancy.

The association between maternal antioxidant levels in midpregnancy and preeclampsia.

OBJECTIVE: We sought to determine whether midpregnancy antioxidant levels are associated with preeclampsia, overall and by timing of onset. STUDY DESIGN: We carried out a case-control study, nested within a cohort of 5337 pregnant women in Montreal, Quebec, Canada. Blood samples obtained at 24-26 weeks were assayed for nonenzymatic antioxidant levels among cases of preeclampsia (n = 111) and unaffected controls (n = 441). We excluded women diagnosed with gestational hypertension only. We used logistic regression with the z-score of each antioxidant level as the main predictor variable for preeclampsia risk. We further stratified early-onset (<34 weeks) and late-onset preeclampsia and carried out multinomial logistic regression. Finally, we assessed associations between antioxidant biomarkers and timing of onset (in weeks) by Cox regression, with appropriate selection weights. We summed levels of correlated biomarkers (r(2) > 0.3) and log-transformed positively skewed distributions. We adjusted for body mass index, nulliparity, preexisting diabetes, hypertension, smoking, and proxies for ethnicity and socioeconomic status. RESULTS: The odds ratios for α-tocopherol, α-tocopherol:cholesterol, lycopene, lutein, and carotenoids (sum of α-carotene, ß-carotene, anhydrolutein, α-cryptoxanthin, and ß-cryptoxanthin) suggested an inverse association between antioxidant levels and overall preeclampsia risk; however, only lutein was significantly associated with overall preeclampsia in adjusted models (odds ratio, 0.60; 95% confidence interval, 0.46-0.77) per SD. In multinomial logistic models, the relative risk ratio (RRR) estimates for the early-onset subgroup were farther from the null than those for the late-onset subgroup. The ratio of α-tocopherol to cholesterol and retinol were significantly associated with early- but not late-onset preeclampsia: RRRs (95% confidence intervals) for early-onset preeclampsia 0.67 (0.46-0.99) and 1.61 (1.12-2.33), respectively. Lutein was significantly associated with both early- and late-onset subtypes in adjusted models; RRRs 0.53 (0.35-0.80) and 0.62 (0.47-0.82), respectively. Survival analyses confirmed these trends. CONCLUSION: Most antioxidants were more strongly associated with early-onset preeclampsia, suggesting that oxidative stress may play a greater role in the pathophysiology of early-onset preeclampsia. Alternatively, reverse causality may explain this pattern. Lutein was associated with both early- and late-onset preeclampsia and may be a promising nutrient to consider in preeclampsia prevention trials, if this finding is corroborated.

Season and preterm birth in Norway: A cautionary tale.

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: Naïve analysis of preterm rates across days of birth shows compelling evidence for seasonality (P < 10(-152)). However, the reconstructed numbers of conceptions also vary with season (P < 10(-307)), confounding results by inducing seasonal variation in the age distribution of the fetal population at risk. When we instead properly treat fetuses as the individuals at risk, restrict analysis to pregnancies with relatively accurate ultrasound-based assessment of gestational age (available since 1998) and adjust for socio-demographic factors and maternal smoking, we find modest effects of both time of year of conception and time of year at risk, with peaks for early preterm near early January and early July. CONCLUSIONS: Analyses of seasonal effects on preterm birth are demonstrably vulnerable to confounding by seasonality of conception, measurement error in conception dating, and socio-demographic factors. The seasonal variation based on fetuses reveals two peaks for early preterm, coinciding with New Year's Day and the early July beginning of Norway's summer break, and may simply reflect a holiday-related pattern of unintended conception.

Do the causes of infertility play a direct role in the aetiology of preterm birth?

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.

Low-technology assisted reproduction and the risk of preterm birth in a hospital-based cohort.

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.

Assessment of symptomatic women for early diagnosis of ovarian cancer: results from the prospective DOvE pilot project.

BACKGROUND: Around 90% of deaths from ovarian cancer are due to high-grade serous cancer (HGSC), which is frequently diagnosed at an advanced stage. Several cancer organisations made a joint recommendation that all women with specified symptoms of ovarian cancer should be tested with the aim of making an early diagnosis. In the Diagnosing Ovarian Cancer Early (DOvE) study we investigated whether open-access assessment would increase the rate of early-stage diagnosis. METHODS: Between May 1, 2008, and April 30, 2011, we enrolled women who were aged 50 years or older and who had symptoms of ovarian cancer. They were offered diagnostic testing with cancer antigen (CA-125) blood test and transvaginal ultrasonography (TVUS) at a central and a satellite open-access centre in Montreal, QC, Canada. We compared demographic characteristics of DOvE patients with those of women in the same age-group in the general population of the area, and compared indicators of disease burden with those in patients with ovarian cancer referred through the usual route to our gynaecological oncology clinic (clinic patients). FINDINGS: Among 1455 women assessed, 402 (27·6%) were in the highest-risk age group (≥ 65 years). 239 (16·4%) of 1455 required additional investigations. 22 gynaecological cancers were diagnosed, 11 (50%) of which were invasive ovarian cancers, including nine HGSC. The prevalence of invasive ovarian cancer, therefore, was one per 132 women (0·76%), which is ten times higher than that reported in screening studies. DOvE patients were significantly younger, more educated, and more frequently English speakers than were women in the general population. They also presented with less tumour burden than did the 75 clinic patients (median CA-125 concentration 72 U/mL, 95% CI 12-1190 vs 888 U/mL, 440-1936; p=0·010); Eight (73%) tumours were completely resectable in DOvE patients, compared with 33 (44%) in clinic patients (p=0·075). Seven (78%) of the HGSC in the DOvE group originated outside the ovaries and five were associated with only slightly raised CA-125 concentrations and minimal or no ovarian abnormalities on TVUS. INTERPRETATION: The proportion of HGSC that originated outside the ovaries in this study suggests that early diagnosis programmes should aim to identify low-volume disease rather than early-stage disease, and that diagnostic approaches should be modified accordingly. Although testing symptomatic women may result in earlier diagnosis of invasive ovarian cancer, large-scale implementation of this approach is premature. FUNDING: Canadian Institutes of Health Research, Montreal General Hospital Foundation, Royal Victoria Hospital Foundation, Cedar's Cancer Institute, and La Fondation du Cancer Monique Malenfant-Pinizzotto.

In utero exposure to tobacco smoke and subsequent reduced fertility in females.

BACKGROUND: Animal studies have shown that in utero exposure to chemicals in tobacco smoke reduces female fertility, but epidemiological findings have been inconsistent. METHODS: We examined the association between in utero exposure to tobacco smoke and female fertility among women in the Norwegian Mother and Child Cohort Study, enrolled from 1999 to 2007. Around the 17th week of pregnancy, participants reported how long they took to conceive (time to pregnancy), and whether their mother smoked while pregnant with the participant. This analysis included 48 319 planned pregnancies among women aged 15-44 years. We estimated fecundability odds ratios (FORs) using a discrete-time survival analysis, adjusting for age, education and adult tobacco smoking. RESULTS: The adjusted FOR for in utero exposure to tobacco smoke among all subjects was 0.96 [95% confidence interval (CI): 0.93, 0.98], among subjects reporting no adult tobacco smoking or passive exposure it was 0.96 (95% CI: 0.93, 0.99) and among subjects reporting adult tobacco smoking or passive exposure it was 0.95 (95% CI: 0.91, 0.99). We performed a probabilistic sensitivity analysis to estimate the effect of exposure and outcome misclassification on the results, and, as expected, the association became more pronounced after taking misclassification into account. CONCLUSIONS: This large cohort study supports a small-to-modest association between in utero exposure to tobacco smoke and reduced fertility.

Maternal pesticide use and birth weight in the agricultural health study.

Studies examining the association between maternal pesticide exposure and low birth weight yield conflicting results. The authors examined the association between maternal pesticide use and birth weight among women in the Agricultural Health Study, a large study of pesticide applicators and their spouses in Iowa and North Carolina. The authors evaluated self-reported pesticide use of 27 individual pesticides in relation to birth weight among 2246 farm women whose most recent singleton birth occurred within 5 years of enrollment (1993-1997). The authors used linear regression models adjusted for site, preterm birth, medical parity, maternal body mass index, height, and smoking. The results showed that mean infant birth weight was 3586 g (+/- 546 g), and 3% of the infants were low birth weight (<2500 g). First-trimester pesticide-related tasks were not associated with birth weight. Ever use of the pesticide carbaryl was associated with decreased birth weight (-82 g, 95% confidence interval [CI] = -132, -31). This study thus provides limited evidence about pesticide use as a modulator of birth weight. Overall, the authors observed no associations between birth weight and pesticide-related activities during early pregnancy; however, the authors have no data on temporal specificity of individual pesticide exposures prior to or during pregnancy and therefore cannot draw conclusions related to these exposure windows. Given the widespread exposure to pesticide products, additional evaluation of maternal pregnancy exposures at specific time windows and subsequent birth outcomes is warranted.

Levels of hexachlorobenzene (HCB) in breast milk in relation to birth weight in a Norwegian cohort.

BACKGROUND: Hexachlorobenzene (HCB) is a ubiquitous environmental contaminant that, even at low doses, causes destruction of ovarian primordial germ cells in experimental studies. However, its potential for reproductive toxicity in humans exposed to background levels has not been fully evaluated. Here we examined the association between maternal levels of HCB and their infants' birth weight. METHODS: HCB was measured in milk samples from a subset of women in the Norwegian Human Milk Study (HUMIS), 2003-2006; 300 subjects were randomly chosen from the cohort and 26 from all small for gestational age (SGA) children. Additional information was obtained through questionnaires and the Medical Birth Registry. RESULTS: Overall, HCB was associated with birth weight (adjusted b = -90 g per 8 microg/kg milk fat, 95% CI-275 to 8) and with SGA (odds ratio 1.8, 95% CI 0.9-3.7 per 8 microg/kg milk fat (difference between the 10th and the 90th percentile)). After stratification, however, the association was present only among smokers. For birth weight for past or current smokers: b = -282, CI -467 to -98; for never smokers: b = 0.5, CI -149 to 150, p-value for interaction: 0.01. Similar results were observed for head circumference, crown-heel length, and SGA. CONCLUSIONS: We saw a moderate association between HCB and markers of impaired fetal growth among past and current smokers. This finding may be non-causal and due to underlying genetic variants tied to both growth and breakdown of HCB or to confounding by unmeasured toxicants that coexist in exposure sources. It may, however, also result from HCB exposure.

Intersecting birth weight-specific mortality curves: solving the riddle.

Small babies from a population with higher infant mortality often have better survival than small babies from a lower-risk population. This phenomenon can in principle be explained entirely by the presence of unmeasured confounding factors that increase mortality and decrease birth weight. Using a previously developed model for birth weight-specific mortality, the authors demonstrate specifically how strong unmeasured confounders can cause mortality curves stratified by known risk factors to intersect. In this model, the addition of a simple exposure (one that reduces birth weight and independently increases mortality) will produce the familiar reversal of risk among small babies. Furthermore, the model explicitly shows how the mix of high- and low-risk babies within a given stratum of birth weight produces lower mortality for high-risk babies at low birth weights. If unmeasured confounders are, in fact, responsible for the intersection of weight-specific mortality curves, then they must also (by virtue of being confounders) contribute to the strength of the observed gradient of mortality by birth weight. It follows that the true gradient of mortality with birth weight would be weaker than what is observed, if indeed there is any true gradient at all.

Infertility, infertility treatment, and fetal growth restriction.

OBJECTIVE: To examine the association between infertility, with or without treatment, and fetal growth, as well as perinatal and infant mortality. METHODS: From the Danish National Birth Cohort (1997-2003), we identified 51,041 singletons born of fertile couples (time to pregnancy 12 months or less), 5,787 born of infertile couples conceiving naturally (time to pregnancy more than 12 months), and 4,317 born after treatment. We defined small for gestational age (SGA) as the lowest 5% of birth weight by sex and gestational age. RESULTS: Crude estimates suggested an increased risk of perinatal mortality and SGA among infertile couples (treated and untreated), but the odds ratios (ORs) of perinatal mortality among infertile couples were attenuated after adjustment for maternal age and body mass index (1.32, 95% confidence interval [CI] 0.95-1.84 among untreated and 1.26, 95% CI 0.86-1.85 among treated couples). The elevated risk of SGA among infertile couples persisted after adjustment for maternal age, parity, and smoking (OR 1.24, 95% CI 1.10-1.40 among untreated, and OR 1.40, 95% CI 1.23-1.60 among treated). The risk of SGA increased with time to pregnancy, and a longer time to pregnancy was associated with a small reduction in birth weight across the whole distribution. CONCLUSION: The increased risk of SGA observed among infertile couples with or without infertility treatment suggests that infertility may be a risk factor for intrauterine growth restriction. Treatment per se may have little effect on fetal growth. A small-to-moderate increased risk of perinatal mortality in infertile couples cannot be ruled out due to the small number of cases. LEVEL OF EVIDENCE: II.