The impact of isolated obesity compared with obesity and other risk factors on risk of stillbirth: a retrospective cohort study.

BACKGROUND: Maternal obesity is associated with stillbirth, but uncertainty persists around the effects of higher obesity classes. We sought to compare the risk of stillbirth associated with maternal obesity alone versus maternal obesity and additional or undiagnosed factors contributing to high-risk pregnancy. METHODS: We conducted a retrospective cohort study using the Better Outcomes Registry and Network (BORN) for singleton hospital births in Ontario between 2012 and 2018. We used multivariable Cox proportional hazard regression and logistic regression to evaluate the relationship between prepregnancy maternal body mass index (BMI) class and stillbirth (reference was normal BMI). We treated maternal characteristics and obstetrical complications as independent covariates. We performed mediator analyses to measure the direct and indirect effects of BMI on stillbirth through major common-pathway complications. We used fully adjusted and partially adjusted models, representing the impact of maternal obesity alone and maternal obesity with other risk factors on stillbirth, respectively. RESULTS: We analyzed data on 681 178 births between 2012 and 2018, of which 1956 were stillbirths. Class I obesity was associated with an increased incidence of stillbirth (adjusted hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.35-1.78). This association was stronger for class III obesity (adjusted HR 1.80, 95% CI 1.44-2.24), and strongest for class II obesity (adjusted HR 2.17, 95% CI 1.83-2.57). Plotting point estimates for odds ratios, stratified by gestational age, showed a marked increase in the relative odds for stillbirth beyond 37 weeks' gestation for those with obesity with and without other risk factors, compared with those with normal BMI. The impact of potential mediators was minimal. INTERPRETATION: Maternal obesity alone and obesity with other risk factors are associated with an increased risk of stillbirth. This risk increases with gestational age, especially at term.

Gestational weight loss and fetal growth in uncomplicated pregnancies among women with obesity: a population-based retrospective cohort study.

OBJECTIVE: The impact of gestational weight loss (GWL) on fetal growth among women with obesity remains unclear. This study aimed to examine the association between weight loss during pregnancy among women with body mass index (BMI) ≥ 30 kg/m2 and the risk of small-for-gestational-age (SGA) and large-for-gestational-age (LGA) neonates. METHODS: We conducted a retrospective, population-based cohort study of women with pre-pregnancy obesity that resulted in a singleton live birth in 2012-2017, using birth registry data in Ontario, Canada. Women with pregnancy complications or health conditions which could cause weight loss were excluded. GWL is defined as negative gestational weight change (≤0 kg). The association between GWL and fetal growth was estimated using generalized estimating equation models and restricted cubic spline regression analysis. Stratified analysis was conducted by obesity class (I:30-34.9 kg/m2, II:35-39.9 kg/m2, and III + : ≥40 kg/m2). RESULTS: Of the 52,153 eligible women who entered pregnancy with a BMI ≥ 30 kg/m2, 5.3% had GWL. Compared to adequate gestational weight gain, GWL was associated with an increased risk of SGA neonates (aRR:1.45, 95% CI: 1.30-1.60) and a decreased risk of LGA neonates (aRR: 0.81, 95% CI:0.73-0.93). Non-linear L-shaped associations were observed between gestational weight change and SGA neonates, with an increased risk of SGA observed with increased GWL. On the contrary, non-linear S-shaped associations were observed between gestational weight change and LGA neonates, with a decreased risk of LGA observed with increased GWL. Similar findings were observed from the stratified analysis by obesity class. CONCLUSION: These findings highlight that GWL in women with obesity may increase the risk of SGA neonates but reduce the risk of LGA neonates. Recommendations of GWL for women with obesity should be interpreted with caution.

Examining the role of pre-pregnancy weight and gestational weight gain in allergic disease development among offspring: A population-based cohort study in Ontario, Canada.

BACKGROUND: Studies suggest maternal weight and weight gain during pregnancy may influence foetal immunological development. However, their role in the aetiology of allergic disease is unclear. OBJECTIVES: We sought to examine the impact of maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) on the incidence of four common paediatric allergic diseases. METHODS: We conducted a retrospective, population-based cohort study of all singleton live births in Ontario, Canada between 2012 and 2014, using maternal-newborn records from the provincial birth registry linked with health administrative databases. Neonates were followed up to 7 years for anaphylaxis, asthma, dermatitis and rhinitis, identified through validated algorithms based on healthcare encounters. We multiply imputed missing data and employed Cox proportional-hazards models to calculate adjusted hazard ratios (aHR) with 95% confidence intervals (CI). To test the robustness of our findings, we also conducted several sensitivity analyses, including probabilistic bias analyses for exposure and outcome misclassification. All methods were prespecified in a published protocol. RESULTS: Of the 248,017 infants followed, 52% were born to mothers with a pre-pregnancy BMI in the normal range and only 19% were born to mothers with adequate weight gain during pregnancy. Incidence rates (per 100,000 person-days) for anaphylaxis, asthma, dermatitis and rhinitis were 0.22, 6.80, 12.41 and 1.54, respectively. Compared with normal BMI, maternal obesity was associated with increased hazards of asthma in offspring (aHR 1.08, 95% CI 1.05, 1.11), but decreased hazards of anaphylaxis (aHR 0.83, 95% CI 0.69, 0.99) and dermatitis (aHR 0.97, 95% CI 0.94, 0.99). In contrast, maternal underweight was associated with increased hazards of dermatitis (aHR 1.06, 95% CI 1.02, 1.10). We found no associations between pre-pregnancy BMI and rhinitis or GWG and any allergic outcome, and no evidence of effect measures modification by infant sex. CONCLUSIONS: These findings provide support for the involvement of maternal pre-pregnancy BMI in paediatric allergic disease development.

Evaluating the correlation between amniotic fluid volume and estimated fetal weight in healthy pregnant women.

OBJECTIVES: The establishment of cut-offs for normal amniotic fluid volume (AFV) is valuable to predict perinatal outcomes. However, the most common methods to measure AFV are not accurate enough. It is important to understand factors that may be able to increase the accuracy of the calculation of AFV cut-off values. The objective of this study was to verify the correlation between AFV and estimated fetal weight (EFW). METHODS: Records from almost 7,000 patients between 2012 and 2017 were accessed through hospital databases. The AFV measurements included in our analysis were obtained using the maximum vertical pocket technique. RESULTS: AFV was positively correlated with EFW in the overall, male and female samples; however, the magnitude of the association was small (0.1

Birth outcomes following cesarean delivery on maternal request: a population-based cohort study.

BACKGROUND: Data on the effect of cesarean delivery on maternal request (CDMR) on maternal and neonatal outcomes are inconsistent and often limited by inadequate case definitions and other methodological issues. Our objective was to evaluate the trends, determinants and outcomes of CDMR using an intent-to-treat approach. METHODS: We designed a population-based retrospective cohort study using data on low-risk pregnancies in Ontario, Canada (April 2012-March 2018). We assessed temporal trends and determinants of CDMR. We estimated the relative risks for component and composite outcomes used in the Adverse Outcome Index (AOI) related to planned CDMR compared with planned vaginal delivery using generalized estimating equation models. We compared the Weighted Adverse Outcome Score (WAOS) and the Severity Index (SI) across planned modes of delivery using analysis of variance. RESULTS: Of 422 210 women, 0.4% (n = 1827) had a planned CDMR and 99.6% (n = 420 383) had a planned vaginal delivery. The prevalence of CDMR remained stable over time at 3.9% of all cesarean deliveries. Factors associated with CDMR included late maternal age, higher education, conception via in vitro fertilization, anxiety, nulliparity, being White, delivery at a hospital providing higher levels of maternal care and obstetrician-based antenatal care. Women who planned CDMR had a lower risk of adverse outcomes than women who planned vaginal delivery (adjusted relative risk 0.42, 95% confidence interval [CI] 0.33 to 0.53). The WAOS was lower for planned CDMR than planned vaginal delivery (mean difference -1.28, 95% CI -2.02 to -0.55). The SI was not statistically different between groups (mean difference 3.6, 95% CI -7.4 to 14.5). INTERPRETATION: Rates of CDMR have not increased in Ontario. Planned CDMR is associated with a decreased risk of short-term adverse outcomes compared with planned vaginal delivery. Investigation into the long-term implications of CDMR is warranted.

Characteristics associated with uncomplicated pregnancies in women with obesity: a population-based cohort study.

BACKGROUND: Approximately one in five pregnant women have obesity. Obesity is associated with an increased risk of antenatal, intrapartum, and perinatal complications, but many women with obesity have uncomplicated pregnancies. At a time where maternity services are advocating for women to make informed choices, knowledge of the chance of having an uncomplicated (healthy) pregnancy is essential. The objective of this study was to calculate the rate of uncomplicated pregnancy in women with obesity and evaluate factors associated with this outcome. METHODS: This prospective cohort study was conducted using the Ontario birth registry dataset in Canada (703,115 women, April 2012-March 2017). The rate of uncomplicated or complicated composite pregnancy outcomes (hypertensive disorders of pregnancy, gestational diabetes, preterm birth, neonate small- or large- for gestational age at birth, congenital anomaly, fetal death, antepartum bleeding or preterm prelabour membrane rupture) were calculated for women with and without obesity. Associations between uncomplicated pregnancy and maternal characteristics were explored in a population of women with obesity but without other pre-existing co-morbidities (e.g., essential hypertension) or obstetric risks identified in the first trimester (e.g., multiple pregnancy), using log binomial regression analysis. RESULTS: Of the studied Ontario maternity population (body mass index not missing) 17·7% (n = 117,236) were obese. Of these 20·6% had pre-existing co-morbidities or early obstetric complicating factors. Amongst women with obesity but without early complicating factors, 58·2% (n = 54,191) experienced pregnancy without complication; this is in comparison to 72·7% of women of healthy weight and no early complicating factors. Women with obesity and no early pregnancy complicating factors are more likely to have an uncomplicated pregnancy if they are multiparous, younger, more affluent, of White or Black ethnicity, of lower weight, with normal placental-associated plasma protein-A and/or spontaneously conceived pregnancies. CONCLUSIONS: The study demonstrates that over half of women with obesity but no other pre-existing medical or early obstetric complicating factors, proceed through pregnancy without adverse obstetric complication. Care in lower-risk settings can be considered as their outcomes appear similar to those reported for low-risk nulliparous women. Further research and predictive tools are needed to inform stratification of women with obesity.

Racial differences in contribution of prepregnancy obesity and excessive gestational weight gain to large-for-gestational-age neonates.

OBJECTIVES: To examine the racial differences in the population attributable fraction (PAF) of prepregnancy obesity and excessive gestational weight gain to large-for-gestational-age (LGA) neonates. METHODS: We conducted a population-based retrospective cohort study among all women who had prenatal screening and had a singleton live birth in a hospital (1 April 2016-31 March 2017) using data from Ontario birth registry in Canada. We used multivariable log-binomial regression models to estimate the PAF and 95% confidence interval (CI) of LGA neonates due to prepregnancy obesity and excessive gestational weight gain. All models were stratified by race (White, Asian, and Black). RESULTS: Of the 74,402 eligible women, the prevalence of prepregnancy obesity, excessive gestational weight gain, and LGA neonate was 21.1%, 60.0%, and 11.3%, respectively, for Whites; 9.3%, 45.9%, and 5.4%, respectively, for Asians; and 28.6%, 52.4%, and 7.9%, respectively, for Blacks. The association of prepregnancy obesity was greater than that of excessive gestational weight gain on LGA for all racial groups. Excessive gestational weight gain contributed more than prepregnancy obesity in Whites (PAF 32.9%, 95% CI [30.3-35.5%] and 16.6%, 95% CI [15.3-17.9%], respectively, for excessive gestational weight gain and prepregnancy obesity) and in Asians (PAF 32.1%, 95% CI [27.2-36.7%] and 11.8%, 95% CI [9.5-14.1%], respectively, for excessive gestational weight gain and prepregnancy obesity). Prepregnancy obesity (PAF 22.8%, 95% CI [17.1-28.1%]) and excessive gestational weight gain (PAF 20.1%, 95% CI [4.7-33.0%]) contributed to LGA neonates almost the same in Blacks. CONCLUSIONS: Excessive gestational weight gain contributed more to LGA neonates than prepregnancy obesity in Whites and Asians, while there was no difference between excessive gestational weight gain and prepregnancy obesity in their contributions to the LGA neonates in Blacks. The differences are mostly driven by the differential prevalence of the two risk factors across racial groups.

The determinants of maternal homocysteine in pregnancy: findings from the Ottawa and Kingston Birth Cohort.

OBJECTIVE: Observational studies have linked elevated homocysteine to vascular conditions. Folate intake has been associated with lower homocysteine concentration, although randomised controlled trials of folic acid supplementation to decrease the incidence of vascular conditions have been inconclusive. We investigated determinants of maternal homocysteine during pregnancy, particularly in a folic acid-fortified population. DESIGN: Data were from the Ottawa and Kingston Birth Cohort of 8085 participants. We used multivariable regression analyses to identify factors associated with maternal homocysteine, adjusted for gestational age at bloodwork. Continuous factors were modelled using restricted cubic splines. A subgroup analysis examined the modifying effect of MTHFR 677C>T genotype on folate, in determining homocysteine concentration. SETTING: Participants were recruited in Ottawa and Kingston, Canada, from 2002 to 2009. PARTICIPANTS: Women were recruited when presenting for prenatal care in the early second trimester. RESULTS: In 7587 participants, factors significantly associated with higher homocysteine concentration were nulliparous, smoking and chronic hypertension, while factors significantly associated with lower homocysteine concentration were non-Caucasian race, history of a placenta-mediated complication and folic acid supplementation. Maternal age and BMI demonstrated U-shaped associations. Folic acid supplementation of >1 mg/d during pregnancy did not substantially increase folate concentration. In the subgroup analysis, MTHFR 677C>T modified the effect of folate status on homocysteine concentration. CONCLUSIONS: We identified determinants of maternal homocysteine relevant to the lowering of homocysteine in the post-folic acid fortification era, characterised by folate-replete populations. A focus on periconceptional folic acid supplementation and improving health status may form an effective approach to lower homocysteine.

The role of maternal homocysteine concentration in placenta-mediated complications: findings from the Ottawa and Kingston birth cohort.

BACKGROUND: Homocysteine is an intermediate metabolite implicated in the risk of placenta-mediated complications, including preeclampsia, placental abruption, fetal growth restriction, and pregnancy loss. Large cohort and case-control studies have reported inconsistent associations between homocysteine and these complications. The purpose of this study was to investigate whether elevated maternal plasma homocysteine concentration in the early to mid-second trimester is associated with an increased risk of placenta-mediated complications. We examined the following potential moderating factors that may explain discrepancies among previous studies: high-risk pregnancy and the MTHFR 677C>T polymorphism. METHODS: We analyzed data from participants recruited to the Ottawa and Kingston (OaK) Birth Cohort from 2002 to 2009 in Ottawa and Kingston, Canada. The primary outcome was a composite of any placenta-mediated complication, defined as a composite of small for gestational age (SGA) infant, preeclampsia, placental abruption, and pregnancy loss. Secondary outcomes were, individually: SGA infant, preeclampsia, placental abruption, and pregnancy loss. We conducted multivariable logistic regression analyses with homocysteine as the primary continuous exposure, adjusting for gestational age at the time of bloodwork and explanatory maternal characteristics. The functional form, i.e., the shape of the homocysteine association with the outcome was examined using restricted cubic splines and information criteria (Akaike's/Bayesian Information Criterion statistics). Missing data were handled with multiple imputation. RESULTS: 7587 cohort participants were included in the study. Maternal plasma homocysteine concentration was significantly associated (linearly) with an increased risk of both the composite outcome of any placenta-mediated complication (p = 0.0007), SGA (p = 0.0010), severe SGA, and marginally with severe preeclampsia, but not preeclampsia, placental abruption and pregnancy loss. An increase in homocysteine concentration significantly increased the odds of any placenta-mediated complication (odds ratio (OR) for a 5 µmol/L increase: 1.63, 95% Confidence Interval (CI) 1.23-2.16) and SGA (OR 1.76, 95% CI 1.25-2.46). Subgroup analyses indicated some potential for modifying effects of the MTHFR 677C>T genotype and high-risk pregnancy, although the interaction was not statistically significant (high-risk subgroup OR 2.37, 95% CI 1.24-4.53, p-value for interaction =0.14). CONCLUSIONS: Our results suggest an independent effect of early to mid-pregnancy elevated maternal homocysteine on placenta-mediated pregnancy complications.

Assessing the accuracy of pregnant women in recalling pre-pregnancy weight and gestational weight gain.

OBJECTIVE: Maternity care providers can use pre-pregnancy weight (PPW) and gestational weight gain (GWG) as markers for difficult delivery, and frequently obtain this information directly from the patient. The goal of this study was to determine whether women report their PPW and GWG correctly at the end of pregnancy. METHODS: We performed a prospective cohort study of 189 women delivering between June 1, 2011, and July 31, 2011, at the Saint John Regional Hospital or the Moncton Hospital in New Brunswick. Self- reported PPW and GWG were compared with measured weights obtained from the antenatal chart and upon presentation for delivery. Patient characteristics, BMI classification, and accuracy and degree of error in recall were assessed. RESULTS: The majority of respondents were under 30 years of age (63.4%) and were delivering at term (96.3%). Ninety women (47.6%) were having their first baby. A record of weight measured in the first trimester was available for 98 respondents (51.9%); using this information, 44 women (44.9%) were determined to be overweight or obese at delivery. Approximately one third of women with a normal BMI were not able to recall their PPW or GWG accurately (± 1 kg). Among all BMI classes, there was a consistent pattern of under-reporting of PPW (by a mean of 1.52 kg) and over-reporting of GWG (by a mean of 1.61 kg), but several extreme outliers were identified. CONCLUSION: At the time of delivery, under-reporting of PPW and over-reporting of GWG are common and difficult to predict. Maternity care providers should be aware of this discrepant reporting of PPW and GWG and recognize the implications for intrapartum management and postpartum weight loss.

Objectif : Les fournisseurs de soins de maternité peuvent utiliser le poids prégrossesse (PPG) et le gain pondéral gestationnel (GPG) à titre de marqueurs pour ce qui est de l'accouchement difficile; de plus, ils peuvent fréquemment obtenir cette information directement de la patiente. Cette étude avait pour objectif de déterminer si les femmes signalent leur PPG et leur GPG correctement à la fin de la grossesse. Méthodes : Nous avons mené une étude de cohorte prospective auprès de 189 femmes ayant accouché entre le 1er juin 2011 et le 31 juillet 2011, au Saint John Regional Hospital ou au Moncton Hospital au Nouveau-Brunswick. Le PPG et le GPG autosignalés ont été comparés aux mesures du poids issues du dossier prénatal et effectuées à l'arrivée de la patiente à l'hôpital pour l'accouchement. Les caractéristiques de la patiente, la classification IMC et la précision et le degré d'erreur en ce qui concerne le signalement des poids ont été évalués. Résultats : La majorité des répondantes avaient moins de 30 ans (63,4 %) et accouchaient à terme (96,3 %). Quatre-vingt-dix femmes (47,6 %) en étaient à leur premier accouchement. Le poids mesuré au cours du premier trimestre avait été consigné en ce qui concerne 98 répondantes (51,9 %); en fonction de ces données, nous avons déterminé que 44 femmes (44,9 %) présentaient une surcharge pondérale ou étaient obèses au moment de l'accouchement. Près du tiers des femmes présentant un IMC normal n'étaient pas en mesure de se rappeler de leur PPG ou de leur GPG avec précision (± 1 kg). Dans toutes les classes d'IMC, nous avons constaté une tendance stable quant au sous-signalement du PPG (de 1,52 kg, en moyenne) et au sursignalement du GPG (de 1,61 kg, en moyenne); cependant, plusieurs valeurs extrêmement aberrantes ont été identifiées. Conclusion : Au moment de l'accouchement, le sous-signalement du PPG et le sursignalement du GPG sont courants et difficiles à prédire. Les fournisseurs de soins de maternité devraient prendre conscience de ces divergences quant signalement du PPG et du GPG, et en reconnaître les conséquences en matière de prise en charge intrapartum et de perte de poids postpartum.

Persisting risk factors for preeclampsia among high-risk pregnancies already using prophylactic aspirin: a multi-country retrospective investigation.

BACKGROUND: Low-dose aspirin is recommended for pregnant individuals at high-risk of developing preeclampsia, but less is known about those that develop preeclampsia even while using prophylactic aspirin for preeclampsia prevention as the best course of treatment. OBJECTIVES: The objective of this study is to investigate the risk factors with the highest risk of developing preeclampsia among pregnant individuals already using aspirin from high-risk obstetrical centers across five countries. DESIGN: This is a secondary analysis of pregnant individuals from the Folic Acid Clinical Trial (FACT) who were using prophylactic aspirin before 16 weeks gestation. The FACT randomized control trial took place in 70 high risk obstetrical centers in Canada, United Kingdom, Australia, Jamaica, and Argentina between 2011-2015. Participants were included if they had any of the risk factors for preeclampsia: diabetes, chronic hypertension, twin pregnancy, history of preeclampsia, and/or obesity (Body Mass Index ≥35). The outcomes of interest were preeclampsia and preterm preeclampsia (<37 weeks). Log binomial regressions assessed factors significantly associated with any preeclampsia or preterm-preeclampsia (<37 weeks) using adjusted risk ratios (ARR) and 95% confidence intervals (CI). RESULTS: There were 2296 pregnant individuals with complete information on aspirin included in this study. At baseline, all patients were at high risk of preeclampsia and were eligible for aspirin prophylaxis, however, only 660 (28.7%) were taking aspirin. Among the 660 pregnant individuals taking aspirin, 132 (20%) developed preeclampsia and 60 (9.09%) preterm preeclampsia. Among pregnant individuals using aspirin, the risks of preeclampsia were highest for twins (ARR:2.62, 95% CI: 1.68-4.11), history of preeclampsia (ARR: 2.42, 95% CI: 1.74-3.38), and hypertension (ARR:1.92, 95% CI: 1.37-2.69). Similar trends were found for preterm-preeclampsia for twins (ARR:4.10, 95% CI:2.15-7.82), history of preeclampsia (ARR:2.75, 95% CI:1.62-4.67), and hypertension (ARR:2.18, 95% CI:1.28-3.72). No significant differences were found for obesity or diabetes. CONCLUSION: These findings suggest that individuals with twin pregnancies, a history of preeclampsia, or hypertension may not benefit from aspirin to the same extent as those with other complications such as obesity or diabetes. Careful clinical monitoring for these risks factors is recommended and future research into the effectiveness in these populations would increase our understanding of the current best practice of prophylactic aspirin use to prevent preeclampsia. TRIAL REGISTRATION: Current Controlled Trials ISRCTN23781770 and ClinicalTrials.gov NCT01355159.

Management of gestational weight gain in obese or overweight women based on resting energy expenditure: A pilot cohort study.

Resting energy expenditure (REE) comprises 60% of total energy expenditure and variations may be associated with gestational weight gain (GWG). This study aims to explore the usability and feasibility of REE guided intervention for GWG in obese and overweight women. We conducted a prospective cohort study in LuHe Hospital of Capital Medical University in Beijing, China between May 1, 2017 and May 31, 2018. Obese/overweight women who had routine prenatal care visit at 10 to 13 weeks of gestation, were recruited after written informed consent was obtained. The intervention group (those women who were recruited between January 1 and May 31, 2018) used REE calculated daily total energy to manage GWG, while the control group (those women who were recruited between May 1 and December 31, 2017) used prepregnancy body mass index calculated daily total energy to manage GWG. GWG and daily total energy between the 2 groups were recorded from 10 to 13 weeks of gestation to delivery. A total of 68 eligible women (35 in intervention group and 33 in control group) were included in the final analysis. Daily total energy in the intervention group increased less than the control group, especially from 2nd trimester to 3rd trimester (1929.54 kcal/d vs. 2138.33 kcal/d). The variation of daily total energy from 1st trimester to 3rd trimester in the intervention group was lower than the control group (226.17 kcal/d vs 439.44 kcal/d). Overall GWG of the intervention group (13.45 kg) was significantly lower than the control group (18.20 kg). The percentage of excess-GWG in the intervention group (31.42%) was also significantly lower than the control (57.57%). Findings from our pilot study suggest that diet recommendation basting on REE may improve management of GWG in obese/overweight women.

Effect of high-dose folic acid supplementation on the prevention of preeclampsia in twin pregnancy.

OBJECTIVE: To determine the efficacy of high-dose folic acid for the prevention of preeclampsia in twin pregnancies. METHODS: Secondary analysis of a randomized controlled trial in 70 obstetrical sites in Argentina, Australia, Canada, Jamaica, and the UK between 2011 and 2015. Eligible women pregnant with twins who were aged 18 y or older and between 8 and 16 completed weeks' gestation were randomized between to receive daily high-dose folic acid (4.0-5.1 mg) or placebo. The primary outcome was preeclampsia, presenting as hypertension after 20 weeks' gestation with significant proteinuria. Secondary outcomes included severe preeclampsia, preterm birth, and adverse fetal and neonatal outcomes. RESULTS: Of 2464 participants randomized between 18 April 2011 and 14 December 2015, 462 (18.8%) had a confirmed twin pregnancy. Thirty-four of these participants withdrew consent or did not have primary outcome data available, and 428 women were analyzed. The rate of preeclampsia was significantly higher in the folic acid group compared to the placebo group in crude analyses (17.2 versus 9.9%; relative risk 1.75 [95% CI 1.06-2.88], p = .029). Multivariable analyses attenuated this effect, rendering it not statistically significant (RR 1.58 [95% CI 0.95-2.63], p = .079). CONCLUSION: High-dose folic acid supplementation was not significantly associated with preeclampsia in a subgroup of twin pregnancies. Although a suggested elevated risk cannot be confirmed, these results may help to gain novel insights in the etiology of preeclampsia, which continues to be poorly understood. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01355159.

Placental Pathology as a Tool to Identify Women for Postpartum Cardiovascular Risk Screening following Preeclampsia: A Preliminary Investigation.

Preeclampsia (PE) is associated with an increased risk of cardiovascular disease (CVD) in later life. Postpartum cardiovascular risk screening could identify patients who would benefit most from early intervention and lifestyle modification. However, there are no readily available methods to identify these high-risk women. We propose that placental lesions may be useful in this regard. Here, we determine the association between placental lesions and lifetime CVD risk assessed 6 months following PE. Placentas from 85 PE women were evaluated for histopathological lesions. At 6 months postpartum, a lifetime cardiovascular risk score was calculated. Placental lesions were compared between CVD risk groups and the association was assessed using odds ratios. Multivariable logistic regression was used to develop prediction models for CVD risk with placental pathology. Placentas from high-risk women had more severe lesions of maternal vascular malperfusion (MVM) and resulted in a 3-fold increased risk of screening as high-risk for CVD (OR 3.10 (1.20-7.92)) compared to women without these lesions. MVM lesion severity was moderately predictive of high-risk screening (AUC 0.63 (0.51, 0.75); sensitivity 71.8% (54.6, 84.4); specificity 54.7% (41.5, 67.3)). When clinical parameters were added, the model's predictive performance improved (AUC 0.73 (0.62, 0.84); sensitivity 78.4% (65.4, 87.5); specificity 51.6% (34.8, 68.0)). The results suggest that placenta pathology may provide a unique modality to identify women for cardiovascular screening.

Cannabis Use in Pregnancy and Downstream effects on maternal and infant health (CUPiD): a protocol for a birth cohort pilot study.

INTRODUCTION: Cannabis use in pregnancy and post partum is increasing. Accessibility to cannabis has expanded due to the legalisation of cannabis in Canada. Therefore, there is a critical need to monitor the impact of cannabis on pregnancy outcomes and infant neurodevelopment. This pilot study will assess the feasibility of modern recruitment and data collection strategies adapted to the current cannabis environment and inform the design of a multicentre prospective birth cohort. METHODS AND ANALYSIS: We will establish a pregnancy and birth cohort of 50 cannabis users and 50 non-users recruited before delivery. We will follow the participants at regular visits from recruitment to 12 weeks post partum. Participants will provide demographic and socioeconomic data, report their cannabis use patterns, and provide biological samples. Biological samples include maternal and infant urine and blood, breastmilk/chestmilk, cord blood, cord tissue, placenta and meconium. All samples will be processed and stored at -80°C until analysis by immunoassay or liquid chromatography-tandem mass spectrometry to determine the presence of cannabis metabolites. In addition, partners will be invited to provide additional socioeconomic and substance use data. ETHICS AND DISSEMINATION: Ethics was obtained from Ottawa Health Science Network Research Ethics Board through Clinical Trials Ontario (3791). Our findings will be published in peer-reviewed journals, presented at scientific conferences and shared broadly with patients, healthcare decision-makers, and project partners online and through social media. TRIAL REGISTRATION NUMBER: NCT05309226.Cite Now.

Maternal Immune Cell and Cytokine Profiles to Predict Cardiovascular Risk Six Months after Preeclampsia.

Women who develop preeclampsia (PE) are at high risk for cardiovascular disease (CVD). Early identification of women with PE who may benefit the most from early cardiovascular risk screening and interventions remains challenging. Our objective was to assess whether cytokine and immune cell profiles after PE are helpful in distinguishing women at low and high CVD risk at 6-months postpartum. Individuals who developed PE were followed for immune cell phenotyping and plasma cytokine quantification at delivery, at 3-months, and at 6-months postpartum. Lifetime CVD risk was assessed at 6-months postpartum, and the immune cell and cytokine profiles were compared between risk groups at each time point. Among 31 participants, 18 (58.1%) exhibited high CVD-risk profiles at 6-months postpartum. The proportion of circulating NK-cells was significantly lower in high-risk participants at delivery (p = 0.04). At 3-months postpartum, high-risk participants exhibited a lower proportion of FoxP3+ regulatory T-cells (p = 0.01), a greater proportion of CD8+ T cells (p = 0.02) and a lower CD4+:CD8+ ratio (p = 0.02). There were no differences in immune cell populations at 6-months postpartum. There were no differences in plasma cytokines levels between risk groups at any time point. Subtle differences in immune cell profiles may help distinguish individuals at low and high CVD risk in the early postpartum period and warrants further investigation.

Weight in pregnancy and its implications: what women report.

OBJECTIVE: Misclassification of body mass index (BMI) by pregnant women could be a significant barrier to minimizing weight-related adverse pregnancy outcomes and improving the short- and long-term health of mother and child. The primary objective in this study was to determine the proportion of a group of pregnant women who were able to correctly classify BMI. Secondary objectives included assessing the direction of BMI misclassification and maternal knowledge of target gestational weight gain and obesity-associated pregnancy complications. METHODS: We designed a cross-sectional survey to assess misclassification of BMI and knowledge of obesity and pregnancy outcomes, and to provide information regarding the participants' sources of knowledge, their perception of appropriate weight gain in pregnancy, and basic demographic information. The questionnaire was completed by participants awaiting routine ultrasound assessment at between 11 and 24 weeks' gestation. RESULTS: Of 117 respondents, 30 (25.6%) were overweight (BMI 25 to 29.9) or obese (BMI ≥ 30.0). Obese or overweight women were significantly more likely to misclassify their BMI. Furthermore, they were significantly more likely to overestimate the minimum and maximum target gestational weight gains for their respective BMI classes. There were no differences between women in the various BMI categories with regard to their awareness of several common obesity-related pregnancy complications. CONCLUSION: Misclassification of pre-pregnancy BMI is common, particularly among women carrying excess weight. Evaluation of pre-pregnancy BMI and education regarding appropriate gestational weight gain are logical initial steps for optimizing weight-related pregnancy outcomes.

Impact of high-dose folic acid supplementation in pregnancy on biomarkers of folate status and 1-carbon metabolism: An ancillary study of the Folic Acid Clinical Trial (FACT).

BACKGROUND: Periconceptional folic acid (FA) supplementation is recommended to prevent the occurrence of neural tube defects. Currently, most over-the-counter FA supplements in Canada and the United States contain 1 mg FA and some women are prescribed 5 mg FA/d. High-dose FA is hypothesized to impair 1-carbon metabolism. We aimed to determine folate and 1-carbon metabolism biomarkers in pregnant women exposed to 1 mg or 5 mg FA. OBJECTIVES: This was an ancillary study within the Folic Acid Clinical Trial (FACT), a randomized, double-blinded, placebo-controlled, phase III trial designed to assess the efficacy of high-dose FA to prevent preeclampsia. METHODS: For FACT, women were randomized at 8-16 gestational weeks to receive daily 4.0 mg FA (high dose) or placebo (low dose) plus their usual supplementation (≤1.1 mg). Women were recruited from 3 Canadian FACT centers and provided nonfasting blood samples at 24-26 gestational weeks for measurement of RBC and serum total folate, serum unmetabolized FA (UMFA), tetrahydrofolate (THF), 5-methylTHF, 5-formylTHF, 5,10-methenylTHF, and MeFox (pyrazino-s-triazine derivative of 4α-hydroxy-5-methylTHF, a 5-methylTHF oxidation product); total vitamins B-12 and B-6; and plasma total homocysteine. Group differences were determined using χ2, Fisher exact, and Wilcoxon rank-sum tests. RESULTS: Nineteen (38%) women received high-dose FA and 31 (62%) received low-dose FA. The median RBC folate concentration was 2701 (IQR: 2243-3032) nmol/L and did not differ between groups. The high-dose group had higher serum total folate (median: 148.4 nmol/L, IQR: 110.4-181.2; P = 0.007), UMFA (median: 4.6 nmol/L, IQR: 2.5-33.8; P = 0.008), and 5-methylTHF (median: 126.6 nmol/L, IQR: 98.8-158.6; P = 0.03) compared with the low-dose group (median: 122.8 nmol/L, IQR: 99.5-136.0; median: 1.9 nmol/L, IQR: 0.9-4.1; median: 108.6 nmol/L, IQR: 96.4-123.2, respectively). Other biomarkers of 1-carbon metabolism did not differ. CONCLUSIONS: High-dose FA supplementation in early pregnancy increases maternal serum folate but not RBC folate concentrations, suggesting tissue saturation. Higher UMFA concentrations in women receiving high-dose FA supplements suggest that these doses are supraphysiologic but with no evidence of altered 1-carbon metabolism.

Guidelines for the management of pregnant women with obesity: A systematic review.

Multiple clinical practice guidelines (CPGs) have been established for pregnant women with obesity. The quality and consistency of recommendations remain unknown. The objective of this study is to conduct a systematic review to synthesize and appraise evidence from CPGs, available worldwide, for pregnant women affected by obesity. An experienced information specialist performed a rigorous search of the literature, searching MEDLINE, Embase, grey literature, and guideline registries to locate CPGs that reported on pregnancy care relating to obesity. CPGs related to antenatal care of pregnant women with obesity (pre-pregnancy body mass index [BMI] ≥ 30 kg/m2 ) in low-risk (eg, care provider = family physician or midwife) or high-risk settings (eg, obstetrician or maternal fetal medicine) were included. CPGs were appraised for quality with independent data collection by two raters. Information was categorized into five domains: preconception care. care during pregnancy, diet and exercise during pregnancy, care immediately before, during, and after delivery, and postpartum care. The literature search yielded 2614 unique citations. Following screening of abstracts and full texts, 32 CPGs were included, with quality ranging between 0 and 100 on the AGREE II tool. The strongest evidence related to nutritional advice, exercise, and pregnancy risk counselling. Guidance was limited for timing of screening tests, antenatal visits and delivery, ideal postpartum care, and management of adverse pregnancy outcomes. Most guidelines in this population are not evidence based. Research is needed to bridge knowledge gaps pertaining to fetal antenatal surveillance, management of adverse outcomes and postpartum care, and enhance consistency across CPGs.

Diffusion MRI brain findings in neonates exposed to chorioamnionitis: a case series.

OBJECTIVE: The primary objective of this study was to determine the feasibility of using diffusion-weighted magnetic resonance imaging (DWMRI) to assess white matter changes in high-risk neonates. Secondary objectives were to determine if exposure to chorioamnionitis (clinical or histopathologic) is associated with DWMRI findings in the neonatal brain, and to calculate the sample size required for a more definitive prospective cohort study. METHODS: Seventeen women with PPROM (preterm premature rupture of the membranes) who delivered 18 infants not requiring ventilatory support were recruited to participate in this case series. When stable, infants underwent DWMRI scanning. All placentas were examined for evidence of histopathologic chorioamnionitis (HCA). RESULTS: There was histopathologic evidence of chorioamnionitis in seven of the 18 placentas examined; three of these patients had clinical chorioamnionitis. Diffusion MRI revealed changes in both the diffusion-weighted imaging and the apparent diffusion coefficient in three of the seven infants confirmed to have HCA (43%), while only one of the 11 infants with normal placentas (9%) showed similar findings. Routine head ultrasound examination demonstrated abnormal cortical findings that would normally prompt further investigation in only one of these infants. CONCLUSION: Exposure to HCA may be associated with abnormal DWMRI findings on imaging of the neonatal brain within 96 hours of delivery. Further study is required to delineate the association of chorioamnionitis and white matter changes with long-term neurodevelopmental sequelae.