Safety of low weight gain or weight loss in pregnancies with class 1, 2, and 3 obesity: a population-based cohort study.

BACKGROUND: There are concerns that current gestational weight gain recommendations for women with obesity are too high and that guidelines should differ on the basis of severity of obesity. In this study we investigated the safety of gestational weight gain below current recommendations or weight loss in pregnancies with obesity, and evaluated whether separate guidelines are needed for different obesity classes. METHODS: In this population-based cohort study, we used electronic medical records from the Stockholm-Gotland Perinatal Cohort study to identify pregnancies with obesity (early pregnancy BMI before 14 weeks' gestation ≥30 kg/m2) among singleton pregnancies that delivered between Jan 1, 2008, and Dec 31, 2015. The pregnancy records were linked with Swedish national health-care register data up to Dec 31, 2019. Gestational weight gain was calculated as the last measured weight before or at delivery minus early pregnancy weight (at <14 weeks' gestation), and standardised for gestational age into z-scores. We used Poisson regression to assess the association of gestational weight gain z-score with a composite outcome of: stillbirth, infant death, large for gestational age and small for gestational age at birth, preterm birth, unplanned caesarean delivery, gestational diabetes, pre-eclampsia, excess postpartum weight retention, and new-onset longer-term maternal cardiometabolic disease after pregnancy, weighted to account for event severity. We calculated rate ratios (RRs) for our composite adverse outcome along the weight gain z-score continuum, compared with a reference of the current lower limit for gestational weight gain recommended by the US Institute of Medicine (IOM; 5 kg at term). RRs were adjusted for confounding factors (maternal age, height, parity, early pregnancy BMI, early pregnancy smoking status, prepregnancy cardiovascular disease or diabetes, education, cohabitation status, and Nordic country of birth). FINDINGS: Our cohort comprised 15 760 pregnancies with obesity, followed up for a median of 7·9 years (IQR 5·8-9·4). 11 667 (74·0%) pregnancies had class 1 obesity, 3160 (20·1%) had class 2 obesity, and 933 (5·9%) had class 3 obesity. Among these pregnancies, 1623 (13·9%), 786 (24·9%), and 310 (33·2%), respectively, had weight gain during pregnancy below the lower limit of the IOM recommendation (5 kg). In pregnancies with class 1 or 2 obesity, gestational weight gain values below the lower limit of the IOM recommendation or weight loss did not increase risk of the adverse composite outcome (eg, at weight gain z-score -2·4, corresponding to 0 kg at 40 weeks: adjusted RR 0·97 [95% CI 0·89-1·06] in obesity class 1 and 0·96 [0·86-1·08] in obesity class 2). In pregnancies with class 3 obesity, weight gain values below the IOM limit or weight loss were associated with reduced risk of the adverse composite outcome (eg, adjusted RR 0·81 [0·71-0·89] at weight gain z-score -2·4, or 0 kg). INTERPRETATION: Our findings support calls to lower or remove the lower limit of current IOM recommendations for pregnant women with obesity, and suggest that separate guidelines for class 3 obesity might be warranted. FUNDING: Karolinska Institutet and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

The effect of changing screening practices and demographics on the incidence of gestational diabetes in British Columbia, 2005-2019.

BACKGROUND: Rates of gestational diabetes are reported to be increasing in many jurisdictions, but the reasons for this are poorly understood. We sought to evaluate the relative contribution of screening practices for gestational diabetes (including completion and methods of screening) and population characteristics to risk of gestational diabetes in British Columbia, Canada, from 2005 to 2019. METHODS: We used a population-based cohort from a provincial registry of perinatal data, linked to laboratory billing records. We used data on screening completion, screening method (1-step 75-g glucose test or 2-step approach of 50-g glucose screening test, followed by a diagnostic test for patients who screen positive) and demographic risk factors. We modelled predicted annual risk for gestational diabetes, sequentially adjusted for screening completion, screening method and risk factors. RESULTS: We included 551 457 pregnancies in the study cohort. The incidence of gestational diabetes more than doubled over the study period, from 7.2% in 2005 to 14.7% in 2019. Screening completion increased from 87.2% in 2005 to 95.5% in 2019. Use of 1-step screening methods increased from 0.0% in 2005 to 39.5% in 2019 among those who were screened. Unadjusted models estimated a 2.04 (95% confidence interval [CI] 1.94-2.13) increased risk of gestational diabetes in 2019 (v. 2005). This increase was 1.89 (95% CI 1.81-1.98) after accounting for the rise in screening completion and 1.34 (95% CI 1.28-1.40) after accounting for changes in screening methods. Further accounting for demographic risk factors (e.g., age, body mass index, prenatal care) had a small impact (increase of 1.25, 95% CI 1.19-1.31). INTERPRETATION: Most of the observed increase in the incidence of gestational diabetes was attributable to changes in screening practices (primarily changes in screening methods) rather than changing population factors. Our findings highlight the importance of understanding variation in screening practices when monitoring incidence rates for gestational diabetes.

Trends in Gestational Diabetes Screening Practices in British Columbia from 2005-2019.

OBJECTIVES: To examine trends in the frequency and method (one-step vs. two-step) of gestational diabetes mellitus (GDM) screening in British Columbia (BC), Canada, across subgroups of pregnant individuals in the context of changing local and national clinical practice guidelines. METHODS: We conducted a retrospective cohort study using de-identified, linked perinatal and laboratory billing data. We included all pregnancies delivered in BC after 28 weeks gestation, with screening dates between June 2004 and May 2019. We calculated the prevalence of each screening method with 95% CI overall and over time, and we examined screening practices in subgroups and different geographic regions. In October 2010, BC began recommending a one-step method; therefore, we examined time periods relative to this and other Canadian guideline changes. RESULTS: Screening completion increased over the study period, from 88% in 2004 to 96% in 2019. After a guideline change in 2010, use of one-step screening increased sharply from 2.0% (95% CI 1.9-2.0) to 45.2% (95% CI 44.9-45.6). Following the 2013 Diabetes Canada guideline change, one-step screening decreased to 42.8% (95% CI 42.5-43.1). Of those receiving one-step screening, 18% were diagnosed with GDM compared to 9% with two-step screening. Use of one-step screening was higher in pregnant people with risk factors and in larger urban centres. CONCLUSION: GDM screening in BC demonstrated higher use of one-step screening among people with risk factors; however, there were strong regional disparities and considerable variation in screening practices over time and across subgroups.

Iron-Deficiency Prevalence and Supplementation Practices Among Pregnant Women: A Secondary Data Analysis From a Clinical Trial in Vancouver, Canada.

BACKGROUND: North American public health guidelines recommend supplementation with an iron-containing prenatal multivitamin throughout pregnancy to meet the RDA of 27 mg of elemental iron daily. However, whether supplementation with standard prenatal multivitamins is sufficient to prevent maternal iron deficiency is unclear, as needs increase substantially with advancing gestation. OBJECTIVES: This study aimed to assess iron status in early and late pregnancy among 60 pregnant women receiving 27 mg/day of elemental iron as part of a randomized trial in Vancouver, Canada. METHODS: Study visits were conducted at 8-21 (baseline) and 24-38 (endline) weeks of gestation. Venous blood specimens were collected for a complete blood count and measurement of iron and inflammatory biomarkers. Supplementation with any additional iron (beyond 27 mg/day) was reported by participants (treatment with additional iron is recommended if ferritin is <30 µg/L). Quantile regression was used to explore predictors of endline ferritin concentrations, including ethnicity, education, income, and baseline ferritin measurement. RESULTS: Overall, 60 and 54 women participated in baseline and endline visits, respectively. Rates of probable iron deficiency (ferritin <30 µg/L) at baseline and endline were 17 (28%) and 44 (81%), respectively. Less than half (n = 18; 41%) of participants with probable iron deficiency at endline reported supplementation with additional iron. Ethnicity was the only significant modifier of endline ferritin, with higher concentrations in those of South, East, and Southeast Asian ethnicity compared to those of European ethnicity (ß: 10.4 µg/L; 95% CI: 0.3-20.5). CONCLUSIONS: Pregnant individuals may require additional supplemental iron beyond 27 mg to meet requirements in later pregnancy, given the high rates of iron deficiency observed in this clinical trial, despite consumption meeting 100% of the RDA. This trial was registered at clinicaltrials.gov as NCT04022135.

The Inclusion of Folic Acid in Weekly Iron-Folic Acid Supplements Confers no Additional Benefit on Anemia Reduction in Nonpregnant Women: A Randomized Controlled Trial in Malaysia.

BACKGROUND: Weekly iron-folic acid (IFA) supplements are recommended for all menstruating women in countries where anemia prevalence is ≥20%; however, it is unknown whether the inclusion of folic acid in weekly IFA supplements reduces anemia. OBJECTIVES: We examined whether the inclusion of folic acid in weekly IFA supplements conferred any benefit on hemoglobin (Hb) concentration, anemia reduction, or iron status [ferritin and soluble transferrin receptor (sTfR)], over iron alone. METHODS: In this secondary analysis of a randomized controlled trial in Malaysia, n = 311 nonpregnant women (18-45 y old) received 60 mg Fe with either 0, 0.4, or 2.8 mg folic acid once-weekly for 16 wk. Fasting blood was collected at baseline and 16 wk. A generalized linear model (normal distribution with identity link) was used to assess Hb concentration at 16 wk (primary outcome). RESULTS: At baseline, 84% of women had low folate status (plasma folate < 14 nmol/L). At 16 wk, marginal mean (95% CI) Hb was 131 (130, 133), 131 (129, 132), and 132 (130, 133) g/L; ferritin was 58.2 (53.9, 62.5), 56.5 (52.2, 60.9), and 58.0 (53.7, 62.3) µg/L; and sTfR was 5.8 (5.5, 6.1), 5.8 (5.5, 6.1), and 5.9 (5.6, 6.2) mg/L in the 0, 0.4, and 2.8 mg/wk groups, respectively, with no differences between groups (P > 0.05). Baseline plasma folate concentration did not modify the effect of treatment on Hb concentration at 16 wk. Among all women, the risks of anemia [risk ratio (RR): 0.65; 95% CI: 0.45, 0.96; P = 0.03] and iron deficiency based on ferritin (RR: 0.30; 95% CI: 0.20, 0.44; P < 0.001) were lower at 16 wk than at baseline. CONCLUSIONS: Despite the low folate status among these nonpregnant Malaysian women, the inclusion of folic acid in weekly IFA supplements did not reduce anemia or improve iron status, over iron alone. However, the benefits of folic acid for neural tube defect prevention still warrant its retention in weekly IFA supplements.This trial was registered at www.anzctr.org.au as ACTRN12619000818134.

Short interpregnancy interval and pregnancy outcomes: How important is the timing of confounding variable ascertainment?

BACKGROUND: Estimation of causal effects of short interpregnancy interval on pregnancy outcomes may be confounded by time-varying factors. These confounders should be ascertained at or before delivery of the first ("index") pregnancy, but are often only measured at the subsequent pregnancy. OBJECTIVES: To quantify bias induced by adjusting for time-varying confounders ascertained at the subsequent (rather than the index) pregnancy in estimated effects of short interpregnancy interval on pregnancy outcomes. METHODS: We analysed linked records for births in British Columbia, Canada, 2004-2014, to women with ≥2 singleton pregnancies (n = 121 151). We used log binomial regression to compare short (<6, 6-11, 12-17 months) to 18-23-month reference intervals for 5 outcomes: perinatal mortality (stillbirth and neonatal death); small for gestational age (SGA) birth and preterm delivery (all, early, spontaneous). We calculated per cent differences between adjusted risk ratios (aRR) from two models with maternal age, low socio-economic status, body mass index, and smoking ascertained in the index pregnancy and the subsequent pregnancy. We considered relative per cent differences <5% minimal, 5%-9% modest, and ≥10% substantial. RESULTS: Adjustment for confounders measured at the subsequent pregnancy introduced modest bias towards the null for perinatal mortality aRRs for <6-month interpregnancy intervals [-9.7%, 95% confidence interval [CI] -15.3, -6.2). SGA aRRs were minimally biased towards the null (-1.1%, 95% CI -2.6, 0.8) for <6-month intervals. While early preterm delivery aRRs were substantially biased towards the null (-10.4%, 95% CI -14.0, -6.6) for <6-month interpregnancy intervals, bias was minimal for <6-month intervals for all preterm deliveries (-0.6%, 95% CI -2.0, 0.8) and spontaneous preterm deliveries (-1.3%, 95% CI -3.1, 0.1). For all outcomes, bias was attenuated and minimal for 6-11-month and 12-17-month interpregnancy intervals. CONCLUSION: These findings suggest that maternally linked pregnancy data may not be needed for appropriate confounder adjustment when studying the effects of short interpregnancy interval on pregnancy outcomes.

Weekly iron-folic acid supplements containing 2.8 mg folic acid are associated with a lower risk of neural tube defects than the current practice of 0.4 mg: a randomised controlled trial in Malaysia.

INTRODUCTION: Weekly iron-folic acid (IFA) supplements are recommended for all menstruating women in countries where anaemia prevalence is >20%. Anaemia caused by folate deficiency is low worldwide, and the need to include folic acid is in question. Including folic acid might reduce the risk of a neural tube defect (NTD) should a woman become pregnant. Most weekly supplements contain 0.4 mg folic acid; however, WHO recommends 2.8 mg because it is seven times the daily dose effective in reducing NTDs. There is a reluctance to switch to supplements containing 2.8 mg of folic acid because of a lack of evidence that this dose would prevent NTDs. Our aim was to investigate the effect of two doses of folic acid, compared with placebo, on red blood cell (RBC) folate, a biomarker of NTD risk. METHODS: We conducted a three-arm double-blind efficacy trial in Malaysia. Non-pregnant women (n=331) were randomised to receive 60 mg iron and either 0, 0.4, or 2.8 mg folic acid once weekly for 16 weeks. RESULTS: At 16 weeks, women receiving 0.4 mg and 2.8 mg folic acid per week had a higher mean RBC folate than those receiving 0 mg (mean difference (95% CI) 84 (54 to 113) and 355 (316 to 394) nmol/L, respectively). Women receiving 2.8 mg folic acid had a 271 (234 to 309) nmol/L greater mean RBC folate than those receiving 0.4 mg. Moreover, women in the 2.8 mg group were seven times (RR 7.3, 95% CI 3.9 to 13.7; p<0.0001) more likely to achieve an RBC folate >748 nmol/L, a concentration associated with a low risk of NTD, compared with the 0.4 mg group. CONCLUSION: Weekly IFA supplements containing 2.8 mg folic acid increases RBC folate more than those containing 0.4 mg. Increased availability and access to the 2.8 mg formulation is needed. TRAIL REGISTRATION NUMBER: This trial is registered with the Australian New Zealand Clinical Trial Registry (ACTRN12619000818134).

Is natural (6S)-5-methyltetrahydrofolic acid as effective as synthetic folic acid in increasing serum and red blood cell folate concentrations during pregnancy? A proof-of-concept pilot study.

BACKGROUND: North American health authorities recommend 0.4 mg/day folic acid before conception and throughout pregnancy to reduce the risk of neural tube defects. Folic acid is a synthetic form of folate that must be reduced by dihydrofolate reductase and then further metabolized. Recent evidence suggests that the maximal capacity for this process is limited and unmetabolized folic acid has been detected in the circulation. The biological effects of unmetabolized folic acid are unknown. A natural form of folate, (6S)-5-methyltetrahydrofolic acid (Metafolin®), may be a superior alternative because it does not need to be reduced in the small intestine. Metafolin® is currently used in some prenatal multivitamins; however, it has yet to be evaluated during pregnancy. METHODS/DESIGN: This double-blind, randomized trial will recruit 60 pregnant women aged 19-42 years. The women will receive either 0.6 mg/day folic acid or an equimolar dose (0.625 mg/day) of (6S)-5-methyltetrahydrofolic acid for 16 weeks. The trial will be initiated at 8-21 weeks' gestation (after neural tube closure) to reduce the risk of harm should (6S)-5-methyltetrahydrofolic acid prove less effective. All women will also receive a prenatal multivitamin (not containing folate) to ensure adequacy of other nutrients. Baseline and endline blood samples will be collected to assess primary outcome measures, including serum folate, red blood cell folate and unmetabolized folic acid. The extent to which the change in primary outcomes from baseline to endline differs between treatment groups, controlling for baseline level, will be estimated using linear regression. Participants will have the option to continue supplementing until 1 week postpartum to provide a breastmilk and blood sample. Exploratory analyses will be completed to evaluate breastmilk and postpartum blood folate concentrations. DISCUSSION: This proof-of-concept trial is needed to obtain estimates of the effect of (6S)-5-methyltetrahydrofolic acid compared to folic acid on circulating biomarkers of folate status during pregnancy. These estimates will inform the design of a definitive trial which will be powered to assess whether (6S)-5-methyltetrahydrofolic acid is as effective as folic acid in raising blood folate concentrations during pregnancy. Ultimately, these findings will inform folate supplementation policies for pregnant women. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT04022135. Registered on 14 July 2019.

Effect of once weekly folic acid supplementation on erythrocyte folate concentrations in women to determine potential to prevent neural tube defects: a randomised controlled dose-finding trial in Malaysia.

INTRODUCTION: Folic acid (0.4 mg) taken prior to and during early pregnancy reduces the risk of neural tube defects (NTDs). Because these birth defects occur early in pregnancy, before women may know they are pregnant, many countries have mandated the addition of folic acid to food staples. In countries where fortification is not possible, and weekly iron folic acid programmes exist to reduce anaemia, the WHO recommends that 2.8 mg (7×0.4 mg) folic acid be given instead of the current weekly practice of 0.4 mg. Currently, there is a lack of evidence to support if the 2.8 mg folic acid per week dose is sufficient to raise erythrocyte folate concentrations to a level associated with a reduced risk of a NTD-affected pregnancy. We aim to conduct a three-arm randomised controlled trial to determine the effect of weekly folic acid with iron on erythrocyte folate, a biomarker of NTD risk. METHODS AND ANALYSIS: We will recruit non-pregnant women (n=300; 18-45 years) from Selangor, Malaysia. Women will be randomised to receive either 2.8, 0.4 or 0.0 (placebo) mg folic acid with 60 mg iron weekly for 16 weeks, followed by a 4-week washout period. The primary outcome will be erythrocyte folate concentration at 16 weeks and the mean concentration will be compared between randomised treatment groups (intention-to-treat) using a linear regression model adjusting for the baseline measure. ETHICS AND DISSEMINATION: Ethical approval was obtained from the University of British Columbia (H18-00768) and Universiti Putra Malaysia (JKEUPM-2018-255). The results of this trial will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: ACTRN12619000818134 and NMRR-19-119-45736.

Development and Validation of a Risk Prediction Model for Cesarean Delivery After Labor Induction.

Objective: The goal of the study was to develop and validate a prediction model for cesarean delivery after labor induction that included factors known before the start of induction, unlike prior studies that focused on characteristics at the time of induction. Materials and Methods: Using 17,370 term labor inductions without documented medical indications occurring at 14 U.S. hospitals, 2007-2012, we created and evaluated a model predicting cesarean delivery. We assessed model calibration and discrimination, and we used bootstrapping for internal validation. We externally validated the model by using 2122 labor inductions from a hospital not included in the development cohort. Results: The model contained eight variables-gestational age, maternal race, parity, maternal age, obesity, fibroids, excessive fetal growth, and history of herpes-and was well calibrated with good risk stratification at the extremes of predicted probability. The model had an area under the curve (AUC) for the receiver operating characteristic curve of 0.82 (95% confidence interval 0.81-0.83), and it performed well on internal validation. The AUC in the external validation cohort was 0.82. Conclusion: This prediction model can help providers estimate a woman's risk of cesarean delivery when planning a labor induction.

Coal smoke, gestational cadmium exposure, and fetal growth.

BACKGROUND: Gestational cadmium exposure may impair fetal growth. Coal smoke has largely been unexplored as a source of cadmium exposure. We investigated the relationship between gestational cadmium exposure and fetal growth, and assessed coal smoke as a potential source of airborne cadmium, among non-smoking pregnant women in Ulaanbaatar, Mongolia, where coal combustion in home heating stoves is a major source of outdoor and indoor air pollution. METHODS: This observational study was nested within the Ulaanbaatar Gestation and Air Pollution Research (UGAAR) study, a randomized controlled trial of portable high efficiency particulate air (HEPA) filter air cleaner use during pregnancy, fetal growth, and early childhood development. We measured third trimester blood cadmium concentrations in 374 out of 465 participants who had a live birth. We used multiple linear and logistic regression to assess the relationships between log2-transformed maternal blood cadmium concentrations and birth weight, length, head circumference, ponderal index, low birth weight, small for gestational age, and preterm birth in crude and adjusted models. We also evaluated the relationships between log2-transformed blood cadmium concentrations and the density of coal-burning stoves within 5000 m of each participant's apartment as a proxy of coal smoke emissions from home heating stoves. RESULTS: The median (25th,75th percentile) blood cadmium concentration was 0.20 (0.15, 0.29) µg/L. A doubling of blood cadmium was associated with a 95 g (95% CI: 34, 155 g) reduction in birth weight in adjusted models. An interquartile range increase in coal stove density (from 3.4 to 4.9 gers/hectare) surrounding participants' apartments was associated with a 12.2% (95% CI: 0.3, 25.6%) increase in blood cadmium concentrations. CONCLUSIONS: Gestational cadmium exposure was associated with reduced birth weight. In settings where coal is a widely used fuel, cadmium may play a role in the putative association between air pollution and impaired fetal growth.

Urinary tract infection prevention after midurethral slings in pelvic floor reconstructive surgery: A systematic review and meta-analysis.

INTRODUCTION: Synthetic midurethral slings are the most common procedures currently performed for stress urinary incontinence in women. Infection is a frequent complication of urogynecologic surgery. We performed a systematic review and meta-analysis to identify interventions that successfully prevent infections, including urinary tract infection (UTI) and/or bacteriuria, compared with no intervention, in women undergoing midurethral sling surgery with or without concomitant pelvic reconstructive procedures for prolapse. MATERIAL AND METHODS: The primary outcome was the development of any infection post-midurethral sling placement in women. MEDLINE, Embase, CINAHL and the Cochrane Library were searched for comparative studies from inception to July 2017, with no language restrictions. We used search terms related to midurethral sling, infections and infection-reduction interventions. Two independent reviewers abstracted data and assessed study quality. Pooled effect size estimates were calculated. We conducted meta-analysis of eligible studies. A protocol for this review has been registered and can be accessed online (http://hdl.handle.net/2429/64731). RESULTS: We identified seven eligible studies of infection risk-reducing interventions; all focused on UTIs. Only one study assessed preoperative antibiotics with midurethral sling alone and was halted early because of low UTI rates. All other studies (three randomized control trials and three observational studies) examined whether postoperative antibiotics decrease UTI/bacteriuria rates after midurethral sling with or without reconstructive procedures for pelvic organ prolapse and using bladder catheterization postoperatively. Due to considerable clinical heterogeneity, we only combined four studies for meta-analysis. Postoperative oral prophylactic nitrofurantoin showed no significant benefit in reducing UTI/bacteriuria in women post-midurethral sling with or without concomitant reconstructive pelvic surgery and the need for bladder catheterization, when compared with the reference group (pooled relative risk 0.73, 95% confidence interval [CI] 0.42-1.25). CONCLUSIONS: Based on the best available evidence, postoperative oral nitrofurantoin is not effective at reducing UTI/bacteriuria rates in catheterized women after midurethral sling with or without concomitant pelvic reconstructive surgery for prolapse. For midurethral sling alone, preoperative antibiotic prophylaxis may not be needed for UTI prevention.

Development and internal validation of the multivariable CIPHER (Collaborative Integrated Pregnancy High-dependency Estimate of Risk) clinical risk prediction model.

BACKGROUND: Intensive care unit (ICU) outcome prediction models, such as Acute Physiology And Chronic Health Evaluation (APACHE), were designed in general critical care populations and their use in obstetric populations is contentious. The aim of the CIPHER (Collaborative Integrated Pregnancy High-dependency Estimate of Risk) study was to develop and internally validate a multivariable prognostic model calibrated specifically for pregnant or recently delivered women admitted for critical care. METHODS: A retrospective observational cohort was created for this study from 13 tertiary facilities across five high-income and six low- or middle-income countries. Women admitted to an ICU for more than 24 h during pregnancy or less than 6 weeks post-partum from 2000 to 2012 were included in the cohort. A composite primary outcome was defined as maternal death or need for organ support for more than 7 days or acute life-saving intervention. Model development involved selection of candidate predictor variables based on prior evidence of effect, availability across study sites, and use of LASSO (Least Absolute Shrinkage and Selection Operator) model building after multiple imputation using chained equations to address missing data for variable selection. The final model was estimated using multivariable logistic regression. Internal validation was completed using bootstrapping to correct for optimism in model performance measures of discrimination and calibration. RESULTS: Overall, 127 out of 769 (16.5%) women experienced an adverse outcome. Predictors included in the final CIPHER model were maternal age, surgery in the preceding 24 h, systolic blood pressure, Glasgow Coma Scale score, serum sodium, serum potassium, activated partial thromboplastin time, arterial blood gas (ABG) pH, serum creatinine, and serum bilirubin. After internal validation, the model maintained excellent discrimination (area under the curve of the receiver operating characteristic (AUROC) 0.82, 95% confidence interval (CI) 0.81 to 0.84) and good calibration (slope of 0.92, 95% CI 0.91 to 0.92 and intercept of -0.11, 95% CI -0.13 to -0.08). CONCLUSIONS: The CIPHER model has the potential to be a pragmatic risk prediction tool. CIPHER can identify critically ill pregnant women at highest risk for adverse outcomes, inform counseling of patients about risk, and facilitate bench-marking of outcomes between centers by adjusting for baseline risk.

The effect of portable HEPA filter air cleaner use during pregnancy on fetal growth: The UGAAR randomized controlled trial.

BACKGROUND: Fine particulate matter (PM2.5) exposure may impair fetal growth. AIMS/OBJECTIVES: Our aim was to assess the effect of portable high efficiency particulate air (HEPA) filter air cleaner use during pregnancy on fetal growth. METHODS: The Ulaanbaatar Gestation and Air Pollution Research (UGAAR) study is a single-blind randomized controlled trial conducted in Ulaanbaatar, Mongolia. Non-smoking pregnant women recruited at ≤18 weeks gestation were randomized to an intervention (1-2 air cleaners in homes from early pregnancy until childbirth) or control (no air cleaners) group. Participants were not blinded to their intervention status. Demographic, health, and birth outcome data were obtained via questionnaires and clinic records. We used unadjusted linear and logistic regression and time-to-event analysis to evaluate the intervention. Our primary outcome was birth weight. Secondary outcomes were gestational age-adjusted birth weight, birth length, head circumference, gestational age at birth, and small for gestational age. The study is registered at ClinicalTrials.gov (NCT01741051). RESULTS: We recruited 540 participants (272 control and 268 intervention) from January 9, 2014 to May 1, 2015. There were 465 live births and 28 losses to follow up. We previously reported a 29% (95% CI: 21, 37%) reduction in indoor PM2.5 concentrations with portable HEPA filter air cleaner use. The median (25th, 75th percentile) birth weights for control and intervention participants were 3450 g (3150, 3800 g) and 3550 g (3200, 3800 g), respectively (p = 0.34). The intervention was not associated with birth weight (18 g; 95% CI: -84, 120 g), but in a pre-specified subgroup analysis of 429 term births the intervention was associated with an 85 g (95% CI: 3, 167 g) increase in mean birth weight. CONCLUSIONS: HEPA filter air cleaner use in a high pollution setting was associated with greater birth weight only among babies born at term.

Absolute risks of obstetric outcomes by maternal age at first birth: a population-based cohort.

BACKGROUND: First deliveries in women older than 35, 40, or 45 years are at increased risk for adverse pregnancy outcomes compared with those in younger women. However, specific relationships between each additional year of maternal age and pregnancy risks remain unclear, and absolute risks at each maternal age are not known. METHODS: Using a population-based cohort of nulliparous women in British Columbia, Canada, from 2004 to 2014 (n = 203,414), We examined relationships between maternal age (modeled flexibly to allow curvilinear shapes) and pregnancy outcomes using logistic regression. We plotted absolute predicted risks to display curves from age 20 to 50 estimated for two risk profiles: (1) population average values of all risk factors; (2) a low-risk profile without preexisting diabetes/hypertension, smoking, prior spontaneous/therapeutic abortion, diagnosed infertility, inadequate prenatal care, low income, rural residence, or obesity. RESULTS: Risks of hypertensive disorders increased gradually until age 35, then accelerated. Risk of multiple gestations, major congenital anomalies, and maternal mortality or severe morbidity increased slowly until age 30, then accelerated. Cesarean delivery and gestational diabetes risks increased linearly with age. While indicated preterm delivery increased rapidly with maternal age, spontaneous preterm delivery did not. Stillbirth, neonatal mortality, and infant mortality had j-shaped relationships with maternal age, with nadirs near 30. Despite age-related increases, risks of severe outcomes remained low for women 35 and 40: < 1-2% for severe maternal morbidity and 5-7% for fetal-infant composite. CONCLUSIONS: This study provides risks for specific maternal ages to inform clinical counseling and public health messaging regarding the potential implications of delayed childbearing.

The effect of oral iron with or without multiple micronutrients on hemoglobin concentration and hemoglobin response among nonpregnant Cambodian women of reproductive age: a 2 x 2 factorial, double-blind, randomized controlled supplementation trial.

Background: Despite a high prevalence of anemia among nonpregnant Cambodian women, current reports suggest that iron deficiency (ID) prevalence is low. If true, iron supplementation will not be an effective anemia reduction strategy.Objective: We measured the effect of daily oral iron with or without multiple micronutrients (MMNs) on hemoglobin concentration in nonpregnant Cambodian women screened as anemic.Design: In this 2 × 2 factorial, double-blind, randomized trial, nonpregnant women (aged 18-45 y) with hemoglobin concentrations ≤117 g/L (capillary blood) were recruited from 26 villages in Kampong Chhnang province and randomly assigned to receive 12 wk of iron (60 mg; Fe group), MMNs (14 other micronutrients; MMN group), iron plus MMNs (Fe+MMN group), or placebo capsules. A 2 × 2 factorial intention-to-treat analysis with the use of a generalized mixed-effects model was used to assess the effects of iron and MMNs and the interaction between these factors. Results: In July 2015, 809 women were recruited and 760 (94%) completed the trial. Baseline anemia prevalence was 58% (venous blood). Mean (95% CI) hemoglobin concentrations at 12 wk in the Fe, MMN, Fe+MMN, and placebo groups were 121 (120, 121), 116 (116, 117), 123 (122, 123), and 116 (116, 117) g/L, with no iron × MMN interaction (P = 0.66). Mean (95% CI) increases in hemoglobin were 5.6 g/L (3.8, 7.4 g/L) (P < 0.001) among women who received iron (n = 407) and 1.2 g/L (-0.6, 3.0 g/L) (P = 0.18) among women who received MMNs (n = 407). The predicted proportions (95% CIs) of women with a hemoglobin response (≥10 g/L at 12 wk) were 19% (14%, 24%), 9% (5%, 12%), 30% (24%, 35%), and 5% (2%, 9%) in the Fe, MMN, Fe+MMN, and placebo groups, respectively.Conclusions: Daily iron supplementation for 12 wk increased hemoglobin in nonpregnant Cambodian women; however, MMNs did not confer additional significant benefit. Overall, ∼24% of women who received iron responded after 12 wk; even fewer would be likely to respond in the wider population. This trial was registered at clinicaltrials.gov as NCT02481375.

Diabetic Pharmacotherapy and Endometrial Cancer Risk Within a Publicly Funded Health Care System.

OBJECTIVE: There is conflicting evidence regarding the association between metformin and endometrial cancer risk. The objective of this study was to evaluate the association between type of diabetic pharmacotherapy and endometrial cancer risk within a population-based study. The hypothesis was that metformin was associated with the lowest risk. METHODS: This was a nested case-control study using data from the BC Cancer Registry (2000-2009) and from a province-wide prescription network (PharmaNet) since 1996. Patients were classified by drug exposure (metformin, thiazolidinediones, secretagogues, with or without insulin). The primary analysis was a conditional logistic regression to estimate the odds ratios for endometrial cancer in the drug exposure groups. Sensitivity analysis was carried out to account for uncertainty regarding various parameters. The secondary analysis evaluated the effect of dosage using a principal components analysis. RESULTS: The study cohort comprised 492 cases and 4404 controls. The primary analysis revealed no difference in endometrial cancer risk between those using metformin and those prescribed other classes of medications (OR 1.5, 95% CI 0.9 to 2.4). Women receiving all classes of medications had almost a two-fold increase in risk (OR 1.9, 95% CI 1.1 to 3.3). The secondary analysis revealed an increased risk associated with a greater duration of treatment and number of prescriptions (OR 1.3, 95% CI 1.2 to 1.4). CONCLUSION: In this population-based study, metformin was not associated with a decreased endometrial cancer risk. Women receiving multiple types of medications over a long time had the highest risk, implying that the extent of insulin resistance, rather than the effect of any specific medication, drives endometrial cancer risk.

Delivery planning for pregnancies with gastroschisis: findings from a prospective national registry.

OBJECTIVE: The purpose of this study was to determine the influence of planned mode and planned timing of delivery on neonatal outcomes in infants with gastroschisis. STUDY DESIGN: Data from the Canadian Pediatric Surgery Network cohort were used to identify 519 fetuses with isolated gastroschisis who were delivered at all tertiary-level perinatal centers in Canada from 2005-2013 (n = 16). Neonatal outcomes (including length of stay, duration of total parenteral nutrition, and a composite of perinatal death or prolonged exclusive total parenteral nutrition) were compared according to the 32-week gestation planned mode and timing of delivery with the use of the multivariable quantile and logistic regression. RESULTS: Planned induction of labor was not associated with decreased length of stay (adjusted median difference, -2.6 days; 95% confidence interval [CI], -9.9 to 4.8), total parenteral nutrition duration (adjusted median difference, -0.2 days; 95% CI, -6.4 to 6.0), or risk of the composite adverse outcome (relative risk, 1.7; 95% CI, 0.1-3.2) compared with planned vaginal delivery after spontaneous onset of labor. Planned delivery at 36-37 weeks' gestation was not associated with decreased length of stay (adjusted median difference, 5.9 days; 95% CI, -5.7 to 17.5), total parenteral nutrition duration (adjusted median difference, 3.2 days; 95% CI, -7.9 to 14.3), or risk of composite outcome (relative risk, 2.3; 95% CI, 0.8-5.4) compared with planned delivery at ≥38 weeks' gestation. CONCLUSION: Infants with gastroschisis who were delivered after planned induction or planned delivery at 36-37 weeks' gestation did not have significantly better neonatal outcomes than planned vaginal delivery after spontaneous onset of labor and planned delivery at ≥38 weeks' gestation.

Risk of adverse pregnancy outcomes by prepregnancy body mass index: a population-based study to inform prepregnancy weight loss counseling.

OBJECTIVE: To estimate the absolute risks of adverse maternal and perinatal outcomes based on small differences in prepregnancy body mass (eg, 10% of body mass or 10-20 pounds). METHODS: This population-based cohort study (N=226,958) was drawn from all singleton pregnancies in British Columbia (Canada) from 2004 to 2012. The relationships between prepregnancy body mass index (BMI) (as a continuous, nonlinear variable) and adverse pregnancy outcomes were examined using logistic regression models. Analyses were adjusted for maternal age, height, parity, and smoking in pregnancy. Adjusted absolute risks of each outcome are reported according to incremental differences in prepregnancy BMI and weight in pounds. RESULTS: A 10% difference in prepregnancy BMI was associated with at least a 10% lower risk of preeclampsia, gestational diabetes, indicated preterm delivery, macrosomia, and stillbirth. In contrast, larger differences in prepregnancy BMI (20-30% differences in BMI) were necessary to meaningfully reduce risks of cesarean delivery, shoulder dystocia, neonatal intensive care unit stay 48 hours or longer, and in-hospital newborn mortality. Prepregnancy BMI was not associated with risk of postpartum hemorrhage requiring intervention, severe maternal morbidity or maternal mortality, or spontaneous preterm delivery before 32 weeks of gestation. CONCLUSION: These results can inform prepregnancy weight loss counseling by defining achievable weight loss goals for patients that may reduce their risk of poor perinatal outcomes. LEVEL OF EVIDENCE: II.

Comparison of gestational weight gain z-scores and traditional weight gain measures in relation to perinatal outcomes.

BACKGROUND: Conventional measures of gestational weight gain (GWG) are correlated with pregnancy duration, and may induce bias to studies of GWG and perinatal outcomes. A maternal weight-gain-for-gestational-age z-score chart is a new tool that allows total GWG to be classified as a standardised z-score that is independent of gestational duration. Our objective was to compare associations with perinatal outcomes when GWG was assessed using gestational age-standardised z-scores and conventional GWG measures. METHODS: We studied normal-weight (n=522 120) and overweight (n=237 923) women who delivered liveborn, singleton infants in Pennsylvania, 2003-11. GWG was expressed using gestational age-standardised z-scores and three traditional measures: total GWG (kg), rate of GWG (kg per week of gestation), and the GWG adequacy ratio (observed GWG/GWG recommended by the Institute of Medicine). Log-binomial regression models were used to assess associations between GWG and preterm birth, and small- and large-for-gestational-age births, while adjusting for race/ethnicity, education, smoking, and other confounders. RESULTS: The association between GWG z-score and preterm birth was approximately U-shaped. The risk of preterm birth associated with weight gain <10th percentile of each measure was substantially overestimated when GWG was classified using total kilogram and was moderately overestimated using rate of GWG or GWG adequacy ratio. All GWG measures had similar associations with small- or large-for-gestational-age birth. CONCLUSIONS: Our findings suggest that studies of gestational age-dependent outcomes misspecify associations if total GWG, rate of GWG, or GWG adequacy ratio are used. The potential for gestational age-related bias can be eliminated by using z-score charts to classify total GWG.