The one-carbon metabolism as an underlying pathway for placental DNA methylation - a systematic review.

Epigenetic modifications, including DNA methylation, are proposed mechanisms explaining the impact of parental exposures to foetal development and lifelong health. Micronutrients including folate, choline, and vitamin B12 provide methyl groups for the one-carbon metabolism and subsequent DNA methylation processes. Placental DNA methylation changes in response to one-carbon moieties hold potential targets to improve obstetrical care. We conducted a systematic review on the associations between one-carbon metabolism and human placental DNA methylation. We included 22 studies. Findings from clinical studies with minimal ErasmusAGE quality score 5/10 (n = 15) and in vitro studies (n = 3) are summarized for different one-carbon moieties. Next, results are discussed per study approach: (1) global DNA methylation (n = 9), (2) genome-wide analyses (n = 4), and (3) gene specific (n = 14). Generally, one-carbon moieties were not associated with global methylation, although conflicting outcomes were reported specifically for choline. Using genome-wide approaches, few differentially methylated sites associated with S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), or dietary patterns. Most studies taking a gene-specific approach indicated site-specific relationships depending on studied moiety and genomic region, specifically in genes involved in growth and development including LEP, NR3C1, CRH, and PlGF; however, overlap between studies was low. Therefore, we recommend to further investigate the impact of an optimized one-carbon metabolism on DNA methylation and lifelong health.

Preconception maternal gastric bypass surgery and the impact on fetal growth parameters.

BACKGROUND: Bariatric surgery is increasingly performed in women of reproductive age. As bariatric surgery will result in postoperative rapid catabolic weight loss which potentially leads to fetal malnutrition and directly related impaired intra-uterine growth, it is advised to postpone pregnancy for at least 12-18 months after surgery. OBJECTIVES: To investigate the consequences of preconception gastric bypass surgery (pGB) on fetal growth parameters and maternal pregnancy outcome. SETTING: Maasstad Hospital, The Netherlands, general hospital and Erasmus Medical Center, The Netherlands, university hospital. METHODS: We included 97 pGB pregnancies (Maasstad hospital) and 440 non-bariatric pregnancies (Rotterdam Periconception cohort, Erasmus Medical Center). Longitudinal second and third trimester fetal growth parameters (head circumference, biparietal diameter, femur length, abdominal circumference, estimated fetal weight) were analyzed using linear mixed models, adjusting for covariates and possible confounders. Fetal growth and birthweight in pGB pregnancies were compared to non-bariatric pregnancies and Dutch reference curves. Maternal pregnancy outcome in the pGB group was compared to non-bariatric pregnancies. RESULTS: All fetal growth parameters of pGB pregnancies were significantly decreased at 20 weeks' gestation (P < .001) and throughout the remaining part of pregnancy (P < .05) compared with non-bariatric pregnancies (crude and adjusted models). In our cohort, gestational weight gain was not significantly associated with birthweight corrected for gestational age. Birthweight was significantly lower in pGB pregnancies (estimate -241 grams [95% CI, -342.7 to -140.0]) with a 2-fold increased risk of small-for-gestational-age (SGA) (adjusted odds ratio 2.053 [95% CI, 1.058 to 3.872]). Compared to the non-bariatric pregnancies, we found no significant differences in maternal pregnancy outcome. CONCLUSIONS: PGB is associated with overall reduced fetal growth trajectories and a 2-fold increased risk of SGA, without significant adverse consequences for maternal pregnancy outcome. We recommend close monitoring of fetal growth after pGB.

The prevalence of thyroid dysfunction and hyperprolactinemia in women with PCOS.

Introduction: Ovulatory dysfunction is usually caused by an endocrine disorder, of which polycystic ovary syndrome (PCOS) is the most common cause. PCOS is usually associated with estrogen levels within the normal range and can be characterized by oligo-/anovulation resulting in decreased progesterone levels. It is suggested that decreased progesterone levels may lead to more autoimmune diseases in women with PCOS. In addition, it is often claimed that there is an association between hyperprolactinemia and PCOS. In this large well-phenotyped cohort of women with PCOS, we have studied the prevalence of thyroid dysfunction and hyperprolactinemia compared to controls, and compared this between the four PCOS phenotypes. Methods: This retrospective cross-sectional study contains data of 1429 women with PCOS and 299 women without PCOS. Main outcome measures included thyroid stimulating hormone (TSH), Free Thyroxine (FT4), and anti-thyroid peroxidase antibodies (TPOab) levels in serum, the prevalence of thyroid diseases and hyperprolactinemia. Results: The prevalence of thyroid disease in PCOS women was similar to that of controls (1.9% versus 2.7%; P = 0.39 for hypothyroidism and 0.5% versus 0%; P = 0.99 for hyperthyroidism). TSH levels were also similar (1.55 mIU/L versus 1.48 mIU/L; P = 0.54). FT4 levels were slightly elevated in the PCOS group, although within the normal range (18.1 pmol/L versus 17.7 pmol/L; P < 0.05). The prevalence of positive TPOab was similar in both groups (5.7% versus 8.7%; P = 0.12). The prevalence of hyperprolactinemia was similarly not increased in women with PCOS (1.3%% versus 3%; P = 0.05). In a subanalysis of 235 women with PCOS and 235 age- and BMI-matched controls, we found no differences in thyroid dysfunction or hyperprolactinemia. In according to differences between PCOS phenotypes, only the prevalence of subclinical hypothyroidism was significantly higher in phenotype B (6.3%, n = 6) compared to the other phenotypes. Conclusion: Women with PCOS do not suffer from thyroid dysfunction more often than controls. Also, the prevalence of positive TPOab, being a marker for future risk of thyroid pathology, was similar in both groups. Furthermore, the prevalence of hyperprolactinemia was similar in women with PCOS compared to controls.

Stimulating the Uptake of Preconception Care by Women With a Vulnerable Health Status Through mHealth App-Based Nudging (Pregnant Faster): Cocreation Design and Protocol for a Cohort Study.

BACKGROUND: Women with a low socioeconomic status often have a vulnerable health status due to an accumulation of health-deteriorating factors such as poor lifestyle behaviors, including inadequate nutrition, mental stressors, and impaired health literacy and agency, which puts them at an unnecessary high risk of adverse pregnancy outcomes. Adequately preparing for pregnancy through preconception care (PCC) uptake and lifestyle improvement can improve these outcomes. We hypothesize that nudging is a successful way of encouraging engagement in PCC. A nudge is a behavioral intervention that changes choice behavior through influencing incentives. The mobile health (mHealth) app-based loyalty program Pregnant Faster aims to reward women in an ethically justified way and nudges to engage in pregnancy preparation by visiting a PCC consultation. OBJECTIVE: Here, we first describe the process of the cocreation of the mHealth app Pregnant Faster that aims to increase engagement in pregnancy preparation by women with a vulnerable health status. Second, we describe the cohort study design to assess the feasibility of Pregnant Faster. METHODS: The content of the app is based on the eHealth lifestyle coaching program Smarter Pregnancy, which has proven to be effective in ameliorating preconceptional lifestyle behaviors (folic acid, vegetables, fruits, smoking, and alcohol) and an interview study pertaining to the preferences of the target group with regard to an mHealth app stimulating PCC uptake. For moral guidance on the design, an ethical framework was developed based on the bioethical principles of Beauchamp and Childress. The app was further developed through iterative cocreation with the target group and health care providers. For 4 weeks, participants will engage with Pregnant Faster, during which opportunities will arise to earn coins such as reading informative blogs and registering for a PCC consultation. Coins can be spent on small fun rewards, such as folic acid, fruits, and mascara. Pregnant Faster's feasibility will be tested in a study including 40 women aged 18 to 45 years, who are preconceptional or <8 weeks pregnant, with a low educational level, and living in a deprived neighborhood. The latter 2 factors will serve as a proxy of a low socioeconomic status. Recruitment will take place through flyers, social media, and health care practices. After finalization, participants will evaluate the app through the "mHealth App Usability Questionnaire" and additional interviews or questionnaires. RESULTS: Results are expected to be published by December 2023. CONCLUSIONS: Pregnant Faster has been designed through iterative cocreation with the target group and health care professionals. With the designed study, we will test Pregnant Faster's feasibility. If overall user satisfaction and PCC uptake is achieved, the app will be further developed and the cohort will be continued with an additional 400 inclusions to establish effectiveness. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/45293.

Periconceptional biomarkers for maternal obesity: a systematic review.

Periconceptional maternal obesity is linked to adverse maternal and neonatal outcomes. Identifying periconceptional biomarkers of pathways affected by maternal obesity can unravel pathophysiologic mechanisms and identify individuals at risk of adverse clinical outcomes. The literature was systematically reviewed to identify periconceptional biomarkers of the endocrine, inflammatory and one-carbon metabolic pathways influenced by maternal obesity. A search was conducted in Embase, Ovid Medline All, Web of Science Core Collection and Cochrane Central Register of Controlled Trials databases, complemented by manual search in PubMed until December 31st, 2020. Eligible studies were those that measured biomarker(s) in relation to maternal obesity, overweight/obesity or body mass index (BMI) during the periconceptional period (14 weeks preconception until 14 weeks post conception). The ErasmusAGE score was used to assess the quality of included studies. Fifty-one articles were included that evaluated over 40 biomarkers. Endocrine biomarkers associated with maternal obesity included leptin, insulin, thyroid stimulating hormone, adiponectin, progesterone, free T4 and human chorionic gonadotropin. C-reactive protein was associated with obesity as part of the inflammatory pathway, while the associated one-carbon metabolism biomarkers were folate and vitamin B12. BMI was positively associated with leptin, C-reactive protein and insulin resistance, and negatively associated with Free T4, progesterone and human chorionic gonadotropin. Concerning the remaining studied biomarkers, strong conclusions could not be established due to limited or contradictory data. Future research should focus on determining the predictive value of the optimal set of biomarkers for their use in clinical settings. The most promising biomarkers include leptin, adiponectin, human chorionic gonadotropin, insulin, progesterone and CRP.

Periconceptional maternal folate status and the impact on embryonic head and brain structures: the Rotterdam Periconceptional Cohort.

RESEARCH QUESTION: Does periconceptional maternal folate status influence the size of human embryonic head and brain structures? DESIGN: The study population was selected from the Rotterdam Periconceptional Cohort conducted at the Erasmus MC. Three-dimensional (3D) ultrasound scans were performed at 9 and 11 weeks of gestational age. Using 3D ultrasound datasets, head volume, head circumference, diencephalon (DTD), mesencephalon (MTD) and left/right telencephalon (TTL/TTR) measurements were performed offline using a virtual reality technique and specialized 3D software. Maternal venous blood samples were taken at study entry to determine red blood cell (RBC) folate. Linear regression models were applied to investigate associations between RBC folate status and embryonic head and brain structures adjusted for gestational age, alcohol use, smoking, maternal age and mode of conception. RESULTS: RBC folate measurements were available for 144 of the 166 singleton pregnancies eligible for analysis. RBC folate quartiles were defined: 466-1078 nmol/l (Q1), 1079-1342 nmol/l (Q2), 1343-1594 nmol/l (Q3), 1595-2919 nmol/l (Q4), with Q3 being used as reference. At 11 weeks of gestational age, head volume was largest in Q1 (ß = 0.866; P = 0.004) and Q4 (ß = 0.764; P = 0.007). In addition, head circumference at 11 weeks of gestational age was significantly larger in Q4 (ß = 2.745; P = 0.03). There were no statistical significantly associations between the RBC folate quartiles and the sizes of the DTD, MTD, TTL and TTR. CONCLUSIONS: U-shaped associations were shown between the periconceptional maternal RBC folate status and embryonic head volume and head circumference. The clinical implication of these findings needs further investigation.

A higher preconceptional paternal body mass index influences fertilization rate and preimplantation embryo development.

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 < 25.0), 94 overweight (BMI 25-29.9), and 41 obese (BMI ≥ 30). These men were part of a couple that underwent IVF/ICSI treatment with ejaculated sperm after which 757 embryos were cultured in a time-lapse incubator. The main outcome parameters consisted of fertilization rate, embryo developmental morphokinetics, embryo quality assessed by a time-lapse prediction algorithm (KIDScore), and live birth rate. RESULTS: A higher paternal BMI was associated with faster development of the preimplantation embryo, especially during the first cleavage divisions (t2: -0.11 h (p = 0.05) and t3: -0.19 h (p = 0.01)). Embryo quality using the KIDScore was not altered. The linear regression analysis, after adjustment for confounders (paternal age, ethnicity, smoking, alcohol use, education, total motile sperm count, and maternal age and BMI), showed an inverse association between paternal BMI and fertilization rate (effect estimate: -0.01 (p = 0.002)), but not with the live birth rate. DISCUSSION AND CONCLUSION: Our data demonstrate that a higher preconceptional paternal BMI is associated with a reduced fertilization rate in IVF/ICSI treatment. Our findings underline the importance of a healthy paternal weight during the preconception period.

Impact of Bariatric surgery on EmbrYONic, fetal and placental Development (BEYOND): protocol for a prospective cohort study embedded in the Rotterdam periconceptional cohort.

INTRODUCTION: The 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 ANALYSIS: We 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 <12+0 weeks pregnant, ≥18 and ≤45 years of age, who have undergone bariatric surgery (cases) or without prior bariatric surgery (controls) and their male partners. Medical charts will be reviewed and questionnaires regarding general health, lifestyle and food intake will be collected. Moreover, we will perform serial three-dimensional ultrasounds to assess embryonic growth and placental development and two-dimensional ultrasounds for fetal growth assessment. The microbiome, including the virome, and blood samples will be sampled during the preconception period and in each trimester. Multivariable linear mixed model analyses will be used to assess the associations between bariatric surgery and pregnancy outcomes. ETHICS AND DISSEMINATION: This 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 NUMBER: NL8217 (www.trialregister.nl).

The effects of bariatric surgery on periconception maternal health: a systematic review and meta-analysis.

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.

IVF with or without ICSI and the impact on human embryonic brain development: the Rotterdam Periconceptional Cohort.

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 < 0.01) and TTR (ß = 0.075, 95% CI = 0.001; 0.149, P < 0.05) sizes were larger in IVF/ICSI pregnancies. In addition, smoking also resulted in larger TTL measurements at 11 weeks of GA (ß = 0.095, 95% CI= 0.005; 0.186, P < 0.05). 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.

Polycystic Ovary Syndrome: A Brain Disorder Characterized by Eating Problems Originating during Puberty and Adolescence.

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.

Determinants of Maternal Renin-Angiotensin-Aldosterone-System Activation in Early Pregnancy: Insights From 2 Cohorts.

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.

First effective mHealth nutrition and lifestyle coaching program for subfertile couples undergoing in vitro fertilization treatment: a single-blinded multicenter randomized controlled trial.

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. NETHERLANDS TRIAL REGISTER NUMBER: NTR4150.

Preconceptional Maternal Vegetable Intake and Paternal Smoking Are Associated with Pre-implantation Embryo Quality.

Inadequate nutrition and lifestyle behaviors, particularly during the periconception period, are associated with a negative impact on embryonic and subsequent fetal development. We investigated the associations between parental nutritional and lifestyle factors and pre-implantation embryo development. A total of 113 women and 41 partners, with a corresponding 490 embryos, who underwent intracytoplasmic sperm injection (ICSI) treatment subscribed to the mHealth coaching platform "Smarter Pregnancy." At baseline, nutrition and lifestyle behaviors (intake of fruits, vegetables, folic acid, and smoking and alcohol use) were identified and risk scores were calculated. A lower risk score represents healthier behavior. As outcome measure, a time-lapse morphokinetic selection algorithm (KIDScore) was used to rank pre-implantation embryo quality on a scale from 1 (poor) to 5 (good) after being cultured in the Embryoscope™ time-lapse incubator until embryonic day 3. To study the association between the nutritional and lifestyle risk scores and the KIDScore in men and women, we used a proportional odds model. In women, the dietary risk score (DRS), a combination of the risk score of fruits, vegetables, and folic acid, was negatively associated with the KIDScore (OR 0.86 (95% CI 0.76 to 0.98), p = 0.02). This could mainly be attributed to an inadequate vegetable intake (OR 0.76 (95% CI 0.59 to 0.96), p = 0.02). In men, smoking was negatively associated with the KIDscore (OR 0.53 (95% CI 0.33 to 0.85), p < 0.01). We conclude that inadequate periconceptional maternal vegetable intake and paternal smoking significantly reduce the implantation potential of embryos after ICSI treatment. Identifying modifiable lifestyle risk factors can contribute to directed, personalized, and individual recommendations that can potentially increase the chance of a healthy pregnancy.

Preconception telomere length as a novel maternal biomarker to assess the risk of spina bifida in the offspring.

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.

Lower S-adenosylmethionine levels and DNA hypomethylation of placental growth factor (PlGF) in placental tissue of early-onset preeclampsia-complicated pregnancies.

INTRODUCTION: The pathophysiology of preeclampsia is largely unknown. Serum placental induced growth factor (PlGF) levels are decreased during second trimester pregnancy. Aberrant DNA methylation is suggested to be involved in the etiology of preeclampsia (PE). We hypothesize that DNA methylation is altered in PE placentas determined the methylation index by measuring placental S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) levels. In addition, we assessed global DNA methylation status by long-interspersed nuclear element-1 (LINE-1) and DNA methylation status of the PlGF gene. METHODS: Placental tissue of 11 early onset PE (EOPE), 11 late onset PE (LOPE) and 60 controls consisting of 25 uncomplicated controls 20 fetal growth restriction (FGR) and 15 preterm births (PTB) controls was collected from a nested case-control study of The Rotterdam Periconceptional Cohort. RNA and DNA was isolated from placental tissue and DNA was treated with sodium bisulfite. SAM and SAH levels were measured by LC-ESI-MS/MS. Methylation of LINE-1 and PlGF genes was analyzed by Sequenom Epityper and. mRNA expression of PlGF was assessed with qPCR. Differences were assessed by analysis of covariance (ANCOVA) corrected for gestational age and birth weight. RESULTS: Placental SAM levels were significantly lower in placental tissue of EOPE pregnancies compared to PTB controls (mean difference -240 ± 71.4 nmol/g protein, P = 0.01). PlGF DNA methylation was decreased in placental tissue of EOPE cases versus LOPE (mean difference -17.4 ± 5.1%, P = 0.01), uncomplicated controls (mean difference -23.4 ± 5.4%%, P <0.001), FGR controls (mean difference -17.9 ± 4.6%, P = 0.002) and PTB controls (mean difference -11.3 ± 3.8% P = 0.04). No significant differences were observed in SAH, SAM:SAH ratio, LINE-1 DNA methylation and PlGF mRNA expression between groups. DISCUSSION: The hypomethylation state of the placenta in EOPE, which is reflected by lower SAM and PlGF DNA hypomethylation underlines the possible role of placental DNA hypomethylation in the pathophysiology of EOPE, which needs further investigation.

The Impact of Neighbourhood Deprivation on Embryonic Growth Trajectories: Rotterdam Periconception Cohort.

BACKGROUND: Neighbourhood deprivation is a risk factor for impaired health and adverse pregnancy outcomes. We investigated whether living in a deprived neighbourhood is associated with embryonic growth. METHODS: From the Predict cohort, we studied 566 women who underwent repeated first trimester ultrasound examinations. Crown rump length (CRL; n = 1707) and embryonic volume (EV; n = 1462) were measured using three-dimensional techniques. Neighbourhood deprivation was assessed using the neighbourhood status scores (NSS) of the Dutch Social Cultural Planning office. A high NSS represents a non-deprived neighbourhood. Associations between the NSS and embryonic growth were investigated using linear mixed models. Adjustment was performed for individual-level factors: maternal age, geographic origin, educational level, BMI, folic acid supplement use, fruit and vegetable intake, alcohol use and smoking habits. RESULTS: The NSS was negatively associated with embryonic growth: a higher score (a less deprived neighbourhood) was associated with a smaller CRL and EV; adjusted ß: -0.025 (95% CI -0.046, -0.003) and adjusted ß: -0.015 (95% CI -0.026, -0.003). At 11 weeks of pregnancy, we observed a 0.55 cm3 smaller EV (7.65 cm3 vs. 7.10 cm3) and 1.08 mm smaller CRL (43.14 mm vs. 42.06 mm) in the highest compared to the lowest category. CONCLUSION: In deprived neighbourhoods, embryos are larger than in non-deprived neighbourhoods.

Towards Prepared mums (TOP-mums) for a healthy start, a lifestyle intervention for women with overweight and a child wish: study protocol for a randomised controlled trial in the Netherlands.

INTRODUCTION: Periconception obesity is associated with a higher risk for adverse perinatal outcomes such as gestational diabetes mellitus, preeclampsia, large for gestational age, operative delivery and preterm birth. Lifestyle interventions during pregnancy have resulted in insufficient effects on reducing these perinatal complications. A few reasons for this disappointing effect can be suggested: (1) the time period during pregnancy for improvement of developmental circumstances is too short; (2) the periconception period in which complications originate is not included; and (3) lifestyle interventions may not have been sufficiently multidisciplinary and customised. A preconception lifestyle intervention might be more effective to reduce perinatal complications. Therefore, the aim of the Towards Prepared mums study is to evaluate the effect of a lifestyle intervention starting prior to conception on lifestyle behaviour change. METHODS AND ANALYSIS: This protocol outlines a non-blinded, randomised controlled trial. One hundred and twelve women (18-40 years of age) with overweight or obesity (body mass index≥25.0 kg/m2) who plan to conceive within 1 year will be randomised to either the intervention or care as usual group. The intervention group will receive a multidisciplinary, customised lifestyle intervention stimulating physical activity, a healthy diet and smoking cessation, if applicable. The lifestyle intervention and monitoring will take place until 12 months postpartum. The primary outcome is difference in weight in kg from baseline to 6 weeks postpartum. Secondary outcomes are gestational weight gain, postpartum weight retention, smoking cessation, dietary and physical activity habits. Furthermore, exploratory outcomes include body composition, cardiometabolic alterations, time to pregnancy, need for assisted reproductive technologies, perinatal complications of mother and child, and lung function of the child. Vaginal and oral swabs, samples of faeces, breast milk, placenta and cord blood will be stored for evaluation of microbial flora, epigenetic markers and breast milk composition. Furthermore, a cost-effectiveness analysis will take place. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Medical Ethical Committee of Maastricht University Medical Centre+ (NL52452.068.15/METC152026). Knowledge derived from this study will be made available by publications in international peer-reviewed scientific journals and will be presented at (inter)national scientific conferences. A dissemination plan for regional and national implementation of the intervention is developed. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02703753.

The impact of periconceptional maternal lifestyle on clinical features and biomarkers of placental development and function: a systematic review.

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.

The impact of maternal lifestyle factors on periconception outcomes: a systematic review of observational studies.

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.