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Introduction Maternal elevated plasma total homocysteine (tHcy) is involved in the origin of several placenta-related pregnancy complications. The first trimester is the most sensitive period for placentation influenced by maternal and paternal health. The aim is to study associations between periconceptional parental tHcy levels and utero-placental growth trajectories in the first trimester of pregnancy. Methods Pregnant women and their partners were enrolled before 10 weeks of gestation in the Virtual Placenta study as subcohort of the Rotterdam periconception cohort (Predict study). A total of 190 women with a singleton pregnancy, of which 109 conceived naturally and 81 after IVF/ICSI treatment, were included. We measured serial utero-placental vascular volumes (uPVV) and placental volumes (PV) at 7, 9 and 11 weeks of gestation. First-trimester trajectories of PV were also measured in 662 pregnancies from the total Predict study. Results Comparing all participants of the virtual placenta study, no association between maternal tHcy and uPVV was observed. However, in IVF/ICSI pregnancies sub-analyses showed significantly negative associations between maternal tHcy in the 3rd and 4th quartile and uPVV trajectories (beta: −0.38 (95%CI -0.74 to −0.02) and beta: −0.42 (95% CI -0.78 to −0.05), respectively) with the 1st quartile as reference. Analysis in the total Predict cohort showed similar negative associations for the total study population. Discussion Periconceptional high maternal tHcy levels are associated with smaller placental growth trajectories depicted as PV and uPVV in the first trimester of pregnancy. The stronger negative associations with uPVV in IVF/ICSI pregnancies underline the need for further investigation.

BACKGROUND Worldwide, the prevalence of obesity in women of reproductive age is increasing. Bariatric surgery is currently viewed as the most effective, long-term solution for this problem. Preconception bariatric surgery can reduce the prevalence of obesity-related subfertility and adverse maternal, pregnancy and birth outcomes. Maternal health during the periconception period is crucial for optimal gametogenesis and for embryonic and fetal development which also affects health in the later lives of both mother and offspring. Although preconception bariatric surgery improves several pregnancy outcomes, it can also increase the prevalence of pregnancy complications due to excessive and rapid weight loss. This can lead to iatrogenic malnutrition with vitamin deficiencies and derangements in metabolic and endocrine homeostasis. Thus, bariatric surgery can greatly influence periconception maternal health with consequences for reproduction, pregnancy and health in later life. However, its influence on periconception maternal health itself has never been reviewed systematically. OBJECTIVE AND RATIONALE The aim of this review was to investigate associations between bariatric surgery and determinants of periconception maternal health such as endocrine changes, fertility, vitamin status, irregular menstrual cycles, miscarriages and congenital malformations. SEARCH METHODS Medline, Embase, PubMed, Web of Science, Google Scholar and the Cochrane databases were used for the literature search until 1 November 2020. The search strategy terms included, among others, bariatric surgery, hormones, fertility, malformations, miscarriages and vitamin status. We searched for human studies that were written in English. Abstracts, reviews, meta-analyses and conference papers were excluded. The ErasmusAGE score was used to assess the quality of the included studies. OUTCOMES A total of 51 articles were analysed. The mean quality score was 5 (range 2–8). After bariatric surgery, hormonal axes normalized and menstrual cycle regularity was restored, resulting in increased fertility. Overall, there were no short-term risks for reproductive outcomes such as the increased risk of miscarriages or congenital malformations. However, the risk of vitamin deficiencies was generally increased after bariatric surgery. A meta-analysis of 20 studies showed a significant decrease in infertility (risk difference (RD) −0.24, 95% confidence interval (CI) −0.42, −0.05) and menstrual cycle irregularities (RD −0.24, 95% CI −0.34, −0.15) with no difference in rates of miscarriage (RD 0.00, 95% CI −0.09, 0.10) and congenital malformations (RD 0.01, 95% CI −0.02, 0.03). WIDER IMPLICATIONS The current systematic review and meta-analysis show associations between bariatric surgery and periconception maternal health and underlines the need for providing and personalizing preconception care for women after bariatric surgery. We recommend preconception care including the recommendation of postponing pregnancy until weight loss has stabilized, irrespective of the surgery-to-pregnancy interval, and until vitamin status is normalized. Therefore, regular monitoring of vitamin status and vitamin supplementation to restore deficiencies is recommended. Furthermore, this systematic review emphasizes the need for a long-term follow-up research of these women from the periconception period onwards as well as their pregnancies and offspring, to further improve care and outcomes of these mothers and children.

Introduction: Impaired placental development is a major cause of fetal growth restriction (FGR) and early detection will therefore improve antenatal care and birth outcomes. Here we aim to investigate serial first-trimester ultrasound markers of utero-placental (vascular) development in association with embryonic and fetal growth. Methods: In a prospective cohort, we periconceptionally included 214 pregnant women. Three-dimensional power Doppler ultrasonography at 7, 9 and 11 weeks gestational age (GA) was used to measure placental volumes (PV) and basal plate surface area by Virtual Organ Computer-aided AnaLysis™, and utero-placental vascular volume (uPVV), crown-rump length (CRL) and embryonic volume (EV) by a V-scope volume rendering application. Estimated fetal weight (EFW) was measured by ultrasound at 22 and 32 weeks GA and birth weight percentile (BW) was recorded. Linear mixed models and regression analyses were applied and appropriately adjusted. All analyses were stratified for fetal sex. Results: PV trajectories were positively associated with CRL (βadj = 0.416, 95%CI:0.255; 0.576, p < 0.001), EV (βadj = 0.220, 95%CI:0.058; 0.381, p = 0.008) and EFW (βadj = 0.182, 95%CI:0.012; 0.352, p = 0.037). uPVV trajectories were positively associated with CRL (βadj = 0.203, 95%CI 0.021; 0.384, p = 0.029). In girls, PV trajectories were positively associated with CRL (p < 0.001), EV (p = 0.018), EFW (p = 0.026), and uPVV trajectories were positively associated with BW (p = 0.040). In boys, positive associations were shown between PV trajectories and CRL (p = 0.002), and between uPVV trajectories and CRL (p = 0.046). Discussion: First-trimester utero-placental (vascular) development is associated with embryonic and fetal growth, with fetal sex specific modifications. This underlines the opportunity to monitor first-trimester placental development and supports the associations with embryonic and fetal growth.

Testicular sperm is increasingly used during in vitro fertilization treatment. Testicular sperm has the ability to fertilize the oocyte after intracytoplasmic sperm injection (ICSI), but they have not undergone maturation during epididymal transport. Testicular sperm differs from ejaculated sperm in terms of chromatin maturity, incidence of DNA damage, and RNA content. It is not fully understood what the biological impact is of using testicular sperm, on fertilization, preimplantation embryo development, and postimplantation development. Our goal was to investigate differences in human preimplantation embryo development after ICSI using testicular sperm (TESE-ICSI) and ejaculated sperm. We used time-lapse embryo culture to study these possible differences. Embryos (n = 639) originating from 208 couples undergoing TESE-ICSI treatment were studied and compared to embryos (n = 866) originating from 243 couples undergoing ICSI treatment with ejaculated sperm. Using statistical analysis with linear mixed models, we observed that pronuclei appeared 0.55 h earlier in TESE-ICSI embryos, after which the pronuclear stage lasted 0.55 h longer. Also, significantly more TESE-ICSI embryos showed direct unequal cleavage from the 1-cell stage to the 3-cell stage. TESE-ICSI embryos proceeded faster through the cleavage divisions to the 5- and the 6-cell stage, but this effect disappeared when we adjusted our model for maternal factors. In conclusion, sperm origin affects embryo development during the first embryonic cell cycle, but not developmental kinetics to the 8-cell stage. Our results provide insight into the biological differences between testicular and ejaculated sperm and their impact during human fertilization., Human embryos originating from fertilization with testicular sperm show a prolonged pronuclear stage and more often direct unequal cleavage than embryos originating from ejaculated sperm, while subsequent cleavage divisions are not impacted.

Research question: Does first-trimester maternal renin–angiotensin–aldosterone system (RAAS) activity determine early and late fetal growth and birthweight? Design: A total of 201 ongoing pregnancies, of which 104 were conceived naturally, seven following single intrauterine insemination (IUI), eight after IUI with ovulation induction and 82 after IVF or intracytoplasmic sperm injection treatment were selected from the Rotterdam Periconceptional Cohort. Renin, prorenin and aldosterone concentrations were determined in blood plasma at 9 and 11 weeks of gestational age. Serial crown–rump length and embryonic volume at 7, 9 and 11 weeks of gestational age were measured using virtual reality software to assess early fetal growth. Estimated fetal weight at 22 and 32 weeks of gestational age and birthweight were measured to assess late fetal growth trajectories. Pregnancy outcomes, small for gestational age (SGA) (z-scores –0.28, 95% CI –0.55 to –0.01, P=0.03), and an increased risk of SGA (1 corpus luteum versus pregnancies with 1 corpus luteum (betaz-scores –0.17, 95% CI –0.32 to –0.01, P=0.04). Conclusion: This study shows that excessive first-trimester prorenin release, resulting in angiotensin up-regulation, can explain why pregnancies with >1 corpus luteum are at risk for offspring with decreased birthweight and SGA. Simultaneously, high concentrations of aldosterone, independent of renin, seem to have a beneficial influence.

Research question: What is the association between the degree of a state of maternal vulnerability, determined by suboptimal periconceptional social, lifestyle and medical exposures and embryonic growth? Design: In total, 555 pregnancies, comprising 324 naturally conceived pregnancies and 231 pregnancies conceived after IVF and intracytoplasmic sperm injection (ICSI) were included from the Rotterdam Periconceptional Cohort (Predict Study) between November 2010 and August 2018. Data on periconceptional social, lifestyle and medical exposures, i.e. vulnerability markers, were collected through self-administered questionnaires. To estimate embryonic growth, crown–rump length (CRL) and embryonic volume measurements were taken at 7, 9 and 11 weeks of gestation using three-dimensional ultrasound scans and virtual reality techniques. Results: Exposure to two or more vulnerability markers was negatively associated with embryonic growth in naturally conceived pregnancies. The CRL and embryonic volume trajectories of embryos of women exposed to two vulnerability markers were reduced compared with those of women exposed to zero or one vulnerability marker (√CRL: β = –0.29 mm, 95% CI –0.56 to –0.02; 3√EV: β = –0.14 cm3, 95% CI –0.27 to –0.01). These associations were not found in pregnancies conceived after IVF or ICSI. Conclusions: This study showed that a higher degree of the periconceptional state of maternal vulnerability is associated with reduced embryonic growth (CRL and embryonic volume) in naturally conceived pregnancies.

Preconception folic acid supplement use is a well-known method of primary prevention of neural tube defects (NTDs). Obese women are at a higher risk for having a child with a NTD. As different international recommendations on folic acid supplement use for obese women before and during pregnancy exist, this narrative review provides an overview of epidemiology of folate deficiency in obese (pre)pregnant women, elaborates on potential mechanisms underlying folate deficiency, and discusses considerations for the usage of higher doses of folic acid supplements. Women with obesity more often suffer from an absolute folate deficiency, as they are less compliant to periconceptional folic acid supplement use recommendations. In addition, their dietary folate intake is limited due to an unbalanced diet (relative malnutrition). The association of obesity and NTDs also seems to be independent of folate intake, with studies suggesting an increased need of folate (relative deficiency) due to derangements involved in other pathways. The relative folate deficiency, as a result of an increased metabolic need for folate in obese women, can be due to: (1) low-grade chronic inflammation (2) insulin resistance, (3) inositol, and (4) dysbiotic gut microbiome, which plays a role in folate production and uptake. In all these pathways, the folate-dependent one-carbon metabolism is involved. In conclusion, scientific evidence of the involvement of several folate-related pathways implies to increase the recommended folic acid supplementation in obese women. However, the physiological uptake of synthetic folic acid is limited and side-effects of unmetabolized folic acid in mothers and offspring, in particular variations in epigenetic (re)programming with long-term health effects, cannot be excluded. Therefore, we emphasize on the urgent need for further research and preconception personalized counseling on folate status, lifestyle, and medical conditions.

STUDY QUESTION Does IVF with or without ICSI (IVF/ICSI) treatment impact the development of embryonic brain structures? SUMMARY ANSWER Our results show associations between IVF/ICSI treatment, smoking and slightly increased sizes of early human embryonic brain structures. WHAT IS KNOWN ALREADY The number of IVF/ICSI procedures is increasing worldwide and is associated with higher risks of obstetric and perinatal complications in pregnancies. STUDY DESIGN, SIZE, DURATION One hundred seventy-five women with a singleton pregnancy were included in the Rotterdam Periconceptional Cohort (Predict study). PARTICIPANTS/MATERIALS, SETTING, METHODS Self-reported questionnaires, verified by a research assistant at enrollment, provided information on periconceptional maternal characteristics and mode of conception. Three-dimensional ultrasound (3D-US) examinations were performed at 9 and 11 weeks of gestational age (GA). Diencephalon total diameter (DTD), mesencephalon total diameter (MTD) and telencephalon thickness on the left and right site (TTL/TTR) were measured offline in standardized planes using 4D View software. Linear regression models with adjustment for GA, maternal age, body mass index, moment of initiation of folic acid supplement use and smoking were used to study associations between mode of conception and embryonic brain measurements at 9 and 11 weeks of GA. MAIN RESULTS AND ROLE OF CHANCE A total of 276 3D-US scans of 166 participants, of which 50 conceived through IVF/ICSI, were included for embryonic brain measurements. Success rates of the DTD and MTD measurements were between 67% and 73% and of the TTL/TTR between 52% and 57%. In the fully adjusted model, we found that at 11 weeks of GA, the MTD (ß = 0.264, 95% CI = 0.101; 0.427, P LIMITATIONS, REASONS FOR CAUTION The implications of these small deviations on brain functioning need further investigation. WIDER IMPLICATIONS OF THE FINDINGS Enlargement of attention for prenatal brain development and postnatal neurodevelopmental outcome after IVF/ICSI treatment. STUDY FUNDING/COMPETING INTERESTS This study was funded by the Department of Obstetrics and Gynecology, Erasmus MC, and Sophia research foundation for Medical Research, Rotterdam, the Netherlands (SSWO grant number 644). No competing interests are declared. TRIAL REGISTRATION NUMBER N/A

Aim: To assess the possibility of embryonic posture evaluation (=feasibility, reproducibility, variation) at rest at 9 weeks' (+0–6 days) gestational age (GA) using four-dimensional ultrasound and virtual reality (VR) techniques. Moreover, it is hypothesized that embryonic posture shows variation at the same time point in an uneventful pregnancy. Methods: In this explorative prospective cohort study, 23 pregnant women were recruited from the Rotterdam periconceptional cohort. A transvaginal four-dimensional ultrasound examination of 30 min per pregnancy was performed between 9 and 10 weeks' GA. The acquired datasets were offline evaluated longitudinally (i.e. per frame) using VR techniques. Results: The ultrasound data of 16 (70%) out of 23 pregnancies were eligible for evaluation. At rest the analysis of the embryonic posture was feasible and showed a strong (>80%) intraobserver and interobserver reproducibility for most body parts. The majority of the body parts were in similar anatomic positions at rest. However, variations in anatomic positions (e.g. 6% rotated head, 9% laterally bent spine), within and between embryos, were seen at 9 weeks' GA. Conclusion: In this unique study, we showed for the first time that embryonic posture measurements at rest can be performed in a reliable way using state-of-the-art four-dimensional ultrasound and VR techniques. Already early in prenatal life there are differences regarding posture within and between embryos.

Objective: To study compliance and effectiveness of the mHealth nutrition and lifestyle coaching program Smarter Pregnancy in couples undergoing in vitro fertilization (IVF) treatment with or without intracytoplasmic sperm injection (ICSI).Design: Multicenter, single-blinded, randomized controlled trial, conducted from July 2014 to March 2017.Setting: IVF clinics.Patient(s): A total of 626 women undergoing IVF treatment with or without ICSI and 222 male partners.Interventions(s): Couples were randomly assigned to the light (control group) or regular (intervention group) Smarter Pregnancy program. Both groups filled out a baseline screening questionnaire on nutrition and lifestyle behaviors, and the intervention group received coaching tailored to inadequate behaviors during the 24-week period.Main Outcome Measure(s): Difference in improvement of a composite dietary and lifestyle risk score for the intake of vegetables, fruits, folic acid supplements, smoking, and alcohol use after 24 weeks of the program.Result(s): Compared with control subjects, women and men in the intervention group showed a significantly larger improvement of inadequate nutrition behaviors after 24 weeks of coaching. At the same time, the women also showed a significantly larger improvement of inadequate lifestyle behaviors.Conclusion(s): The mHealth coaching program Smarter Pregnancy is effective and improves the most important nutritional and lifestyle behaviors among couples undergoing IVF/ICSI treatment. International multicenter randomized trials are recommended to study the effect of using Smarter Pregnancy on pregnancy, live birth, and neonatal outcome. ((C)2020 by American Society for Reproductive Medicine.)yy

Context The corpus luteum (CL) secretes prorenin, renin’s inactive precursor. It may thus contribute to the renin-angiotensin-aldosterone-system (RAAS) activation that is required for maternal adaptation in pregnancy. Whether this activation is disturbed in pregnancies lacking a CL is unknown. Objective The objective of this work is to investigate maternal RAAS determinants in early pregnancy. Design and Setting Two observational prospective cohort studies took place at 2 tertiary referral hospitals. Patients and Intervention(s) Pregnancies (n = 277) were stratified by CL number and in vitro fertilization (IVF) protocol: 0 CL (programmed cycle frozen embryo transfer [FET], n = 28), 1 CL (natural cycle FET, n = 41 and spontaneous conceptions, n = 139), and more than 1 CL (ovarian stimulation and fresh embryo transfer, n = 69). Methods Quantification was performed for maternal prorenin, renin, and aldosterone blood levels at 5, 9, and 11 weeks of gestation. Results Prorenin and renin were lower in the absence of a CL at all time points when compared to 1 CL, whereas prorenin, renin, and aldosterone were higher in the presence of more than 1 CL vs 1 CL (P < .05). Ovarian stimulation with menopausal gonadotropin resulted in higher prorenin, renin, and aldosterone concentrations during the late first trimester than recombinant follicle-stimulating hormone (P < .05). Prorenin, and to a lesser degree renin, correlated positively with serum progesterone and relaxin, but not serum estradiol. Total follicle diameter, body mass index (BMI), polycystic ovary syndrome (PCOS), and antimüllerian hormone (AMH) were additional determinants of circulating prorenin. Finally, pregnancies conceived in the absence of a CL were more disposed to develop preeclampsia. Conclusions CL number, IVF protocol, BMI, PCOS, and AMH affect maternal RAAS activation in early pregnancy, and may thus contribute to pregnancy complications.

Background & aims: Periconceptional maternal dietary patterns contribute to embryonic growth and development. No knowledge is available about the impact of periconceptional maternal ultra-processed food consumption on embryonic growth. Therefore, the aim of the present study is to investigate the impact of periconceptional maternal ultra-processed food consumption on embryonic growth using repeated crown-rump length (CRL) and embryonic volume (EV) measurements. Methods: This study is embedded in the ongoing prospective observational Rotterdam periconceptional cohort (Predict Study). A total of 701 pregnancies, of which 446 were conceived after natural conception and 255 after IVF or ICSI treatment were included. Women were at least 18 years of age and were recruited at the outpatient clinic before 13+0 weeks of gestation. CRL and EV were measured using three-dimensional ultrasound datasets and virtual reality techniques at the 7th, 9th and 11th week of gestation. The food frequency questionnaire of each participant was used to calculate the percentage of maternal energy consumed from ultra-processed foods (PEI-UPF) for each participant. The association between PEI-UPF and the first trimester CRL and EV measurements was studied with linear mixed models and adjusted for potential confounders including maternal factors, gestational age, foetal sex, and total energy intake. Results: PEI-UPF ranged from 16% to 88%. In fully adjusted linear mixed models, a 10% increase in maternal PEI-UPF was significantly associated with smaller growth trajectories of CRL and EV (b −0.041 √mm (95% confidence interval (CI) −0.074 to −0.008), P = 0.02 and b −0.016 ∛cm (95% CI -0.030 to −0.001), P = 0.04, respectively). When additionally adjusted for micronutrient content of diet (vitamins B1, B2, B6, B11 and B12, and zinc), the associations for the CRL and EV measurements lost significance. Conclusion: Periconceptional maternal consumption of ultra-processed foods is associated with smaller embryonic growth. Interventions promoting healthy food practices during pregnancy could be beneficial for embryonic growth.

A healthy diet before and during pregnancy is beneficial in acquiring essential B vitamins involved in 1-carbon metabolism, and in maintaining a healthy gut microbiota. Each play important roles in fetal development, immune-system remodeling, and pregnancy-nutrient acquisition. Evidence shows that there is a reciprocal interaction between the one-carbon metabolism and the gut microbiota given that dietary intake of B vitamins has been shown to influence the composition of the gut microbiota, and certain gut bacteria also synthesize B vitamins. This reciprocal interaction contributes to the individual's overall availability of B vitamins and, therefore, should be maintained in a healthy state during pregnancy. There is an emerging consensus that obese pregnant women often have derangements in 1-carbon metabolism and gut dysbiosis owing to high intake of nutritiously poor foods and a chronic systemic inflammatory state. For example, low folate and vitamin B12 in obese women coincide with the decreased presence of B vitamin-producing bacteria and increased presence of inflammatory-associated bacteria from approximately mid-pregnancy. These alterations are risk factors for adverse pregnancy outcomes, impaired fetal development, and disruption of fetal growth and microbiota formation, which may lead to potential long-term offspring metabolic and neurologic disorders. Therefore, preconceptional and pregnant obese women may benefit from dietary and lifestyle counseling to improve their dietary nutrient intake, and from monitoring their B vitamin levels and gut microbiome by blood tests and microbiota stool samples. In addition, there is evidence that some probiotic bacteria have folate biosynthetic capacity and could be used to treat gut dysbiosis. Thus, their use as an intervention strategy for obese women holds potential and should be further investigated. Currently, there are many knowledge gaps concerning the relationship between one-carbon metabolism and the gut microbiota, and future research should focus on intervention strategies to counteract B vitamin deficiencies and gut dysbiosis in obese pregnant women, commencing with the use of probiotic and prebiotic supplements.

Background Pregnancies with > 1 corpus luteum (CL) display a hyperdynamic circulation and an increased risk of small-for-gestational age deliveries. Among the factors released by the CL is prorenin, the inactive precursor of renin. Since the renin-angiotensin-aldosterone system (RAAS) is involved in early hemodynamic pregnancy adaptation, we linked both CL number and first-trimester concentrations of prorenin (as an indicator of RAAS activity) and the aldosterone/renin ratio (as an indicator of angiotensin-independent aldosterone effectiveness) to non-invasive markers of utero-placental (vascular) development, measured longitudinally from the first trimester onwards. Methods A total of 201 women, who conceived naturally or after in-vitro fertilization treatment (with 0 (n = 8), 1 (n = 143), or > 1 (n = 51) CL), were selected from the Rotterdam Periconceptional Cohort. Maternal RAAS components were determined at 11 weeks gestation. Placental volume and utero-placental vascular volume were measured from transvaginal 3D ultrasound scans at 7, 9 and 11 weeks gestation, pulsatility and resistance indices of the uterine arteries were assessed by pulsed wave Doppler ultrasounds at 7, 9, 11, 13, 22 and 32 weeks gestation. At birth placental weight was obtained using standardized procedures. Results Pregnancies without a CL show lower uterine artery indices throughout gestation than 1 CL and > 1 CL pregnancies, while parameters of placental development are comparable among the CL groups. After adjustment for patient- and treatment-related factors, first-trimester prorenin concentrations are positively associated with uterine artery pulsatility and resistance indices (β 0.06, 95% CI 0.01;0.12, p = 0.04 and β 0.10, 95% CI 0.01;0.20, p = 0.04, respectively), while high prorenin concentrations are negatively associated with first-trimester utero-placental vascular volume (β -0.23, 95% CI -0.44;-0.02, p = 0.04) and placental weight (β -93.8, 95%CI -160.3;-27.4, p = 0.006). In contrast, the aldosterone/renin ratio is positively associated with first-trimester placental volume (β 0.12, 95% CI 0.01;0.24, p = 0.04). Conclusions The absence of a CL, resulting in low prorenin concentrations, associates with low uterine artery pulsatility and resistance, while high prorenin concentrations associate with a low utero-placental vascular volume and weight. These data support a scenario in which excess prorenin, by upregulating angiotensin II, increases uterine resistance, thereby preventing normal placental (vascular) development, and increasing the risk of small-for-gestational age deliveries. Simultaneously, high aldosterone concentrations, by ensuring volume expansion, exert the opposite.

Objective: Women with obesity have an increased risk of pregnancy complications. Although complications generally present in the second and third trimester of pregnancy, most of them develop in the periconception period. Moreover, fetal sex also impacts pregnancy course and outcome. Therefore, our aim is to study (sex-specific) associations between periconceptional maternal body mass index (BMI) and embryonic growth and morphological development. Methods: A total of 884 women with singleton pregnancies were selected from the Rotterdam Periconception Cohort, comprising 15 women with underweight, 483 with normal weight, 231 with overweight and 155 with obesity. Longitudinal three-dimensional ultrasound examinations were performed at 7, 9, and 11 weeks of gestation for offline measurements of crown-rump length (CRL), embryonic volume (EV), and Carnegie stages. Analyses were adjusted for maternal age, parity, ethnicity, education, and periconceptional lifestyle. Results: A negative trend was observed for embryos of women with obesity (βEV −0.03, p = 0.086), whereas embryonic growth and developmental trajectories in women with overweight were comparable to those with normal weight. Maternal underweight was associated with faster morphological development (βCarnegie 0.78, p = 0.004). After stratification for fetal sex, it was demonstrated that female embryos of underweight women grow and morphologically develop faster than those of normal weight women (βEV 0.13, p = 0.008; βCarnegie 1.39, p < 0.001), whereas female embryos of women with obesity grow slower (βEV −0.05, p = 0.027). Conclusion: We found that periconceptional maternal underweight is associated with faster embryonic growth, especially in females. In contrast, female embryos of women with obesity grow slower than female embryos of women with normal weight. This may be the result of altered female adaptation to the postnatal environment. Future research should focus on strategies for optimizing preconceptional maternal weight, to reduce BMI-related pregnancy complications and improve the health of future generations.

Background: Obesity is a worldwide problem affecting the health of millions of people throughout the life course. Studies reveal that obesity impairs sperm parameters and epigenetics, potentially influencing embryonic development. Objective: To investigate the association between preconceptional paternal body mass index (BMI) and embryo morphokinetics using a time-lapse incubator and in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) outcomes. Materials and methods: Participants were recruited from a tertiary hospital in this prospective periconceptional cohort study. A total of 211 men were included: 86 with normal weight (BMI

The maternal environment during the periconceptional period influences foetal growth and development, in part, via epigenetic mechanisms moderated by one-carbon metabolic pathways. During embryonic development, one-carbon metabolism is involved in brain development and neural programming. Derangements in one-carbon metabolism increase (i) the short-term risk of embryonic neural tube-related defects and (ii) long-term childhood behaviour, cognition, and autism spectrum disorders. Here we investigate the association between maternal one-carbon metabolism and foetal and neonatal brain growth and development. Database searching resulted in 26 articles eligible for inclusion. Maternal vitamin B6, vitamin B12, homocysteine, and choline were not associated with foetal and/or neonatal head growth. First-trimester maternal plasma folate within the normal range (>17 nmol/L) associated with increased foetal head size and head growth, and high erythrocyte folate (1538–1813 nmol/L) with increased cerebellar growth, whereas folate deficiency (

Background Overweight and obesity affect millions of people globally, which has also serious implications for reproduction. For example, treatment outcomes after in vitro fertilisation (IVF) are worse in women with a high body mass index (BMI). However, the impact of maternal BMI on embryo quality is inconclusive. Our main aim is to study associations between preconceptional maternal BMI and morphokinetic parameters of preimplantation embryos and predicted implantation potential. In addition, associations with clinical IVF outcomes are investigated. Methods From a tertiary hospital, 268 women undergoing IVF or IVF with intracytoplasmic sperm injection (ICSI) were included; 143 normal weight, 79 overweight and 46 obese women. The embryos of these women were cultured in the EmbryoScope, a time-lapse incubator. The morphokinetic parameters of preimplantation embryos and predicted implantation potential, assessed by the KIDScore algorithm were longitudinally evaluated as primary and secondary outcomes, respectively. The tertiary outcomes included clinical outcomes, i.e., fertilization, implantation and live birth rate. Results After adjustment for patient- and treatment-related factors, we demonstrated in 938 embryos that maternal BMI is negatively associated with the moment of pronuclear appearance (βtPNa -0.070 h (95%CI -0.139, -0.001), p = 0.048), pronuclear fading (βtPNf -0.091 h (95%CI -0.180, -0.003), p = 0.043 and the first cell cleavage (βt2 -0.111 h (95%CI -0.205, -0.016), p = 0.022). Maternal BMI was not significantly associated with the KIDScore and tertiary clinical treatment outcomes. In embryos from couples with female or combined factor subfertility, the impact of maternal BMI was even larger (βtPNf -0.170 h (95%CI -0.293, -0.047), p = 0.007; βt2 -0.199 h (95%CI -0.330, -0.067), p = 0.003). Additionally, a detrimental impact of BMI per point increase was observed on the KIDScore (β -0.073 (se 0.028), p = 0.010). Conclusions Higher maternal BMI is associated with faster early preimplantation development. In couples with female or combined factor subfertility, a higher BMI is associated with a lower implantation potential as predicted by the KIDScore. Likely due to power issues, we did not observe an impact on clinical treatment outcomes. However, an effect of faster preimplantation development on post-implantation development is conceivable, especially since the impact of maternal BMI on pregnancy outcomes has been widely demonstrated.

IntroductionThe worldwide obesity epidemic has resulted in a rise of bariatric surgery in women of reproductive age, which can lead to ‘iatrogenic undernutrition’. Long-lasting undernutrition can affect maternal health, pregnancy outcomes and offspring. We hypothesise that embryonic and placental growth are impaired in pregnancies after bariatric surgery due to the changed nutritional and microbiome dynamics. Therefore, our aim is to conduct the Bariatrics and EmbrYONic Development (BEYOND) study to investigate parameters of maternal nutritional and health status after bariatric surgery, both periconceptionally and during pregnancy, particularly concentrating on embryonic and fetal growth trajectories as well as placental development.Methods and analysisWe designed a single-centre prospective, observational cohort, which investigates the iatrogenic nutritional and health status of women after bariatric surgery, periconceptionally and during pregnancy. The BEYOND study is embedded in the Rotterdam Periconceptional Cohort, a tertiary hospital-based birth cohort study. Eligible participants are women planning pregnancy or Ethics and disseminationThis proposal was approved by the Medical Ethics Committee from the Erasmus MC, Rotterdam, The Netherlands. Study results will be submitted for publication in high-impact journals, presented at scientific conferences, implemented into guidelines and communicated through the Erasmus MC and collaborating partners.Trial registration numberNL8217 (www.trialregister.nl).

Background Maternal overweight has a substantial impact on reproductive, maternal, pregnancy, and neonatal outcomes with long-term and transgenerational health consequences. Interventions that aim to optimize periconception maternal lifestyle can improve maternal and fetal health during pregnancy and throughout the life course. However, it remains difficult to change and adopt adequate lifestyle behaviors. We hypothesize that additional psychological therapy targeting cognitive and affective factors substantially contribute to the effectiveness of these interventions. Objective The proposed study aims to examine the feasibility and effectiveness of a blended personalized periconception lifestyle care intervention with additional psychological therapy aimed at women with a BMI≥25 and who are contemplating pregnancy or are already pregnant (≤12 weeks) in reducing inadequate lifestyle behaviors and improving early and late pregnancy outcome. Methods The eHealth and Face-to-face Counseling (eFUSE) study follows a single-center two-arm randomized controlled trial design at the Erasmus MC, University Medical Center, with a multicenter regional referral. The female patients with overweight (BMI≥25), together with their male partner, will be stratified by pregnancy status (preconception vs pregnant) and randomized to receive either the blended personalized periconception lifestyle care intervention with additional psychological therapy (n=313) or usual care (n=313). The primary outcome is a change in the lifestyle risk score (between baseline and 24 weeks) between the randomization arms (difference in differences). Secondary outcomes include measurements defined as most relevant by the International Consortium for Health Outcomes Measurement, including behavioral determinants, patient satisfaction, provider feasibility, and maternal pregnancy and neonatal complications. Results The study will be open for recruitment from Fall 2021 onward. Data collection is expected to be completed by the beginning of 2023, and the results are expected to be published by Fall 2023. Conclusions This study will evaluate the feasibility and effectiveness of a blended periconception lifestyle intervention with additional psychological therapy, aimed at women with a BMI≥25. Positive results of this innovative care approach will be used for implementation in routine medical care of all women with overweight, with the ultimate aim to improve clinical outcomes of these high-risk pregnancies. Trial Registration Netherlands Trial Register NL9264; https://www.trialregister.nl/trial/9264 International Registered Report Identifier (IRRID) PRR1-10.2196/28600

Polycystic ovary syndrome (PCOS) is an endocrine condition associated with reproductive and psychiatric disorders, and with obesity. Eating disorders, such as bulimia and recurrent dieting, are also linked to PCOS. They can lead to the epigenetic dysregulation of the hypothalamic–pituitary–gonadal (HPG) axis, thereby impacting on ovarian folliculogenesis. We postulate that PCOS is induced by psychological distress and episodes of overeating and/or dieting during puberty and adolescence, when body dissatisfaction and emotional distress are often present. We propose that upregulated activation of the central HPG axis during this period can be epigenetically altered by psychological stressors and by bulimia/recurrent dieting, which are common during adolescence and which can lead to PCOS. This hypothesis is based on events that occur during a largely neglected stage of female reproductive development. To date, most research into the origins of PCOS has focused on the prenatal induction of this disorder, particularly in utero androgenization and the role of anti-Müllerian hormone. Establishing causality in our peripubertal model requires prospective cohort studies from infancy. Mechanistic studies should consider the role of the gut microbiota in addition to the epigenetic regulation of (neuro) hormones. Finally, clinicians should consider the importance of underlying chronic psychological distress and eating disorders in PCOS.

Research question: Is there an association between the use of sympathomimetics for asthmatic disease and semen quality in humans? Design: Between 2007 and 2012 a prospective cohort study was conducted among couples visiting the preconception counselling clinic at a tertiary hospital in the Netherlands. The study included 882 men of subfertile couples and information on medication use was obtained from self-administered questionnaires. Moreover, data on semen parameters were retrieved from medical records. Results: The study population of men revealed a mean (± SD) age of 34 ± 4 years with a mean body mass index (BMI) of 26.1 ± 2.3 kg/m2, and sympathomimetic use was reported by 3.6%. The use of sympathomimetics was positively associated with a 10% higher sperm motility (beta 10.265; 95% confidence interval [CI] 3.258–17.272) after adjustment for smoking, alcohol use, age, geographic background, BMI, folic acid supplement use, the four astronomical seasons and asthma/bronchitis. Subgroup analysis between men with total motile sperm count (TMSC) < or ≥10 million showed that this association remained (P ≤ 0.001) after adjustment for these confounders. After adjustment for confounders the sperm concentration was also positively associated with the use of sympathomimetics, but only in men with TMSC ≥10 million (beta 0.300; 95% CI 0.032–0.568). Conclusions: These preliminary data show the potential benefits of the use of sympathomimetics to improve sperm motility in men of subfertile couples, which needs further investigation.

Objectives In a previous mass spectrometry study of our research group, 25 proteins were found to be differentially expressed in cerebrospinal fluid of patients with preeclampsia compared to controls. The objective of the current study was to investigate DNA methylation of the genes encoding for the former mentioned proteins in an independent dataset. Study design In a nested case-control study of the Rotterdam Periconceptional Cohort, placental tissue, umbilical cord white blood cells and human umbilical vein endothelial cells (HUVEC) were obtained of 13 patients with early-onset preeclampsia, 16 patients with late-onset preeclampsia and 83 normotensive controls (27 patients with fetal growth restriction, 20 patients with spontaneous preterm birth and 36 uncomplicated pregnancies). DNA methylation of 783 CpGs in regions of 25 genes was measured. Main outcome measures DNA methylation of selected candidate genes in early- and late-onset preeclampsia compared to fetal growth restriction, spontaneous preterm birth and uncomplicated controls. Results From the 783 CpGs of the 25 selected genes, 15 CpGs were differentially methylated between early-onset preeclampsia and spontaneous preterm birth (3.80 E-5 ≤ p ≤ 0.036). Four CpGs were differentially methylated between early-onset preeclampsia and fetal growth restriction (0.0002 ≤ p ≤ 0.037) and 13 CpGs were differentially methylated between early onset preeclampsia and uncomplicated controls (0.0001 ≤ p ≤ 0.04). Conclusion Differences in DNA methylation were found in placental tissue, umbilical cord white blood cells and HUVEC of patients with early onset preeclampsia compared to (un)complicated controls, but not in patients with late-onset preeclampsia. The genes showing the largest differential methylation encode insulin-like growth factor 2 binding protein and receptor and cadherin 13.

Summary Background & aim Several studies show the importance of periconceptional maternal dietary patterns on human embryonic growth. Healthy paternal nutrition has been associated with better semen quality and fecundability, however, evidence on the impact on pregnancy outcome is limited. Therefore, the aim of this study was to investigate the association between preconception paternal dietary patterns and first trimester embryonic growth using the parameters longitudinal crown-rump length (CRL) and embryonic volume (EV). Methods A total of 638 couples were enrolled in the Rotterdam Periconceptional Cohort and received longitudinal three dimensional transvaginal ultrasound scans from 7+0 up to 12+0 weeks of gestation. Virtual reality software was used to perform offline measurements of the embryonic CRL and EV. Food frequency questionnaires (FFQ) were used to estimate habitual food intake in couples. Principal component analysis (PCA) was performed to identify paternal and maternal dietary patterns. Linear mixed models adjusted for potential confounders were applied to analyze associations between paternal and maternal dietary patterns and embryonic growth parameters. Results The paternal dietary patterns retrieved were identified as “Whole wheat grains and Vegetables”, “Sauces and Snacks Refined Grains”, “Fish and Legumes” and explained 27.5% of the total variance of the dietary intake. No significant additional effects, independent of maternal dietary patters and other maternal and paternal potential confounders, were shown of these paternal dietary patterns on embryonic growth in spontaneous or IVF/ICSI pregnancies. Conclusion No significant effects of paternal dietary patterns independent of maternal dietary patters and other parental potential confounders on embryonic growth parameters could be established in spontaneous or IVF/ICSI pregnancies. The biological importance of paternal nutrition on semen quality, however, supports the need of periconceptional tailored nutritional counselling of couples trying to conceive.

The objective of the study is to provide evidence-based guidance on nutritional management and optimal care for pregnancy after bariatric surgery. A consensus meeting of international and multidisciplinary experts was held to identify relevant research questions in relation to pregnancy after bariatric surgery. A systematic search of available literature was performed, and the ADAPTE protocol for guideline development followed. All available evidence was graded and further discussed during group meetings to formulate recommendations. Where evidence of sufficient quality was lacking, the group made consensus recommendations based on expert clinical experience. The main outcome measures are timing of pregnancy, contraceptive choice, nutritional advice and supplementation, clinical follow-up of pregnancy, and breastfeeding. We provide recommendations for periconception, antenatal, and postnatal care for women following surgery. These recommendations are summarized in a table and print-friendly format. Women of reproductive age with a history of bariatric surgery should receive specialized care regarding their reproductive health. Many recommendations are not supported by high-quality evidence and warrant further research. These areas are highlighted in the paper. ispartof: OBESITY REVIEWS vol:20 issue:11 pages:1507-1522 ispartof: location:England status: published

Study question What is the (sex-specific) impact of two different culture media used in in vitro fertilization (IVF) treatment on post-implantation growth and development? Summary answer Embryos, especially males, cultured in SAGE 1-Step grow and morphologically develop faster in the first trimester, when compared to those cultured in Vitrolife G-1 PLUS. What is known already Increasing success rates after IVF can be attributed to several advancements, such as improved culture conditions. Culture media are of special interest, as they supply the embryo with essential nutrients and have previously been shown to impact birthweight. Moreover, IVF pregnancies are associated with an increased male:female ratio. However, it is unknown if culture media also have an impact prenatally. Therefore, our aim is to study the (sex-specific) impact of two different culture media (SAGE 1-Step and Vitrolife G-1 PLUS) used in IVF treatment on first-trimester embryonic growth and development, and fetal outcomes. Study design, size, duration Women with a viable singleton pregnancy were included before 10 weeks of gestation in the Rotterdam Periconception Cohort, an ongoing prospective tertiary hospital-based study, conducted since November 2009. Participants/materials, setting, methods A total of 879 pregnancies were included; 153 after culture in Vitrolife G-1 PLUS, 251 after culture in SAGE 1-Step and 475 naturally conceived. First-trimester growth and development, defined by serial crown-rump length (CRL), embryonic volume (EV) and Carnegie stages measurements were performed using state-of-the-art imaging techniques. Secondary outcomes included second trimester estimated fetal weight (EFW) and birth outcomes, and were retrieved from medical records. Main results and the role of chance Linear mixed model analyses, adjusted for gestational age and maternal characteristics, showed that embryos cultured in SAGE 1-Step grow faster than those cultured in Vitrolife G-1 PLUS (βEV 0.030 ∛cm3 (95%CI 0.008-0.052), p=0.007). CRL and Carnegie stages were not statistically different between culture media. After stratification for fetal sex, similar results were observed for male embryos (βEV 0.048 ∛cm3 (95%CI 0.015-0.081), p=0.005), but not for female embryos. EFW and birth outcomes were comparable between culture media in the total population and after stratification for fetal sex. Embryos cultured in SAGE 1-Step also grow faster than those conceived naturally (βEV 0.033 ∛cm3 (95%CI 0.006-0.060), p=0.018). This association was also most pronounced in male embryos (βEV 0.066 ∛cm3 (95%CI 0.024-0.108), p=0.002). Limitations, reasons for caution Although this study has a prospective design, its observational character does not exclude residual confounding. Furthermore, the external validity of this explorative study is limited, since participants were recruited from a tertiary university hospital. Wider implications of the findings Culture in SAGE 1-Step culture medium is associated with faster first-trimester growth and development, especially in male embryos. This may be the result of altered susceptibility to preimplantation environmental stressors. Further research should focus on the (sex-specific) impact of culture media on postnatal development and the susceptibility to non-communicable diseases. Trial registration number N/A

Background: In patients with azoospermia, pregnancy can be achieved after surgical techniques using sperm retrieved from the testis or epididymis, which can impact on DNA integrity and epigenetics. DNA of the fetus and placenta is equally derived from both parents; however, genes important for placental development are expressed from the paternal alleles. Therefore, the origin of sperm may affect fetal and placental development. Objectives: To investigate whether first-trimester trajectories of embryonic and placental development of pregnancies conceived after intracytoplasmic sperm injection (ICSI) with testicular sperm extraction (TESE) or microsurgical epididymal sperm aspiration (MESA), are different from pregnancies after ICSI with ejaculated sperm or natural conceptions. Materials and methods: A total of 147 singleton ICSI pregnancies, including pregnancies conceived after TESE (n = 23), MESA (n = 25) and ejaculated sperm (n = 99), and 380 naturally conceived and 140 after IVF treatment without ICSI were selected from the prospective Rotterdam periconception cohort. Crown-rump length (CRL), embryonic volume (EV), Carnegie stages, and placental volume (PV) at 7, 9, and 11 weeks of gestation were measured using 3D ultrasound and virtual reality technology. Results: Linear mixed model analysis showed no differences in trajectories of CRL, EV, and Carnegie stages between pregnancies conceived after ICSI with testicular, epididymal, and ejaculated sperm. A significantly positive association was demonstrated for PV between pregnancies conceived after TESE-ICSI (adjusted beta: 0.28(95%CI: 0.05-0.50)) versus ICSI with ejaculated sperm. Retransformation to original values showed that the PV of pregnancies after TESE-ICSI is 14.6% (95%CI: 1.4%-25.5%) larger at 11 weeks of gestation compared to ICSI pregnancies conceived with ejaculated sperm. Discussion and Conclusion: Here we demonstrate that the first-trimester growth trajectory of the placenta is increased in pregnancies conceived after TESE-ICSI compared to those conceived after ICSI with ejaculated sperm. Findings are discussed in the light of known differences in sperm DNA integrity, epigenetics, and placental gene expression.

Epigenetic programming is essential for lineage differentiation, embryogenesis and placentation in early pregnancy. In epigenetic association studies, DNA methylation is often examined in DNA derived from white blood cells, although its validity to other tissues of interest remains questionable. Therefore, we investigated the tissue specificity of epigenome-wide DNA methylation in newborn and placental tissues. Umbilical cord white blood cells (UC-WBC, n = 25), umbilical cord blood mononuclear cells (UC-MNC, n = 10), human umbilical vein endothelial cells (HUVEC, n = 25) and placental tissue (n = 25) were obtained from 36 uncomplicated pregnancies. Genome-wide DNA methylation was measured by the Illumina HumanMethylation450K BeadChip. Using UC-WBC as a reference tissue, we identified 3595 HUVEC tissue-specific differentially methylated regions (tDMRs) and 11,938 placental tDMRs. Functional enrichment analysis showed that HUVEC and placental tDMRs were involved in embryogenesis, vascular development and regulation of gene expression. No tDMRs were identified in UC-MNC. In conclusion, the extensive amount of genome-wide HUVEC and placental tDMRs underlines the relevance of tissue-specific approaches in future epigenetic association studies, or the use of validated representative tissues for a certain disease of interest, if available. To this purpose, we herewith provide a relevant dataset of paired, tissue-specific, genome-wide methylation measurements in newborn tissues.

Background Approximately 1 in 7 couples experience subfertility, many of whom have lifestyles that negatively affect fertility, such as poor nutrition, low physical activity, obesity, smoking, or alcohol consumption. Reducing lifestyle risk factors prior to pregnancy or assisted reproductive technology treatment contributes to the improvement of reproductive health, but cost-implications are unknown. Objective The goal of this study was to evaluate reproductive, maternal pregnancy, and birth outcomes, as well as the costs of pre-conception lifestyle intervention programs in subfertile couples and obese women undergoing assisted reproductive technology. Methods Using a hypothetical model based on quantitative parameters from published literature and expert opinion, we evaluated the following lifestyle intervention programs: (1) Smarter Pregnancy, an online tool; (2) LIFEstyle, which provides outpatient support for obese women; (3) concurrent use of both Smarter Pregnancy and LIFEstyle for obese women; (4) smoking cessation in men; and (5) a mindfulness mental health support program using group therapy sessions. The model population was based on data from the Netherlands. Results All model-based analyses of the lifestyle interventions showed a reduction in the number of in vitro fertilization, intracytoplasmic sperm injection, or intrauterine insemination treatments required to achieve pregnancy and successful birth for couples in the Netherlands. Smarter Pregnancy was modeled to have the largest increase in spontaneous pregnancy rate (13.0%) and the largest absolute reduction in potential assisted reproductive technology treatments. Among obese subfertile women, LIFEstyle was modeled to show a reduction in the occurrence of gestational diabetes, maternal hypertensive pregnancy complications, and preterm births by 4.4%, 3.8%, and 3.0%, respectively, per couple. Modeled cost savings per couple per year were €41 (US $48.66), €360 (US $427.23), €513 (US $608.80), €586 (US $695.43), and €1163 (US $1380.18) for smoking cessation, mindfulness, Smarter Pregnancy, combined Smarter Pregnancy AND LIFEstyle, and LIFEstyle interventions, respectively. Conclusions Although we modeled the potential impact on reproductive outcomes and costs of fertility treatment rather than collecting real-world data, our model suggests that of the lifestyle interventions for encouraging healthier behaviors, all are likely to be cost effective and appear to have positive effects on reproductive, maternal pregnancy, and birth outcomes. Further real-world data are required to determine the cost-effectiveness of pre-conception lifestyle interventions, including mobile apps and web-based tools that help improve lifestyle, and their effects on reproductive health. We believe that further implementation of the lifestyle app Smarter Pregnancy designed for subfertile couples seeking assistance to become pregnant is likely to be cost-effective and would allow reproductive health outcomes to be collected.

Research question: Is an online lifestyle coaching platform more effective at modifying periconceptional behaviours than standard advice offered by the UK National Health Service (NHS)? Design: Women with subfertility or recurrent miscarriage were recruited to a two-centre randomized controlled trial. They were randomized to either the online lifestyle coaching platform Smarter Pregnancy (intervention) or periconceptional advice provided by NHS websites (control). Participants completed a lifestyle questionnaire at baseline, 6, 12, 18 and 24 weeks, and the results were used to tailor lifestyle coaching in the intervention group. At baseline, 12 and 24 weeks, composite risk scores (CRS) were calculated. A lower CRS corresponds to a healthier lifestyle. Results: Of the 400 women recruited, 262 women were randomized (131 in each arm). At 12 weeks, a reduction in CRS (includes risk score for intake of folic acid, vegetables and fruits, smoking and alcohol) was observed in the intervention versus control arms. After correcting for baseline, the difference in the CRS between intervention and control was –0.47 (95% CI –0.97 to 0.02) at 12 weeks and –0.32 (95% CI –0.82 to 0.15) at 24 weeks. A statistically significant reduction in lifestyle risk scores was found in women with a body mass index (BMI) of 25 kg/m2 or above compared with those with a BMI below 25kg/m2. The odds of being pregnant at 24 weeks was increased in the intervention versus control (OR 2.83, 95% CI 0.35 to 57.76). Conclusions: The Smarter Pregnancy coaching platform is more effective in delivering lifestyle advice and modulating behaviours to support women with a history of subfertility or recurrent miscarriage than standard online NHS advice.

STUDY QUESTION Does frozen-thawed or fresh embryo transfer (ET) influence utero-placental (vascular) development, when studied using three-dimensional (3D) ultrasound and virtual reality imaging techniques? SUMMARY ANSWER In the first trimester, placental developmental parameters, that is, placental volume (PV) and utero-placental vascular volume (uPVV), were comparable between pregnancies resulting from frozen-thawed ET, fresh ET and natural conception; and in the second and the third trimester, uterine artery Doppler indices were lower in pregnancies after frozen-thawed ET compared to pregnancies after fresh ET and natural conception. WHAT IS KNOWN ALREADY Pregnancies after frozen-thawed ET are at risk of developing placenta-related pregnancy complications. There is strong evidence that impaired first-trimester spiral artery remodelling is involved in the pathophysiology of these complications. Studies on longitudinal placental development in pregnancies with different modes of conception, that is, after frozen-thawed ET, fresh ET or natural conception, are lacking. STUDY, DESIGN, SIZE, DURATION Women with singleton pregnancies were included before 10 weeks of gestation, between January 2017 and July 2018, as a subcohort of the ongoing Rotterdam Periconception cohort. Results were partially validated in 722 women from the total cohort, which was conducted from November 2010 onwards. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 214 women, of whom 32 conceived after frozen-thawed ET, 56 conceived after fresh ET and 126 conceived naturally, were selected. PV and uPVV measurements were obtained at 7, 9 and 11 weeks of gestation by transvaginal 3D (power Doppler) ultrasound. The uterine artery pulsatility index (UtA-PI) and resistance index (UtA-RI) were measured transvaginally at 7, 9, 11 and 13 weeks and abdominally at 22 and 32 weeks of gestation by pulsed wave Doppler ultrasound. In the validation cohort, the PV was measured in 722 women. Associations between mode of conception and placental development were studied using linear mixed models. MAIN RESULTS AND THE ROLE OF CHANCE First-trimester parameters of placental development, that is, PV, uPVV, UtA-PI and UtA-RI, were comparable between pregnancies after frozen-thawed and fresh ET and naturally conceived pregnancies. In our validation cohort, comparable results were found for PV. However, the second- and third-trimester UtA-PI and UtA-RI in pregnancies after frozen-thawed ET were significantly lower than in pregnancies after fresh ET (βUtA-PI −0.158 (95% CI: −0.268, −0.048), P = 0.005; βUtA-RI −0.052 (95% CI: −0.089, −0.015), P = 0.006). The second- and third-trimester uterine artery indices in pregnancies after fresh ET were comparable to those in pregnancies after natural conception. LIMITATIONS, REASONS FOR CAUTION The main limitation of this study is the lack of power to optimally detect differences in placental development and placenta-related pregnancy outcomes between pregnancies after different modes of conception. Moreover, our population was selected from a tertiary hospital and included a relatively limited number of pregnancies. Therefore, external validity of the results should be confirmed in a larger sample size. WIDER IMPLICATIONS OF THE FINDINGS These findings indicate no significant impact of conception mode on early placental development and a beneficial impact for frozen-thawed ET on the second- and third-trimester Doppler indices. This suggests that frozen-thawed ET may not be as detrimental for placental perfusion as previous research has demonstrated. As the number of clinics applying the ‘freeze-all strategy’ increases, future research should focus on establishing the optimal uterine environment, with regards to hormonal preparation, prior to ET to reduce placental-related pregnancy complications after frozen-thawed ET. STUDY FUNDING/COMPETING INTEREST(S) This research was funded by the Erasmus MC Medical Research Advisor Committee’s ‘Health Care Efficiency Research’ program and the department of Obstetrics and Gynaecology of the Erasmus MC, University Medical Center, Rotterdam, The Netherlands. JSEL reports grants and personal fees from Ferring, personal fees from Titus Healthcare, grants and personal fees from Ansh Labs, grants from NIH, grants from Dutch Heart Association and grants from ZonMW outside the submitted work. None of the other authors have a conflict of interest. TRIAL REGISTRATION NUMBER Registered at the Dutch Trial Register (NTR6684).

Background Hypertensive disorders of pregnancy (HDP), including pregnancy-induced hypertension (PIH), Preeclampsia (PE), Hemolysis Elevated Liver enzymes and Low Platelets (HELLP) and chronic hypertension, are leading causes of maternal and perinatal morbidity and mortality. Although the pathophysiology of HDP is complex, preconceptional weight reduction in obese women might reduce these complications. We conducted a systematic review and meta-analysis to investigate the effectiveness of preconceptional weight loss by lifestyle intervention or bariatric surgery in overweight and obese women and the reduction of the risk of HDP. Methods and results Databases are searched until September 2019 resulting in 2547 articles: 110 full-text analysis and 29 detailed analysis. Reduced risks were shown for HDP in seven articles (n = 4381) of weight loss after lifestyle intervention or bariatric surgery (OR range 0.10-0.64), for PIH in four articles (n = 46,976) (OR range 0.14-0.79), and for PE in seven articles (n = 169,734) (OR range 0.14-0.84). The stratified analysis of weight loss after lifestyle intervention and bariatric surgery shows comparable results. The meta-analysis of 20 studies of the effectiveness of lifestyle intervention and bariatric surgery revealed reduced risks of HDP (OR 0.45 (95% CI 0.32-0.63)), PIH (OR 0.61 (95%CI 0.44-0.85)) and PE (OR 0.67 (95%CI 0.51-0.88)). Conclusions Preconceptional weight loss after lifestyle intervention or bariatric surgery is effective in reducing risks of HDP, PIH and PE, and emphasizes the need to optimize weight in overweight and obese women with a child wish. More research is recommended to investigate short-term and long-term beneficial and harmful side-effects of these interventions on maternal and offspring health.

Pregnancy demands major cardiovascular, renal and endocrine changes to provide an adequate blood supply for the growing fetus. The renin-angiotensin-aldosterone system plays a key role in this adaptation process. One of its components, prorenin, is released in significant amounts from the ovary and uteroplacental unit. This review describes the sources of prorenin in the periconception period and in pregnancy, including its modulation by in-vitro fertilization protocols, and discusses its potential effects, among others focusing on preeclampsia. It ends with discussing the long-term consequences, even in later life, of inappropriate renin-angiotensin-aldosterone system activity in pregnancy and offers directions for future research. Ultimately, a full understanding of the role of prorenin periconceptionally and during pregnancy will help to develop tools to diagnose and/or prevent reproductive complications.

BACKGROUND: Periconception interactions between maternal conditions and environmental and genetic factors are involved in the pathogenesis and prevention of neural tube defects (NTD), such as spina bifida. These factors have in common that they can impair the oxidative pathway, resulting in excessive (chronic) oxidative stress and inflammation. METHODS: Review of the literature concerning underlying mechanisms and biomarkers of aging particularly during reproduction. A number of molecular markers for biological aging have been identified, including telomere length (TL). Excessive telomere shortening is an index of senescence, causes genomic instability and is associated with a higher risk of age-related diseases. Furthermore, TL shortening is associated with the similar environmental and lifestyle exposures associated with NTD risk. RESULTS: Embryonic mice deficient in the telomerase gene show shorter TL and failure of closure of the neural tube as the main defect, suggesting that this developmental process is among the most sensitive to telomere loss and chromosomal instability. CONCLUSIONS: From this background, we hypothesize that preconceptional long term exposure to harmful environmental and lifestyle risk factors accelerates a woman's aging process, which can be measured by TL, and thereby her underlying risk of NTD offspring. Alternatively, it might be that women with an increased NTD risk already exhibit a more advanced biological age before the onset of pregnancy compared to women of identical calendar age. ispartof: Birth Defects Research vol:112 issue:9 pages:645-651 ispartof: location:United States status: published

Scope The effectiveness of maternal folate in reducing the risk of congenital malformations during pregnancy is well established. However, the role of the paternal folate status is scarcely investigated. The aim of this study is to investigate the evidence of associations between the paternal folate status and sperm quality, sperm epigenome, and pregnancy outcomes. Methods and results Databases are searched up to December 2017 resulting in 3682 articles, of which 23 are retrieved for full‐text assessment. Four out of thirteen human and two out of four animal studies show positive associations between folate concentrations and sperm parameters. An additional meta‐analysis of four randomized controlled trials in subfertile men shows that the sperm concentration increases (3.54 95% confidence interval (CI) [−1.40 to 8.48]) after 3–6 months of 5 mg folic acid use per day compared to controls. Moreover, two out of two animal and one out of three human studies show significant alterations in the overall methylation of the sperm epigenome. One animal and one human study show associations between low folate intake and an increased risk of congenital malformations. Conclusions This systematic review and meta‐analysis shows evidence of associations between paternal folate status and sperm quality, fertility, congenital malformations, and placental weight., The aim of this study is to investigate and provide an overview of the evidence of associations between the periconceptional paternal folate status and folic acid supplement use and sperm quality, sperm epigenome, and pregnancy outcomes in both human and animal studies. It is concluded that more research is necessary into the periconceptional roles of paternal micronutrients.

Background During the turbulent postpartum period, there is an urgent need by parents for support and information regarding the care for their infant. In the Netherlands, professional support is provided during the first 8 days postpartum and for a maximum of 8 hours a day. This care is delivered by maternity care assistants (MCAs). Despite the availability of this extensive care, a majority of women prefer to make use of a lesser amount of postpartum care. After this period, access to care is less obvious. Where parents are automatically offered care in the first 8 days after birth, they must request care in the period thereafter. To compensate for a possible gap in information transfer, electronic health (eHealth) can be a valuable, easily accessible addition to regular care. Objective We explored the needs and preferred content by new parents and health care professionals of a web-based platform dedicated to the postpartum period and identified barriers and facilitators for using such a platform. Methods We conducted 3 semistructured focus groups among (1) parents of newborns, (2) MCAs, and (3) clinicians and administrators in maternity care. A topic list based on a framework designed for innovation processes was used. Thematic content analysis was applied. Results In the focus group for parents, 5 mothers and 1 male partner participated. A total of 6 MCAs participated in the second focus group. A total of 5 clinicians and 2 administrators—a member of a stakeholder party and a manager of a maternity care organization—participated in the third focus group. All user groups underlined that a platform focusing on the postpartum period was missing in current care, especially by parents experiencing a gap following the intensive care ending after the first week of childbirth. Parents indicated that they would perceive a postpartum platform as a proper source of reliable information on topics regarding breastfeeding, growth, and developmental milestones, but also as a tool to support them in seeking care with appropriate professionals. They also emphasized the need to receive personalized information and the opportunity to ask questions via the platform. MCAs acknowledged added value of providing additional information on topics that they address during the early postpartum period. MCAs as well as clinicians and administrators would guide parents to such a platform for additional support. All user groups experienced disadvantages of using an authentication procedure and filling out extra questionnaires to receive tailored information. Conclusions Our research shows that parents of newborns, MCAs, and clinicians and administrators foresee the additional value of a web-based postpartum platform for at least the whole postpartum period. The platform should be easily accessible and personalized. Content on the platform should contain information regarding breastfeeding, growth, and developmental milestones. A chat function with professionals could be considered as an option.

Objective: We aimed to validate a food-frequency questionnaire (FFQ) for Dutch pregnant women, against three 24 h-recalls and blood concentrations of B-vitamins and fatty acids, using the method of triads. Methods: We included 83 pregnant women from the general population of Rotterdam, the Netherlands, at a median gestational age of 15.6 weeks. Participants completed three non-consecutive 24 h-recalls, and subsequently filled out the 293-item FFQ. Participants provided blood samples from which we analyzed serum folate and vitamin B12, as well as red blood cell folate, linoleic acid, and total saturated, monounsaturated, and polyunsaturated fatty acids. Results: Estimated energy intake did not differ between the FFQ and 24 h-recalls. Deattenuated Pearson&rsquo, s correlation coefficients, between energy-adjusted nutrient intake estimates from the FFQ and the 24 h-recalls, ranged from 0.41 (fat) to 0.88 (fiber) for macronutrients, and were around 0.6 for most micronutrients, except for vitamin E (0.27). Using the triad method, we obtained validity coefficients of 0.86 (95% Confidence Interval (CI) 0.36, 1.00) for serum folate, 0.86 (95% CI 0.18, 1.00) for red blood cell folate, and 1.00 (95% CI 0.42, 1.00) for vitamin B12. Validity coefficients for serum fatty acids ranged from 0.22 to 0.67. Conclusion: This FFQ is a reliable tool for estimating intake of energy, macronutrients, folate and vitamin B12 among women in mid-pregnancy.

The preconceptional presence of microbiota in the female and male reproductive organs suggests that fertilization is taking place in a nonsterile environment and contributes to reproductive success. The concept of embryonic development in a sterile uterus has also been challenged with recent reports of the existence of a microbiome of the placenta, amniotic fluid and the fetal gut in normal, uncomplicated pregnancies. The maternal origins of the microbiota colonising the fetus and its surroundings are unknown as are the mechanisms of maternal-to-fetal transfer. In this review, we aim to highlight the preconception male and female microbiome, the maternal vaginal and gut microbiome during pregnancy and the fetal microbiome, including their possible roles in reproduction, and maternal and neonatal pregnancy outcome.

The main risk factors for important reproductive health issues such as subfertility and perinatal mortality largely originate in the periconception period. To evaluate associations between modifiable maternal lifestyle factors and periconception outcomes, a systematic search was conducted for relevant studies published from 1990 to February 2017 on Embase, Medline, Web of Science, Cochrane database, PubMed and Google Scholar. The initial search identified 6166 articles, of which 49 studies were eligible for inclusion. Fecundity (the capacity to have a live birth) showed significant inverse associations with smoking, alcohol use and poor diet. Studies regarding time to pregnancy showed a decline in fecundity ratios (the monthly conception rate among exposed relative to unexposed couples) with increasing body mass index (BMI). Furthermore, risk of first-trimester miscarriage was found to be increased in smokers, alcohol and caffeine consumers, and with increasing BMI. Vitamin supplement use showed a decrease in this risk. This review demonstrates that maternal modifiable lifestyle factors affect periconception outcomes. If couples planning a pregnancy are more aware and supported to adopt healthy lifestyles during the periconceptional ‘window of opportunity’, short-term reproductive health as well as health in later life and even of future generations can be further improved.

textabstractAim: In anatomic studies of the embryo, it has been established that during the development of the lower limb, several changes in foot position can be observed defined as a temporary ‘physiological clubfoot’. The aim of this study was to develop and test a measurement tool for objective documentation of the first trimester foot position in vivo and made an attempt to create a chart for first trimester foot position. Methods: We developed a virtual orthopedic protractor for measuring foot positioning using three-dimensional virtual reality visualization. Three-dimensional ultrasound volumes of 112 pregnancies of women examined during the first trimester were studied in a BARCO I-Space. The frontal angle (plantar flexion) and the lateral angle (adduction) between the leg and foot were measured from 8 until 13 weeks gestational age. Results: We observed that the frontal angle steadily decreases, whereas the lateral angle first increases, resulting in transient physiological clubfeet position at 10- to 11-week gestation, followed by a decrease to a normal foot position. Conclusion: A transient clubfoot position is present during the normal development of the lower limbs, and it has been measured in vivo for the first time. This study emphasizes that a diagnosis of congenital clubfoot should not be made in the first trimester of pregnancy.

Background Worldwide, placenta-related complications contribute to adverse pregnancy outcomes, such as pre-eclampsia, fetal growth restriction and preterm birth, with implications for the future health of mothers and offspring. The placenta develops in the periconception period and forms the interface between mother and embryo/fetus. An unhealthy periconceptional maternal lifestyle, such as smoking, alcohol and under- and over-nutrition, can detrimentally influence placental development and function. Objective and rationale The impact of maternal lifestyle on placental health is largely unknown. Therefore, we aim to summarize the evidence of the impact of periconceptional maternal lifestyle on clinical features and biomarkers of placental development and function throughout pregnancy. Search methods A comprehensive search in Medline, Embase, Pubmed, The Cochrane Library Web of Science and Google Scholar was conducted. The search strategy included keywords related to the maternal lifestyle, smoking, alcohol, caffeine, nutrition (including folic acid supplement intake) and body weight. For placental markers throughout pregnancy, keywords related to ultrasound imaging, serum biomarkers and histological characteristics were used. We included randomized controlled trials and observational studies published between January 2000 and March 2017 and restricted the analysis to singleton pregnancies and maternal periconceptional lifestyle. Methodological quality was scored using the ErasmusAGE tool. A protocol of this systematic review has been registered in PROSPERO International prospective register of systematic reviews (PROSPERO 2016:CRD42016045596). Outcomes Of 2593 unique citations found, 82 studies were included. The median quality score was 5 (range: 0-10). The findings revealed that maternal smoking was associated with lower first-trimester placental vascularization flow indices, higher second- and third-trimester resistance of the uterine and umbilical arteries and lower resistance of the middle cerebral artery. Although a negative impact of smoking on placental weight was expected, this was less clear. Alcohol use was associated with a lower placental weight. One study described higher second- and third-trimester placental growth factor (PlGF) levels after periconceptional alcohol use. None of the studies looked at caffeine intake. Adequate nutrition in the first trimester, periconceptional folic acid supplement intake and strong adherence to a Mediterranean diet, were all associated with a lower resistance of the uterine and umbilical arteries in the second and third trimester. A low caloric intake resulted in a lower placental weight, length, breadth, thickness, area and volume. Higher maternal body weight was associated with a larger placenta measured by ultrasound in the second and third trimester of pregnancy or weighed at birth. In addition, higher maternal body weight was associated with decreased PlGF-levels. Wider implications Evidence of the impact of periconceptional maternal lifestyle on placental health was demonstrated. However, due to poorly defined lifestyle exposures and time windows of investigation, unstandardized measurements of placenta-related outcomes and small sample sizes of the included studies, a cautious interpretation of the effect estimates is indicated. We suggest that future research should focus more on physiological consequences of unhealthy lifestyle during the critical periconception window. Moreover, we foresee that new evidence will support the development of lifestyle interventions to improve the health of mothers and their offspring from the earliest moment in life.

Previously, embryonic growth has been assumed to be uniform, but in recent years, it has become more clear that genetic and environmental factors may influence the intrauterine environment and therefore embryonic growth trajectories as well as pregnancy course and outcome. The objective of this study was to investigate associations between modifiable maternal nutrition and lifestyle factors during the periconception period and embryonic growth. We established a prospective cohort including 342 women less than 13 weeks pregnant. At enrollment, women filled out a questionnaire regarding demographic and medical data and a validated food frequency questionnaire. Participants received multiple 3-dimensional ultrasound examinations up until the 12th week of pregnancy, and crown–rump length (CRL) and embryonic volume (EV) were measured offline using V-Scope Virtual Reality software (version 1.0.0) in a Barco I-Space. Associations between maternal periconception vegetable and fruit intake, folic acid supplement use, smoking, and alcohol consumption and embryonic growth measurements were assessed by linear mixed models adjusted for potential confounders. No or postconception initiation of folic acid supplement use was significantly associated with a 0.76 mm (−7.8%) and 1.63 mm (−3.7%) smaller CRL and a 0.01 cm3 (−19.5%) and 0.86 cm3 (−12.2%) smaller EV at 7+0 and 11+0 weeks of gestation, respectively. Smoking, alcohol consumption, and inadequate fruit and vegetable intake showed weaker associations with embryonic growth parameters. These results emphasize the influence of periconceptional maternal folic acid supplement use on embryonic growth. Results regarding maternal nutrition and lifestyle factors also suggest an association with embryonic growth, but this has to be confirmed in a larger study.

Embryonic growth is often impaired in miscarriages. It is postulated that derangements in embryonic growth result in abnormalities of the embryonic curvature. This study aims to create first trimester reference charts of the human embryonic curvature and investigate differences between ongoing pregnancies and miscarriages. Weekly ultrasonographic scans from ongoing pregnancies and miscarriages were used from the Rotterdam periconceptional cohort and a cohort of recurrent miscarriages. In 202 ongoing pregnancies and 33 miscarriages, first trimester crown rump length and total arch length were measured to assess the embryonic curvature. The results show that the total arch length increases and shows more variation with advanced gestation. The crown rump length/total arch length ratio shows a strong increase from 8+0 to 10+0 weeks and flattening thereafter. No significant difference was observed between the curvature of embryos of ongoing pregnancies and miscarriages. The majority of miscarried embryos could not be measured. Therefore, this technique is too limited to recommend the measurement of the embryonic curvature in clinical practice.

Poor lifestyle behaviors impact (pre)pregnant women by affecting pregnancy outcomes and offspring health. This systematic review provides an overview of psychological therapies to support lifestyle behavior changes among (pre)pregnant women. Scientific databases were searched from their inception to 20 December 2020 for studies investigating the effects of psychological therapies on improvements in lifestyle behaviors. Studies were eligible if they included (pre)pregnant women, examined the effects of a psychological therapy on at least one lifestyle behavior and used a control group receiving usual pregnancy care or a non-psychological intervention. Lifestyle behaviors of interest were dietary intake, physical activity, smoking, alcohol consumption, drug use, body weight loss and body weight gain during pregnancy. Pregnancy complications were included as outcome measures. Motivational interviewing (MI) (n=21), cognitive behavioral therapy (CBT) (n=8), incentive-based contingency management (IBCM) (n=9), mindfulness (n=1) and hypnosis (n=1) were investigated as lifestyle behavior interventions. The findings revealed that MI was effective in reducing (self-reported) smoking and alcohol consumption and restricting gestational weight gain (GWG). CBT was only studied as an intervention to restrict GWG and the results predominantly confirmed its effectiveness. IBCM showed the strongest effect on reducing smoking and substance use. The studies using hypnosis or mindfulness to reduce smoking or restrict GWG, respectively, showed no associations. The use of psychological therapies to improve lifestyle behaviors among (pre-)pregnant women is new and the scientific proof is promising. Before wide implementation is legitimated, more evidence is needed on the consequences of lifestyle change for pregnancy outcomes.

Background Interactions between genetic and environmental factors, including modifiable maternal nutrition and lifestyle, play a significant role in the pathogenesis of most congenital heart defects (CHD). The aim of this study was to investigate associations between periconceptional maternal vitamin D status and the prevalence of CHD in offspring. Methods A case-control study was performed in 345 mothers of a child with CHD and 432 mothers of a child without CHD from four tertiary hospitals in the Netherlands between 2003 and 2005. Approximately 15 months after pregnancy mothers filled out questionnaires regarding general characteristics and periconceptional lifestyle. Maternal blood was obtained to determine serum 25-hydroxyvitamin D and lipid concentrations. The 25-hydroxyvitamin D concentration was stratified into a deficient 75 nmol/l status. Logistic regression was performed to study associations between vitamin D status and CHD risk, adjusted for maternal age, body mass index, ethnicity, smoking and total cholesterol concentration. Results Case mothers less often had an adequate vitamin D status compared with controls (27% vs. 38%; p = 0.002). The use of multivitamin supplements, ethnicity, season and body mass index were associated with vitamin D concentrations. A moderate (odds ratio 1.58, [95%CI 1.08, 2.32]) and deficient (odds ratio 2.15, [95%CI 1.44–3.19]) vitamin D status were associated with CHD in offspring. Conclusion A compromised maternal vitamin D status is associated with an approximately two-fold increased prevalence of CHD in offspring. Therefore, improvement of the periconceptional maternal vitamin D status is recommended.

Background/objectives: Maternal dietary patterns were associated with embryonic growth and congenital anomalies. We aim to evaluate associations between early first trimester maternal dietary patterns and embryonic morphological development among pregnancies with non-malformed outcome. Subjects/methods: A total of 228 strictly dated, singleton pregnancies without congenital malformations were enrolled in a periconceptional hospital-based cohort. Principal component analysis was performed to extract early first trimester maternal dietary patterns from food frequency questionnaires. Serial transvaginal three-dimensional ultrasound (3D US) scans were performed between 6+0 and 10+2 gestational weeks and internal and external morphological criteria were used to define Carnegie stages in a virtual reality system. Associations between dietary patterns and Carnegie stages were investigated using linear mixed models. Results: A total of 726 3D US scans were included (median: three scans per pregnancy). The ‘high fish and olive oil and low meat’ dietary pattern was associated with accelerated embryonic development in the study population (β = 0.12 (95%CI: 0.00; 0.24), p < 0.05). Weak adherence to this dietary pattern delayed embryonic development by 2.1 days (95%CI: 1.6; 2.6) compared to strong adherence. The ‘high vegetables, fruit and grain’ dietary pattern accelerated embryonic development in the strictly dated spontaneous pregnancy subgroup without adjustment for energy intake. Conclusions: Early first trimester maternal dietary patterns impacts human embryonic morphological development among pregnancies without congenital malformations. The clinical meaning of delayed embryonic development needs further investigation.