Paternal age and first trimester placental size and growth:The Rotterdam Periconceptional Cohort

Introduction: Despite a noticeable trend of delayed fatherhood, less is known about the impact of paternal age on the paternally programmed placenta. We hypothesize that paternal aging affects seminal quality and as such induces ageing-related epigenetic alterations that influence placental growth. Our main aim is to investigate associations between paternal age and first trimester (vascular) placental growth trajectories. Methods: Pregnant women were enrolled before 10 weeks of gestation in the Rotterdam Periconceptional Cohort (Predict study). Placental volumes (PV) and utero-placental vascular volumes (uPVV) were measured at 7, 9, and 11 weeks gestation. Associations between paternal age and PV and uPVV were investigated using linear mixed models and the maximum likelihood ratio test to test non-linear relationships. We adjusted for gestational age, fetal sex, parental smoking and maternal age, BMI, education and parity, and stratified for conception mode. Results: From 808 pregnancies we obtained 1313 PV and from 183 pregnancies 345 uPVV measurements. We show no associations between paternal age and PV (p = 0.934) and uPVV (p = 0.489) in our total population or in pregnancies conceived naturally (PV p = 0.166; uPVV p = 0.446) and after IVF/ICSI (PV p = 0.909; uPVV p = 0.749). For example, PV was 0.9% smaller (95% CI -5.7%—7.1%) in fathers aged 40 compared to 30 years old at 9 weeks gestation in the total study population. Discussion: We are not demonstrating a significant impact of paternal age on first trimester placental growth in a tertiary care population. Given the trend of increasing paternal age, our study should be repeated in the general population.</p

Morphologic development of the first-trimester utero-placental vasculature is positively associated with embryonic and fetal growth:the Rotterdam Periconception Cohort

STUDY QUESTION: Is morphologic development of the first-trimester utero-placental vasculature associated with embryonic growth and development, fetal growth, and birth weight percentiles?SUMMARY ANSWER: Using the utero-placental vascular skeleton (uPVS) as a new imaging marker, this study reveals morphologic development of the first-trimester utero-placental vasculature is positively associated with embryonic growth and development, fetal growth, and birth weight percentiles. WHAT IS KNOWN ALREADY: First-trimester development of the utero-placental vasculature is associated with placental function, which subsequently impacts embryonic and fetal ability to reach their full growth potential. The attribution of morphologic variations in the utero-placental vascular development, including the vascular structure and branching density, on prenatal growth remains unknown. STUDY DESIGN, SIZE, DURATION: This study was conducted in the VIRTUAL Placental study, a subcohort of 214 ongoing pregnancies, embedded in the prospective observational Rotterdam Periconception Cohort (Predict study). Women were included before 10 weeks gestational age (GA) at a tertiary referral hospital in The Netherlands between January 2017 and March 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: We obtained three-dimensional power Doppler volumes of the gestational sac including the embryo and the placenta at 7, 9, and 11 weeks of gestation. Virtual Reality-based segmentation and a recently developed skeletonization algorithm were applied to the power Doppler volumes to generate the uPVS and to measure utero-placental vascular volume (uPVV). Absolute vascular morphology was quantified by assigning a morphologic characteristic to each voxel in the uPVS (i.e. end-, bifurcation-crossing-, or vessel point). Additionally, total vascular length (mm) was calculated. The ratios of the uPVS characteristics to the uPVV were calculated to determine the density of vascular branching. Embryonic growth was estimated by crown-rump length and embryonic volume. Embryonic development was estimated by Carnegie stages. Fetal growth was measured by estimated fetal weight in the second and third trimester and birth weight percentiles. Linear mixed models were used to estimate trajectories of longitudinal measurements. Linear regression analysis with adjustments for confounders was used to evaluate associations between trajectories of the uPVS and prenatal growth. Groups were stratified for conception method (natural/IVF-ICSI conceptions), fetal sex (male/female), and the occurrence of placenta-related complications (yes/no). MAIN RESULTS AND THE ROLE OF CHANCE: Increased absolute vascular morphologic development, estimated by positive random intercepts of the uPVS characteristics, is associated with increased embryonic growth, reflected by crown-rump length (endpoints β = 0.017, 95% CI [0.009; 0.025], bifurcation points β = 0.012, 95% CI [0.006; 0.018], crossing points β = 0.017, 95% CI [0.008; 0.025], vessel points β = 0.01, 95% CI [0.002; 0.008], and total vascular length β = 0.007, 95% CI [0.003; 0.010], and similarly with embryonic volume and Carnegie stage, all P-values ≤ 0.01. Density of vascular branching was negatively associated with estimated fetal weight in the third trimester (endpoints: uPVV β = -94.972, 95% CI [-185.245; -3.698], bifurcation points: uPVV β = -192.601 95% CI [-360.532; -24.670]) and birth weight percentiles (endpoints: uPVV β = -20.727, 95% CI [-32.771; -8.683], bifurcation points: uPVV β -51.097 95% CI [-72.257; -29.937], and crossing points: uPVV β = -48.604 95% CI [-74.246; -22.961])), all P-values &lt; 0.05. After stratification, the associations were observed in natural conceptions specifically.LIMITATION, REASONS FOR CAUTION: Although the results of this prospective observational study clearly demonstrate associations between first-trimester utero-placental vascular morphologic development and prenatal growth, further research is required before we can draw firm conclusions about a causal relationship. WIDER IMPLICATIONS OF THE FINDINGS: Our findings support the hypothesis that morphologic variations in utero-placental vascular development play a role in the vascular mechanisms involved in embryonic and fetal growth and development. Application of the uPVS could benefit our understanding of the pathophysiology underlying placenta-related complications. Future research should focus on the clinical applicability of the uPVS as an imaging marker for the early detection of fetal growth restriction. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Department of Obstetrics and Gynecology of the Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: Registered at the Dutch Trial Register (NTR6854).</p

Current preconception care practice in the Netherlands — An evaluation study among birth care professionals

Objective: To evaluate the current practice of preconception care in the Netherlands and the perceptions of birth care professionals concerning preconception care. Methods: We have developed a digital questionnaire and conducted a cross-sectional study by distributing the questionnaire among 102 organisations: 90 primary care midwifery practices and obstetric departments of 12 hospitals in the Southwest region of the Netherlands between December 2020 and March 2021. One birth care professional per organization was asked to complete the questionnaire. Descriptive statistics were used to present the results. Findings: Respondents of eighty-three organisations (81.4 %) filled in the questionnaire, of whom 74 respondents were independent primary care midwives and 9 respondents were obstetricians. Preconception care mostly consisted of an individual consultation in which personalized health and lifestyle advice was given. Among the respondents, 44.4 % reported that the organization had a preconception care protocol. The way in which the consultation was carried out, as well as the health and lifestyle related questions asked, differed between respondents. More than 85 % of the respondents inquire about the following possible risk factors for complications: maternal illnesses, obstetric history, folic acid supplement intake, alcohol intake, smoking, substance abuse, hereditary disease, prescription medication, dietary habits, overweight, and birth defects in the family. The respondents acknowledged that preconception care should be offered to all couples who wish to become pregnant, as opposed to offering preconception care only to those with an increased risk of complications. Still, respondents do not receive many questions regarding the preconception period or requests for preconception care consultations. Key conclusion: Birth care professionals acknowledge the need for preconception care for all couples. In the Netherlands, preconception care consists mostly of an individual consultation with recommendations for health and lifestyle advice. However, the identification of risk factors varies between birth care professionals and less than half of the respondents indicate that they have a protocol available in their practice. Furthermore, the demand of parents-to-be for preconception care is low. More research, that includes more obstetricians, is necessary to investigate if there is a difference between the care provided by primary care midwives and obstetricians. Implications for practice:To increase the awareness and uptake of preconception care, it would be prudent to emphasize its importance to parents-to-be and professionals, and actively promote the use of widespread, standardized protocols for birth care professionals.</p

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. ((C)2020 by American Society for Reproductive Medicine.)y

Potential benefits of the use of sympathomimetics for asthmatic disease, on semen quality in men of subfertile couples

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

The tissue-specific aspect of genome-wide DNA methylation in newborn and placental tissues: Implications for epigenetic epidemiologic studies

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

Chlamydia trachomatis infection during pregnancy associated with preterm delivery: A population-based prospective cohort study

Chlamydia trachomatis infection is the most prevalent bacterial sexually transmitted infection and may influence pregnancy outcome. This study was conducted to assess the effect of chlamydial infection during pregnancy on premature delivery and birthweight. Pregnant women attending a participating midwifery practice or antenatal clinic between February 2003 and January 2005 were eligible for the study. From 4,055 women self-administered questionnaires and urine samples, tested by PCR, were analysed for C. trachomatis infection. Pregnancy outcomes were obtained from midwives and hospital registries. Gestational ages and birthweights were analysed for 3,913 newborns. The C. trachomatis prevalence was 3.9%, but varied by age and socio-economic background. Chlamydial infection was, after adjustment for potential confounders, associated with preterm delivery before 32 weeks (OR 4.35 [95% CI 1.3, 15.2]) and 35 weeks gestation (OR 2.66 [95% CI 1.1, 6.5]), but not with low birthweight. Of all deliveries before 32 weeks and 35 weeks gestation 14.9% [95% CI 4.5, 39.5] and 7.4% [95% CI 2.5, 20.1] was attributable to C. trachomatis infection. Chlamydia trachomatis infection contributes significantly to early premature delivery and should be considered a public health problem, especially in young women and others at increased risk of C. trachomatis infection

Tailored preconceptional dietary and lifestyle counselling in a tertiary outpatient clinic in the Netherlands

Background Adverse reproductive performance has been linked to unhealthy dietary intake and lifestyles. Our objectives were to investigate the prevalence of unhealthy dietary intake and lifestyles before conception and to evaluate whether tailored preconception counselling modifies these behaviours. Methods Between October 2007 and April 2009, 419 couples received tailored preconception dietary and lifestyle counselling at the outpatient clinic of Obstetrics and Gynaecology of the Erasmus University Medical Center Rotterdam, the Netherlands. A subgroup (n = 110 couples) was counselled twice with a fixed time interval of 3 months. Self-administered questionnaires were used for tailored dietary and lifestyle counselling. A cumulative score based on six Dutch dietary guidelines was displayed in the personal Preconception Dietary Risk score (PDR score). In a similar manner, the Rotterdam Reproduction Risk score (R3 score) was calculated from lifestyle factors (women: 13 items, men: 10 items). Univariate and paired tests were used. Results Most couples (93.8) were subfertile. At the second counselling, the percentage consuming the recommended intake of fruit had increased from 65 to 80 in women and from 49 to 68 in men and the percentage of women getting the recommended intake of fish increased from 39 to 52. As a consequence, the median PDR score was decreased [women: 2.6 (95 CI 2.4-2.9) to 2.4 (95 CI 2.1-2.6), men: 2.5 (95 CI 2.3-2.7) to 2.2 (95 CI 1.9-2.4), both P < 0.05]. The median R3 scores were also lower [women: 4.7 (95 CI 4.3-5.0) to 3.1 (95 CI 2.8-3.4), men: 3.0 (95 CI 2.8-3.3) to 2.0 (95 CI 1.7-2.3), both P < 0.01] due to less alcohol use (-14.6), more physical exercise and folic acid use in women, and less alcohol use in men (-19.4) (all P < 0.01). The R3 scores in women and men were decreased in all ethnicity, educational level, neighbourhood and BMI categories. However, low educated women appeared to show a larger reduction than better educated women and men with a normal BMI to show a larger decrease than overweight men. The reduction in the PDR score of women was similar in both ethnic groups. More than 85 women and men found the counselling useful and around 70 would recommend it to others. Conclusions Tailored preconception counselling about unhealthy dietary and lifestyle behaviours of subfertile couples in an outpatient tertiary clinic is feasible and seems to decrease the prevalence of harmful behaviours in the short term. These Results with subfertile couples are promising and illustrate their opportunities to contribute to reproductive performance and pregnancy outcome

Periconceptional Maternal Folic Acid Use of 400 µg per Day Is Related to Increased Methylation of the IGF2 Gene in the Very Young Child

Background: Countries worldwide recommend women planning pregnancy to use daily 400 mg of synthetic folic acid in the periconceptional period to prevent birth defects in children. The underlying mechanisms of this preventive effect are not clear, however, epigenetic modulation of growth processes by folic acid is hypothesized. Here, we investigated whether periconceptional maternal folic acid use and markers of global DNA methylation potential (S-adenosylmethionine and S-adenosylhomocysteine blood levels) in mothers and children affect methylation of the insulin-like growth factor 2 gene differentially methylation region (IGF2 DMR) in the child. Moreover, we tested whether the methylation of the IGF2 DMR was independently associated with birth weight. Methodology/Principal Findings: IGF2 DMR methylation in 120 children aged 17 months (SD 0.3) of whom 86 mothers had used and 34 had not used folic acid periconceptionally were studied. Methylation was measured of 5 CpG dinucleotides covering the DMR using a mass spectrometry-based method. Children of mother who used folic acid had a 4.5% higher methylation of the IGF2 DMR than children who were not exposed to folic acid (49.5% vs. 47.4%; p = 0.014). IGF2 DMR methylation of the children also was associated with the S-adenosylmethionine blood level of the mother but not of the child (+1.7% methylation per SD S-adenosylmethionine; p = 0.037). Finally, we observed an inverse independent association between IGF2 DMR methylation and birth weight (-1.7% methylation per SD birthweight; p = 0.034). Conclusions: Periconceptional folic acid use is associated with epigenetic changes in IGF2 in the child that may affect intrauterine programming of growth and development with consequences for health and disease throughout life. These results indicate plasticity of IGF2 methylation by periconceptional folic acid use