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.

Type of infertility and prevalence of congenital malformations.

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.

Inferring fetal growth restriction as rare, severe, and stable over time.

Reduced birthweight is a marker of pathologies that impair growth and also decrease survival. However, "fetal growth restriction" remains poorly defined. Assuming that birthweight itself has no causal effect on neonatal mortality, we can estimate the features of pathological fetal growth that would be required to produce the observed pattern of weight-specific mortality. Under the simplest possible scenario, we find that at 39-41 weeks, pathological fetal growth restriction affects only about 0.5% of U.S. births, with a neonatal mortality risk up to 220-fold. This surprising concentration of pathology among a tiny subset of babies would account for roughly half of neonatal deaths at term. Moreover, the prevalence of these pathological births appears to have remained relatively stable over recent decades, even as neonatal mortality in the U.S. has declined by 90%. In our model, the decline has been driven by the reduction in baseline mortality (i.e., mortality among babies unaffected by growth pathologies), while the relative risk of death among pathologically grown infants has apparently remained stable. Fetal growth restriction is conventionally regarded as common and preventable. In contrast, our observations suggest that pathological fetal growth is rare and constant over time, perhaps the result of unpreventable stochastic errors in embryonic development. Public health strategies may be more effective by setting aside attempts to increase birthweight, and focusing instead on the discovery and support of factors (unrelated to birthweight) that have produced the striking reductions in neonatal mortality over time.

Fresh Compared With Frozen Embryo Transfer and Risk of Severe Maternal Morbidity: A Study of In Vitro Fertilization Pregnancies in Ontario, Canada.

OBJECTIVES: To quantify the risk of severe maternal morbidity (SMM) in fresh versus frozen-thawed embryo transfers (ETs) among pregnancies conceived by in vitro fertilization (IVF) and to assess SMM risk according to the number of fresh ETs prior to the index pregnancy. METHODS: Retrospective cohort study using the provincial birth registry in Ontario, Canada. We included 13 929 individuals aged 18-55 years who conceived via IVF between January 1, 2013, and March 5, 2018, and delivered a live or stillborn infant ≥20 weeks gestation. We compared the primary outcome, a composite of SMM or death, between fresh and frozen ETs. RESULTS: A total of 174 individuals who conceived via fresh ETs had SMM (30.7 per 1000), compared with 280 among individuals who received frozen ETs (33.9 per 1000); adjusted risk ratio (aRR) 0.85 (95% CI 0.70-1.04). Compared with frozen ET, fresh ET was associated with a lower risk of severe hemorrhage (aRR 0.63; 95% CI 0.48-0.82) but no difference in risk of preeclampsia. Among individuals with 1 (n = 211) or ≥2 (n = 88) prior fresh cycles, the risk of SMM was not increased compared with having no prior cycles; aRR 0.96 (95% CI 0.78-1.18) and 0.91 (95% CI 0.67-1.25), respectively. CONCLUSION: Fresh ET was associated with a lower risk of severe hemorrhage compared with frozen ET. These findings may be partly explained by the increased popularity of a freeze-all strategy, reserving fresh ETs for patients with fewer comorbidities.

The influence of regulation of medically assisted reproduction on the risk of hospitalization in the first 2 years of life.

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.

Parents' age at birth and daughters' time to pregnancy: a study within the Norwegian Mother, Father and Child Cohort.

STUDY QUESTION: Is parents' age at birth associated with daughters' fecundability? SUMMARY ANSWER: Daughters born to mothers <25 years or fathers ≥35 years had slightly lower fecundability. WHAT IS KNOWN ALREADY: Two recent studies reported lower fecundability in women born to mothers <20 years, which may be partly due to daughters of young mothers being less likely to plan their pregnancies. 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 <20 years and 0.97 (0.95, 0.99) for 20-24 years). Results were similar for the composite outcome TTP ≥ 12 months or treatment, although driven by TTP ≥ 12. Compared with Norwegian-born women with ≥1 pregnancy, planners born to mothers <20 years were underrepresented. Including non-planners with very high fecundability weakened the association with mother's age <20 years. 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 <20 years. 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.

Infertility treatment and postpartum mental illness: a population-based cohort study.

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.

Differences in birthweight by maternal and paternal nativity status in Canada.

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.

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.

The limits of small-for-gestational-age as a high-risk category.

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.

Development and internal validation of a model predicting severe maternal morbidity using pre-conception and early pregnancy variables: a population-based study in Ontario, Canada.

BACKGROUND: Improvement in the prediction and prevention of severe maternal morbidity (SMM) - a range of life-threatening conditions during pregnancy, at delivery or within 42 days postpartum - is a public health priority. Reduction of SMM at a population level would be facilitated by early identification and prediction. We sought to develop and internally validate a model to predict maternal end-organ injury or death using variables routinely collected during pre-pregnancy and the early pregnancy period. METHODS: We performed a population-based cohort study using linked administrative health data in Ontario, Canada, from April 1, 2006 to March 31, 2014. We included women aged 18-60 years with a livebirth or stillbirth, of which one birth was randomly selected per woman. We constructed a clinical prediction model 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 model included variables collected from 12 months before estimated conception until 19 weeks' gestation. We developed a separate model 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 model 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 and external validation of this model are warranted and can support evidence-based improvements in clinical practice.

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.

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.

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.

The fragile foundations of the extended fetuses-at-risk approach.

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.

Infertility treatment and risk of severe maternal morbidity: a propensity score-matched cohort study.

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.

Maternal hypertension and survival in singletons and twins born at 23-29 weeks: not just one answer .

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.