Genetic causal relationship between placental weight and autism spectrum disorder: A two-sample Mendelian randomization study.

OBJECT: Previous research has suggested an association between placental tissue abnormalities and the diagnosis of autism spectrum disorder. This study aims to explore the causal relationship between placental weight and autism spectrum disorder. METHODS: This study employed Mendelian randomization analysis to investigate the potential causal relationship between placental weight and autism spectrum disorder. The study design involved two sample populations, with data for the exposed population sourced from previous studies focusing on PW, and data for the outcome population obtained from the Integrative Psychiatric Research and the Psychiatric Genomics Consortium study. To ensure the robustness of the results, three sensitivity analyses were performed, including heterogeneity testing, pleiotropy testing, and a leave-one-out analysis. The inverse variance weighted method served as the gold standard for the Mendelian randomization analysis. RESULTS: The results of the first analysis revealed a significant correlation between an increase in placental weight and an elevated risk of autism spectrum disorder (p = 0.02). Sensitivity analysis detected heterogeneity and outliers. After removing two outlier SNPs in the second round of analysis, the results still supported a genetic causal relationship between placental weight and autism spectrum disorder (p = 0.01). The second-round sensitivity analysis did not reveal any heterogeneity or outliers. CONCLUSION: Our study provides compelling evidence supporting a causal relationship between elevated placental weight and increased risk of autism spectrum disorder. These findings underscore the significance of placental development in the etiology of autism spectrum disorder and propose a potential early predictive indicator for autism spectrum disorder.

Associations between synthetic phenols, phthalates, and placental growth/function: a longitudinal cohort with exposure assessment in early pregnancy.

STUDY QUESTION: Is exposure to environmental chemicals associated with modifications of placental morphology and function? SUMMARY ANSWER: Phthalates, a class of ubiquitous chemicals, showed an association with altered placental weight, placental vascular resistance (PVR), and placental efficiency. WHAT IS KNOWN ALREADY: Only a few epidemiological studies have assessed the effects of phenols and phthalates on placental health. Their results were affected by exposure measurement errors linked to the rapid excretion of these compounds and the reliance on a limited number of spot urine samples to assess exposure. STUDY DESIGN SIZE DURATION: A prospective mother-child cohort, with improved exposure assessment for non-persistent chemicals, recruited participants between 2014 and 2017. Sample size ranged between 355 (placental parameters measured at birth: placental weight and placental-to-fetal weight ratio (PFR): a proxy for placental efficiency) and 426 (placental parameters measured during pregnancy: placental thickness and vascular resistance). PARTICIPANTS/MATERIALS SETTING METHODS: Phenols (four parabens, two bisphenols, triclosan, and benzophenone-3), 13 phthalate metabolites, and two non-phthalate plasticizer metabolites were measured in within-subject pools of repeated urine samples collected during the second and third trimesters of pregnancy (median = 21 samples/trimester/woman). Placental thickness and PVR were measured during pregnancy. The placenta was weighed at birth and the PFR was computed. Both adjusted linear regression and Bayesian Kernel Machine Regression were used to evaluate associations between phenols and phthalates (alone or as a mixture) and placental parameters. Effect modification by child sex was also investigated. MAIN RESULTS AND THE ROLE OF CHANCE: Several phthalate metabolites were negatively associated with placental outcomes. Monobenzyl phthalate (MBzP) concentrations, during the second and third trimesters of pregnancy, were associated with a decrease in both placental weight at birth (ß = -20.1 g [95% CI: -37.8; -2.5] and ß = -17.4 g [95% CI: -33.2; -1.6], for second and third trimester, respectively) and PFR (ß = -0.5 [95% CI: -1, -0.1] and ß = -0.5 [95% CI: -0.9, -0.1], for the second and third trimester, respectively). Additionally, MBzP was negatively associated with PVR during the third trimester (ß= -0.9 [95% CI: -1.8; 0.1]). Mono-n-butyl phthalate (MnBP), was negatively associated with PVR in both trimesters (ß = -1.3, 95% CI: [-2.3, -0.2], and ß = -1.2, 95% CI: [-2.4, -0.03], for the second and third trimester, respectively). After stratification for child sex, Σ diisononyl phthalate (DiNP) (either second or third-trimester exposures, depending on the outcomes considered) was associated with decreased PVR in the third trimester, as well as decreased placental weight and PFR in males. No associations were observed for phenol biomarkers. LIMITATIONS REASONS FOR CAUTION: False positives cannot be ruled out. Therefore, chemicals that were associated with multiple outcomes (MnBP and DiNP) or reported in existing literature as associated with placental outcomes (MBzP) should be considered as the main results. WIDER IMPLICATIONS OF THE FINDINGS: Our results are consistent with in vitro studies showing that phthalates target peroxisome proliferator-activated receptor γ, in the family of nuclear receptors involved in key placental development processes such as trophoblast proliferation, migration, and invasion. In addition to placental weight at birth, we studied placental parameters during pregnancy, which could provide a broader view of how environmental chemicals affect maternal-fetal exchanges over the course of pregnancy. Our findings contribute to the increasing evidence indicating adverse impacts of phthalate exposure on placental health. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the French Research Agency-ANR (MEMORI project ANR-21-CE34-0022). The SEPAGES cohort was supported by the European Research Council (N°311765-E-DOHaD), the European Community's Seventh Framework Programme (FP7/2007-206-N°308333-892 HELIX), the European Union's Horizon 2020 research and innovation programme (N° 874583 ATHLETE Project, N°825712 OBERON Project), the French Research Agency-ANR (PAPER project ANR-12-PDOC-0029-01, SHALCOH project ANR-14-CE21-0007, ANR-15-IDEX-02 and ANR-15-IDEX5, GUMME project ANR-18-CE36-005, ETAPE project ANR-18-CE36-0005-EDeN project ANR-19-CE36-0003-01), the French Agency for Food, Environmental and Occupational Health & Safety-ANSES (CNAP project EST-2016-121, PENDORE project EST-2016-121, HyPAxE project EST-2019/1/039, PENDALIRE project EST-2022-169), the Plan Cancer (Canc'Air project), the French Cancer Research Foundation Association de Recherche sur le Cancer-ARC, the French Endowment Fund AGIR for chronic diseases-APMC (projects PRENAPAR, LCI-FOT, DysCard), the French Endowment Fund for Respiratory Health, the French Fund-Fondation de France (CLIMATHES-00081169, SEPAGES 5-00099903, ELEMENTUM-00124527). N.J. was supported by a doctoral fellowship from the University Grenoble Alpes. V.M. was supported by a Sara Borrell postdoctoral research contract (CD22/00176), granted by Instituto de Salud Carlos III (Spain) and NextGenerationEU funds. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02852499.

Effect of docosahexaenoic acid and olive oil supplementation on pup weight in alcohol-exposed pregnant rats.

Background: Low birth weight has been observed in offspring of alcoholic mothers due likely to unresolved inflammation and oxidative injury. Dietary lipids play a role in inflammation and its resolution. The primary objective was to investigate the effect of DHA and olive oil on the birth weight of pups born to alcohol-exposed dams. Methods: Pregnant rats were randomized to the control or three treatment (alcohol) groups. From gestational days (GD) 8-19, the control group received daily olive oil and malto/dextrose, whereas groups 2 and 3 received olive oil and low-dose alcohol or high-dose alcohol, respectively. Group 4 received daily DHA and high-dose alcohol. The dam's blood was collected on GD 15 and 20 for cytokine analysis. Dams were sacrificed on GD 20. The mean birth weight of pups was compared by one-way ANOVA with post hoc Duncan's test. Results: There was a significant increase in the pups' mean birth weight in the high-dose alcohol/DHA and high-dose alcohol/olive oil. Higher pro-inflammatory cytokines (IL-1ß and IL-12p70) were noted in the alcohol-exposed dams. Conclusions: DHA and olive oil supplementation in alcohol-exposed pregnant rats significantly increased their pups' birth weight despite having high pro-inflammatory cytokines. The mechanism of this effect remains to be determined.

Sociodemographic factor associations with maternal and placental outcomes: A cluster and partial least squares regression analysis.

INTRODUCTION: Maternal social disadvantage adversely affects maternal and offspring health, with limited research on placental outcomes. Therefore, we examined maternal sociodemographic factor associations with placental and birth outcomes in general (Lifeways Cross-Generation Cohort) and at-risk (PEARS Study of mothers with overweight or obesity) populations of pregnant women. METHODS: TwoStep cluster analysis profiled Lifeways mothers (n = 250) based on their age, parity, marital status, household income, private healthcare insurance, homeowner status, and education. Differences in placental and birth outcomes (untrimmed placental weight (PW), birthweight (BW) and BW:PW ratio) between clusters were assessed using one-way ANOVA and chi-square tests. Partial least squares regression analysed individual effects of sociodemographic factors on placental and birth outcomes in Lifeways and PEARS mothers (n = 461). RESULTS: Clusters were classified as "Married Homeowners" (n = 140, 56 %), "Highest Income" (n = 58, 23.2 %) and "Renters" (n = 52, 20.8 %) in the Lifeways Cohort. Renters were younger, more likely to smoke, have a means-tested medical card and more pro-inflammatory diets compared to other clusters (p < 0.01). Compared to Married Homeowners, renters' offspring had lower BW (-259.26 g, p < 0.01), shorter birth length (-1.31 cm, p < 0.01) and smaller head circumference (-0.59 cm, p = 0.02). PLS regression analyses identified nulliparity as having the greatest negative effect on PW (Lifeways and PEARS) while being a homeowner had the greatest positive effect on PW (Lifeways). CONCLUSION: Certain combinations of sociodemographic factors (particularly homeownership) were associated with less favourable lifestyle factors, and with birth, but not placental outcomes. When explored individually, parity contributed to the prediction of placental and birth outcomes in both cohorts of pregnant women.

Reference Values for Placental Weight and Placental:Fetal Weight Ratio in a Swedish Population.

INTRODUCTION: There is important clinical information from placental weight and its ratio to the fetal weight. The aim with this study was to establish reference values for the placental weight and the placental:fetal weight ratio for gestational weeks 13-43 in a Swedish population. MATERIALS AND METHODS: Cases were retrospectively collected from the database used at the Pathology Department at Karolinska University Hospital and information about the placental weight, fetal weight, and gestational age was retrieved. Conditions, which could affect the placental- or fetal weight were excluded. Thereafter percentile curves were calculated for the placental weight and the placental:fetal weight ratio for gestational weeks. RESULTS: A total of 730 cases were included and percentile curves for the placental weight for gestational week 13-43 and placental:fetal weight ratio for gestational week 18-43 are presented. CONCLUSIONS: Reference values for post fixation placental weight and its ratio to fetal weight for a Swedish population are presented. The reference values are lower than the current reference values used in our institution, and this will be of importance when interpreting findings after placental examination.

Smoking during pregnancy and its effect on placental weight: a Mendelian randomization study.

BACKGROUND: The causal relationship between maternal smoking in pregnancy and reduced offspring birth weight is well established and is likely due to impaired placental function. However, observational studies have given conflicting results on the association between smoking and placental weight. We aimed to estimate the causal effect of newly pregnant mothers quitting smoking on their placental weight at the time of delivery. METHODS: We used one-sample Mendelian randomization, drawing data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (N = 690 to 804) and the Norwegian Mother, Father and Child Cohort Study (MoBa) (N = 4267 to 4606). The sample size depends on the smoking definition used for different analyses. The analysis was performed in pre-pregnancy smokers only, due to the specific role of the single-nucleotide polymorphism (SNP) rs1051730 (CHRNA5 - CHRNA3 - CHRNB4) in affecting smoking cessation but not initiation. RESULTS: Fixed effect meta-analysis showed a 182 g [95%CI: 29,335] higher placental weight for pre-pregnancy smoking mothers who continued smoking at the beginning of pregnancy, compared with those who stopped smoking. Using the number of cigarettes smoked per day in the first trimester as the exposure, the causal effect on placental weight was 11 g [95%CI: 1,21] per cigarette per day. Similarly, smoking at the end of pregnancy was causally associated with higher placental weight. Using the residuals of birth weight regressed on placental weight as the outcome, we showed evidence of lower offspring birth weight relative to the placental weight, both for continuing smoking at the start of pregnancy as well as continuing smoking throughout pregnancy (change in z-score birth weight adjusted for z-score placental weight: -0.8 [95%CI: -1.6,-0.1]). CONCLUSION: Our results suggest that continued smoking during pregnancy causes higher placental weights.

Impact of birth weight to placental weight ratio and other perinatal risk factors on left ventricular dimensions in newborns: a prospective cohort analysis.

OBJECTIVES: To investigate the association between birth weight to placental weight (BW/PW) ratio, and echocardiographic left ventricle (LV) morphology at birth, while accounting for other relevant perinatal factors. METHODS: A prospective cohort study was conducted on neonates at NewYork-Presbyterian Brooklyn Methodist Hospital from 2014 to 2018, categorized by their BW/PW percentile. Missing data were imputed with principal component analysis. Chi-squared and one-way analysis of variance were used to compare BW/PW groups and the best regression model was selected using a genetic and backward stepwise algorithm. RESULTS: We analyzed 827 neonates in three BW/PW groups: small (n=16), normal (n=488), and large (n=323). Placental thickness and smallest diameter were positively correlated with several LV parameters, including inter-ventricular septal thickness during diastole (IVSd) (p=0.002, p<0.001) and systole (IVSs) (p=0.001, p<0.001), LV posterior wall thickness at end of diastole (LVPWd) (p=0.003, p<0.001) and systole (LVPWs) (p<0.001, p<0.001), LV mass (p=0.017, p<0.001), and LV mass/volume (p=0.011, p<0.001). The BW/PW ratio correlated with an increased shortening fraction (estimate=0.29, 95 % CI 0.03-0.55, p=0.027). PW correlated with IVSs (p=0.019), while the longest placental diameter was linked to a decrease in LV internal dimension during diastole (LVIDd) (estimate=-0.07, p=0.039), LV mass (estimate=-0.11, p=0.024), and LV mass/volume (estimate=-0.55, p=0.005). CONCLUSIONS: This study found that several placental factors, including the BW/PW ratio, can independently affect LV dimension and morphology, highlighting the importance of fetal growth and placental health in the physiological adaptation of the fetal heart. More research is needed to establish causation and inform newborn prevention strategies.

Placental weight, surface area, shape and thickness - Relations with maternal ethnicity and cardio-metabolic factors during pregnancy.

INTRODUCTION: A better understanding of the determinants of placental growth is needed. Our primary aim was to explore associations between maternal ethnic origin and cardio-metabolic factors during pregnancy, and placental weight, surface area, shape and thickness. METHODS: A multi-ethnic population-based cohort study of 474 pregnant women examined at mean 15 and 28 weeks' gestation. Placentas were inspected after birth by a placental pathologist. Outcome measures were trimmed placental weight and three uncorrelated placental components; surface area, shape (oval vs round) and thickness, created through a principal components analysis. Multivariate linear regression models were used to explore the associations with maternal factors. RESULTS: Compared with ethnic European women, mothers with South- and East Asian ethnicity had placentas with lower weight (-51 g (95% CI: 75, -27) and -55 g (-95, -14) respectively), primarily due to a smaller surface area. The association between South Asian ethnicity and placental surface area was still significant after adjusting for maternal characteristics and cardio-metabolic factors. Fat mass index in early pregnancy was associated with higher placental weight and thickness. Placental surface area was positively associated with mid-gestational increases in fat mass, fasting glucose and triglycerides and with the 2-h glucose value at the 28 week oral glucose tolerance test, and inversely with a mid-gestational increase in HDL-cholesterol. DISCUSSION: Mid-gestational changes in fat mass, glucose, triglycerides and cholesterol were associated with, but only partly explained ethnic differences in placental surface area, while maternal fat mass in early pregnancy was associated with placental thickness.

Placental weight percentile curves in a Danish population.

INTRODUCTION: The role of the placenta is to transport oxygen and nutrients to the fetus, and a well-functioning placenta is vital to fetal health. Our aim was to develop placental weight percentile curves adjusted by gestational age, and stratified by major maternal comorbidities. MATERIAL AND METHODS: The study was a population study in a Danish cohort. Data was drawn from The Medical Birth Register and the National Patient Register. We included singleton births with a gestational age of 22 + 0 to 42 + 6 weeks. We excluded multiple pregnancies, stillbirths and retained placentas. A total of 611 418 placentas were included. Percentile line graphs were created in groups of all placentas, hypertensive disorders and diabetic disorders. RESULTS: Tables and figures are presented for placental weight percentile curves according to gestational age for all placentas, hypertensive disorders and diabetic disorders, respectively. Placental weight was generally higher in the diabetic placentas, and lower in the hypertensive placentas. CONCLUSIONS: These percentile curves may serve as a reference for other populations, and may be useful for other studies investigating the role of the placenta in relation to pregnancy outcomes, and health in later life.

Morphometric Evaluation of Human Placental and Umbilical Cord for Neonatal Indices: A Cross-Sectional Study.

BACKGROUND: In India, there is only limited data on studies related to umbilical cord and placental indices in newborn infants. The present study was undertaken to evaluate the morphometric analysis of placental and umbilical cord indices and their association with length, weight, and head size in newborns. MATERIALS AND METHODS: This was a longitudinal cross-sectional study conducted on placentas and fetal measures from 245 women who gave birth during the study period. The placental variables, umbilical cord indices, and neonatal indices were measured. The association between the parameters was done using Pearson's correlation, and p<0.05 was considered statistically significant.  Results: The placental weight (p=0.01) and placental volume (p=0.01) showed a significant positive correlation with newborn weight. The mean placental diameter was 16.32 ± 1.54 cm, and there was no significant correlation between placental diameter and infant weight (p=0.232), length (p=0.658), or head circumference (0.842). In addition, there was a significant association between placental diameter, placental volume (p=0.000), and placental weight (p=0.000). There was a significant positive correlation (p<0.05) between ponderable index and birth weight, length, and head circumference. CONCLUSION: Placental weight and newborn weight were significantly associated in this study. The length of the umbilical cord was found to be related to placental weight. So, placental measurements are reliable indicators for the assessment of fetal wellbeing.

Inter-pregnancy interval and placental weight. A population based follow-up study in Norway.

INTRODUCTION: We studied changes in placental weight from the first to the second delivery according to length of the inter-pregnancy interval. METHODS: We followed all women in Norway from their first to their second successive singleton pregnancy during the years 1999-2019, a total of 271 184 women. We used data from the Medical Birth Registry of Norway and studied changes in placental weight (in grams (g)) according to the length of the inter-pregnancy. Adjustments were made for year and maternal age at first delivery, changes in the prevalence of maternal diseases (hypertension and diabetes), and a new father to the second pregnancy. RESULTS: Mean placental weight increased from 655 g at the first delivery to 680 g at the second. The adjusted increase in placental weight was highest at inter-pregnancy intervals <6 months; 38.2 g (95 % CI 33.0g-43.4 g) versus 23.2 g (95 % CI 18.8g-27.7 g) at inter-pregnancy interval 6-17 months. At inter-pregnancy intervals ≥18 months, placental weight remained higher than at the first delivery, but was non-different from inter-pregnancy intervals 6-17 months. Also, after additional adjustment for daily smoking and body mass index in sub-samples, we found the highest increase in placental weight at the shortest inter-pregnancy interval. We estimated no difference in gestational age at delivery or placental to birthweight ratio according to inter-pregnancy interval. DISCUSSION: Placental weight increased from the first to the second pregnancy, and the increase was most pronounced at short inter-pregnancy intervals. The biological causes and implications of such findings remain to be studied.

The associations of gestational weight gain and midpregnancy lipid levels with placental size and placental-to-birth weight ratio: findings from a chinese birth cohort study.

BACKGROUND: The placenta serves as the sole maternal organ responsible for transmitting nutrients to the fetus, playing a crucial role in supporting standard fetal growth and development. To date, only a small number of studies have investigated the impact of maternal gestational weight gain and lipid concentrations on placental development. This study aimed to explore the influence of weight gain during pregnancy and lipid levels in the second trimester on placental weight, volume, and the placental weight ratio. METHODS: This birth cohort study encompassed 1,358 mother-child pairs. Placental data for each participant was gathered immediately post-delivery, and the study incorporated data on gestational weight gain throughout pregnancy and lipid profiles from the mid-trimester. A linear regression model was employed to assess the correlations between gestational weight gain, mid-trimester lipid levels, and metrics such as placental weight, placental volume, and the placental-to-birth weight ratio (PFR). RESULTS: In the study groups of pre-pregnancy underweight, normal weight, and overweight, the placental weight increased by 4.93 g (95% CI: 1.04-8.81), 2.52 g (95% CI: 1.04-3.99), and 3.30 g (95% CI: 0.38-6.22) per 1 kg of gestational weight gain, respectively. Within the pre-pregnancy underweight and normal weight groups, the placental volume increased by 6.79 cm^3 (95% CI: 3.43-10.15) and 2.85 cm^3 (95% CI: 1.31-4.39) per 1 kg of gestational weight gain, respectively. Additionally, placental weight exhibited a positive correlation with triglyceride (TG) levels (ß = 9.81, 95% CI: 3.28-16.34) and a negative correlation with high-density lipoprotein (HDL-C) levels (ß = - 46.30, 95% CI: - 69.49 to - 23.11). Placental volume also showed a positive association with TG levels (ß = 14.54, 95% CI: 7.69-21.39). Conversely, PFR demonstrated a negative correlation with increasing HDL-C levels (ß = - 0.89, 95% CI: - 1.50 to - 0.27). CONCLUSIONS: Gestational weight gain was significantly correlated with both placental weight and volume. This association was especially pronounced in women who, prior to pregnancy, were underweight or of normal weight. Additionally, TG and HDL-C levels during the mid-trimester were linked to placental development.

Impact of Fluoride Exposure on Rat Placenta: Foetal/Placental Morphometric Alterations and Decreased Placental Vascular Density.

Inorganic fluoride is a geogenic and anthropogenic contaminant widely distributed in the environment and commonly identified in contaminated groundwater. There is limited information on the effect of fluoride exposure on pregnancy. The aim of this study was to evaluate possible placental alterations of fluoride exposure in a rat model simulating preconception and pregnancy exposure conditions in endemic areas. Fluoride exposure was administered orally to foetuses of dams exposed to 2.5 and 5 mg fluoride/kg/d. Foetal weight, height, foetal/placental weight ratio, placental zone thickness, levels of malondialdehyde (MDA) and vascular endothelial growth factor-A (VEGF-A) and vascular density in placental tissue were evaluated. The results showed a nonlinear relationship between these outcomes and the dose of fluoride exposure. In addition, a significant increase in the fluoride concentration in placental tissue was observed. The group that was exposed to 2.5 mg fluoride/kg/d had a greater increase in both MDA levels and VEGF-A levels than the higher dose group. A significant increase in the thickness of the placental zones and a decrease in the vascular density of the labyrinth zone area were also observed in the fluoride-exposed groups. In conclusion, the data obtained demonstrate that fluoride exposure results in morpho-structural alterations in the placenta and that non-monotonic changes in MDA, VEGF-A levels and placental foetal weight ratio were at environmentally relevant concentrations.

Low placental weight may be involved in the etiology of congenital cryptorchidism in neonatal boys.

INTRODUCTION: Several factors have been reported to be associated with the etiology of cryptorchidism; however, clear evidence regarding the risk factors for cryptorchidism is elusive. In the present study, we evaluated the clinical characteristics of cryptorchidism using the common neonatal intensive-care unit (NICU) database of the National Hospital Organization and explored one of possible factors associated with the development of cryptorchidism. METHODS: A total of 7882 male neonates were included in this study. We separated them into two groups: those without cryptorchidism (n = 7852) and those with cryptorchidism (n = 30) at the time of discharge from the NICU. Cryptorchidism was defined as a condition in which the testis was located out of the scrotum on the route of descent at the time of NICU discharge. The associations between cryptorchidism and the maternal, placental, and neonatal information were analyzed. Analyses were performed statistically to compare nominal variables between the groups using Fisher's direct establishment calculation method and logistic regression analyses. RESULTS: Univariate analyses showed the placental weight <10% tile (odds ratio 3.31, 95% confidence interval [CI] 1.18-8.64), birth height <-2 standard deviations (SD) (odds ratio 3.65, 95% CI 0.92-10.6), birth weight <-2SD (odds ratio 4.06, 95% CI 1.55-9.51), and small for gestational age (odds ratio 3.82, 95% CI 1.46-8.97) were significantly associated with the development of cryptorchidism. Multivariate analyses showed that placental weight <10th percentile (odds ratio 2.86, 95% CI 1.11-7.44) was significantly associated with the development of cryptorchidism. DISCUSSION: Although, this study population was limited to infants admitted to the ICU, the data indicated a possible association between low placental weight and the development of cryptorchidism in neonatal boys.

Smoking during pregnancy and its effect on placental weight: A Mendelian randomization study.

Background: The causal relationship between maternal smoking in pregnancy and reduced offspring birth weight is well established and is likely due to impaired placental function. However, observational studies have given conflicting results on the association between smoking and placental weight. We aimed to estimate the causal effect of newly pregnant mothers quitting smoking on their placental weight at the time of delivery. Methods: We used one-sample Mendelian randomization, drawing data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (up to N = 805) and the Norwegian Mother, Father and Child Cohort Study (MoBa) (up to N = 4475). The analysis was performed in pre-pregnancy smokers only, due to the specific role of the genetic instrument SNP rs1051730 (CHRNA5 - CHRNA3 - CHRNB4) in affecting smoking cessation but not initiation. Results: Fixed effect meta-analysis showed a 175 g [95%CI: 16, 334] higher placental weight for pre-pregnancy smoking mothers who continued smoking at the beginning of pregnancy, compared with those who stopped smoking. Using the number of cigarettes smoked per day in the first trimester as the exposure, the causal estimate was a 12 g [95%CI: 2,22] higher placental weight per cigarette per day. Results were similar when the smoking exposures were measured at the end of pregnancy. Using the residuals of birth weight regressed on placental weight as the outcome, we showed weak evidence of lower offspring birth weight relative to the placental weight for continuing smoking. Conclusion: Our results suggest that continued smoking during pregnancy causes higher placental weights.

Diverse mechanisms underlying the fetal growth course in gastroschisis and omphalocele.

BACKGROUND: Gastroschisis and omphalocele are the 2 most common congenital fetal abdominal wall defects. Both malformations are commonly associated with small-for-gestational-age neonates. However, the extent and causes of growth restriction remain controversial in both gastroschisis and omphalocele without associated malformations or aneuploidy. OBJECTIVE: This study aimed to examine the role of the placenta and the birthweight-to-placental weight ratio in fetuses with abdominal wall defects. STUDY DESIGN: This study included all cases of abdominal wall defects examined at our hospital between January 2001 and December 2020, retrieving the data from the hospital's software. Fetuses with any other combined congenital anomalies, known chromosomal abnormalities, or lost to follow-up were excluded. Overall, 28 singleton pregnancies with gastroschisis and 24 singleton pregnancies with omphalocele met the inclusion criteria. Patient characteristics and pregnancy outcomes were reviewed. The primary outcome was to investigate the association between birthweight and placental weight in pregnancies with abdominal wall defects as measured after delivery. To correct for gestational age and to compare total placental weights, ratios between the observed and expected birthweights for the given gestational age in singletons were calculated. The scaling exponent ß was compared with the reference value of 0.75. Statistical analysis was performed using GraphPad Prism (version 8.2.1; GraphPad Software, San Diego, CA) and IBM SPSS Statistics. A P value of <.05 indicated statistical significance. RESULTS: Women pregnant with a fetus with gastroschisis were significantly younger and more often nulliparous. In addition, in this group, the gestational age of delivery was significantly earlier and almost exclusively for cesarean delivery. Of 28 children, 13 (46.7%) were born small for gestational age, only 3 of them (10.7%) had a placental weight <10th percentile. There is no correlation between birthweight percentiles and placental weight percentiles (P=not significant). However, in the omphalocele group, 4 of 24 children (16.7%) were born small for gestational age (<10th percentile), and all children also had a placental weight <10th percentile. There is a significant correlation between birthweight percentiles and placental weight percentiles (P<.0001). The birthweight-to-placental weight ratio differs significantly between pregnancies diagnosed with gastroschisis and pregnancies diagnosed with omphalocele (4.48 [3.79-4.91] vs 6.05 [5.38-6.47], respectively; P<.0001). Allometric metabolic scaling revealed that placentas complicated by gastroschisis and placentas complicated by omphalocele do not scale with birthweight. CONCLUSION: Fetuses with gastroschisis displayed impaired intrauterine growth, which seemed to differ from the classical placental insufficiency growth restriction.

Does maternal vitamin D status influence placental weight or vascular and inflammatory pathology? Secondary analysis from the Kellogg Pregnancy Study.

INTRODUCTION: Positive effects of vitamin D (vitD) supplementation on comorbidities of pregnancy (COP) have been explored; however, few studies have elucidated the pathophysiology behind the development of these COP and the potential relationship with derangements in placental development and morphology. Additionally, it is known that placentas weighing 10th-90th % for gestational age are associated with better outcomes. Therefore, the objective of this study was to assess the impact of resulting circulating serum 25(OH)D concentrations associated with intake of high or low doses of supplementary vitD on placental development and morphology in women who participated in a randomized double blind, placebo-controlled trial of vitD supplementation. We hypothesized that if maternal serum 25(OH)D concentration (vitD status marker) is insufficient/deficient, then placental weight and % for gestational age (GA) will be smaller and will correlate with increased vascular and inflammatory placental pathologic findings. METHODS: The findings of the present study are a secondary analysis of data generated from a previously reported randomized controlled trial (RCT), the Kellogg Vitamin D Pregnancy Study. Pregnant women (n = 297) in this RCT (January 2013 - April 2018) were randomly assigned to 400 IU vs. 4400 IU vitD/day (10-14 weeks' gestational age) and followed to delivery. 132 placentas were analyzed by pathologists blinded to treatment, and the 2016 Amsterdam Consensus Criteria were used to categorize grouping/grading of placental pathology and weight. Total [25(OH)D] was measured using radioimmunoassay (ng/mL). Chi-square and Student's t-test were used to show the difference in maternal characteristics by treatment group and by placental weight. Chi-square analysis was used to determine differences between the percent pathology findings by treatment group. Students t-test was used to determine the differences in vitD status and the frequency of placental lesions. Association between [25(OH)D] area under the curve (AUC) and placental morphology were determined in a regression model that included maternal BMI ≥ 30 kg/m2, race/ethnicity, and vitD treatment group allocation. Data were analyzed using SAS v9.4 (Cary, NC) and statistical significance was indicated by p < 0.05. RESULTS: The percent pathology findings by treatment group were not significantly different for each of the placental pathology categories as defined by the 2016 Amsterdam Consensus Criteria including placental weight. However, when using 25(OH)D as a biomarker for vitD status, linear regression model showed maternal serum [25(OH)D] AUC was significantly associated with greater placental weight (p = 0.023). Logistic regression models showed mothers with BMI ≥ 30 kg/m2 had larger placental weight (p = 0.046), and Hispanic and white/Caucasian mothers had greater placental weights than Black American mothers (p = 0.025). When placentas ≥ 90th % for GA, n = 7, were removed from the placental pool, Pearson correlation still showed a positive association between maternal serum 25(OH)D AUC and placental weight (p = 0.011). In a second linear regression model of placentas ≥ 90th % for GA (n = 7) vs. placentas < 90th % (n = 108), maternal serum 25(OH)D AUC was significantly greater in those placentas ≥ 90th % (p = 0.03); however, this was not associated with increased perinatal mortality. CONCLUSION FINDINGS: suggest increasing maternal serum [25(OH)D] via vitamin D supplementation during pregnancy did not adversely affect placental morphology; trends showed those in the treatment group had fewer placental lesions. Placental weight was found to be significantly associated with [25(OH)D] AUC, which represents maternal vitamin D status over the course of pregnancy; 7 placentas ≥ 90th % for GA were not associated with perinatal mortality.

Prenatal exposure to perceived stress, maternal asthma, and placental size.

INTRODUCTION: Prenatal exposure to stress has been associated with poor pregnancy outcomes, yet evidence linking stress and placental size is limited. Asthma is associated with worse pregnancy outcomes and women with asthma may be more susceptible to stress. Using the asthma-enriched B-WELL-Mom cohort, we examined the association between perceived stress and placental size. METHODS: Placental measures of weight, length, width, and thickness were available for 345 women (262 with asthma) via placental pathology report. Perceived Stress Scale (PSS) scores were obtained in each trimester of pregnancy and categorized into quartiles (low quartile as reference). For associations between PSS and placental size, generalized estimating equations adjusted for maternal and infant factors were used to estimate regression coefficients (ß) and 95% confidence intervals (95% CI). Full models and models stratified by asthma status were run. RESULTS: Compared to Quartile 1, high levels of stress (Quartile 4) were associated with smaller placental weight (-20.63 95% CI: -37.01,-4.26) and length (-0.55 95% CI: -0.96,-0.15), but not width or thickness. Results by asthma status show a stronger association between perceived stress and shorter placental length in those with asthma and a stronger association between perceived stress and smaller placental thickness in those without asthma. Findings were robust to sensitivity analyses DISCUSSION: Higher levels of perceived stress were associated with smaller placental size. Additional research is warranted to understand the relationship between stress and placental size.

Association between maternal cholesterol level during pregnancy and placental weight and birthweight ratio: data from the Japan Environment and Children's Study.

BACKGROUND: Placental weight to birthweight ratio (PW/BW ratio), or its inverse, is used as an indicator of placental efficiency. Past studies have shown an association between an abnormal PW/BW ratio and adverse intrauterine environment, however, no previous studies have examined the effect of abnormal lipid levels during pregnancy on PW/BW ratio. We aimed to evaluate the association between maternal cholesterol levels during pregnancy and placental weight to birthweight ratio (PW/BW ratio). METHODS: This study was a secondary analysis using the data from the Japan Environment and Children's Study (JECS). 81 781 singletons and their mothers were included in the analysis. Maternal serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels during pregnancy were obtained from participants. Associations between maternal lipid levels and placental weight and PW/BW ratio were assessed by regression analysis using restricted cubic splines. RESULTS: Dose-response relationships were observed between maternal lipid level during pregnancy and placental weight and PW/BW ratio. High TC and LDL-C levels were associated with heavy placental weight and high PW/BW ratio, i.e., inappropriately heavy placenta for birthweight. Low HDL-C level was also associated with inappropriately heavy placenta. Low TC and LDL-C levels were associated with low placental weight and low PW/BW ratio, i.e., inappropriately light placenta for birthweight. High HDL-C was not associated with PW/BW ratio. These findings were independent of pre-pregnancy body mass index and gestational weight gain. CONCLUSIONS: Abnormal lipid levels such as elevated TC and LDL-C, and low HDL-C level, during pregnancy were associated with inappropriately heavy placental weight.

Associations between the maternal healthy lifestyle score and its individual components during early pregnancy with placental outcomes.

INTRODUCTION: The influence of maternal lifestyle behaviours on placental growth have been investigated individually, but with conflicting results, and their combined effect is under-researched. Therefore, we examined associations between a composite maternal healthy lifestyle score (HLS), and its individual components, during early pregnancy with placental outcomes. METHODS: Participants included Lifeways Cross-Generational Cohort mother-child pairs (n = 202). A composite HLS based on a less inflammatory diet (bottom 40% of the energy-adjusted Dietary Inflammatory Index (E-DII™)), moderate-to-vigorous physical activity (MVPA), healthy pre-pregnancy BMI (18.5-24.9 kg/m2), never smoking, and non-/moderate alcohol intake was calculated. Quantile regression analysed HLS (and individual components) associations with measures of placental development (untrimmed placental weight (PW)) and function (birth weight:placental weight (BW:PW) ratio) at the 10th, 25th, 50th, 75th and 90th centiles. RESULTS: A more pro-inflammatory diet was positively, and smoking and heavy alcohol consumption were negatively, associated with PW at median centiles (B: 41.97 g, CI: 3.71, 80.22, p < 0.05; B: -58.51 g, CI: -116.24, -0.77, p < 0.05; B: -120.20 g, CI: -177.97, -62.43, p < 0.05 respectively). Low MVPA was inversely associated with BW:PW ratio at the 10th and 90th centiles (B: -0.36, CI: -0.132, -0.29, p < 0.01 and B: -0.45, CI: -0.728, -0.182, p < 0.01, respectively). Heavy alcohol intake was positively associated with BW:PW ratio at the 10th centile (B: 0.54, CI: 0.24, 0.85, p < 0.01). Results of sex-stratified analysis provide evidence of sexual dimorphism. DISCUSSION: Associations of certain lifestyle factors, but not the composite HLS, during early pregnancy with measures of placental development (PW) and function (BW:PW ratio) varied by quantiles and by sex.