Living in a low socioeconomic status neighbourhood is associated with lower cumulative ongoing pregnancy rate after IVF treatment.

RESEARCH QUESTION: Does an association exist between neighbourhood socioeconomic status (SES) and the cumulative rate of ongoing pregnancies after 2.5 years of IVF treatment? DESIGN: A retrospective observational study involving 2669 couples who underwent IVF or IVF and intracytoplasmic sperm injection treatment between 2006 and 2020. Neighbourhood SES for each couple was determined based on their residential postal code. Subsequently, SES was categorized into low (p80). Multivariable binary logistic regression analyses were conducted, with the cumulative ongoing pregnancy within 2.5 years as the outcome variable. The SES category (reference category: high), female age (reference category: 32-36 years), body mass index (reference category: 23-25 kg/m2), smoking status (yes/no), number of oocytes after the first ovarian stimulation, embryos usable for transfer or cryopreservation after the first cycle, duration of subfertility before treatment and insemination type were used as covariates. RESULTS: A variation in ongoing pregnancy rates was observed among SES groups after the first fresh embryo transfer. No difference was found in the median number of IVF treatment cycles carried out. The cumulative ongoing pregnancy rates differed significantly between SES groups (low: 44%; medium: 51%; high: 56%; P < 0.001). Low neighbourhood SES was associated with significantly lower odds for achieving an ongoing pregnancy within 2.5 years (OR 0.66, 95% CI 0.52 to 0.84, P < 0.001). CONCLUSION: Low neighbourhood SES compared with high neighbourhood SES is associated with reducing odds of achieving an ongoing pregnancy within 2.5 years of IVF treatment.

Socioeconomic inequalities in the uptake of postpartum care at home across Dutch neighbourhoods.

BACKGROUND: Postpartum care focuses on prevention of health problems by performing medical check-ups and through enhancing maternal empowerment, the parent-infant interaction and knowledge about mother's own health and that of her newborn. We aimed to investigate whether there was significant clustering within neighbourhoods regarding the uptake of postpartum care and to what extent neighbourhood-level differences are explained by individual socio-demographic factors, pregnancy-related factors and neighbourhood-level determinants (i.e. deprivation and urbanization). METHODS: A nationwide population-based observational study was carried out using linked routinely collected healthcare data from appropriate-for-gestational-age weight live-born term singleton deliveries (2015-18) in the Netherlands. We performed two-level multivariable logistic regression analyses, using three different models. Model 1 contained no explanatory variables and was used to assess clustering of postpartum care uptake within neighbourhoods. In model 2, individual-level determinants were added one by one and in model 3, neighbourhood-level determinants were added. RESULTS: About 520 818 births were included. Multilevel modelling showed that 11% of the total variance in postpartum care uptake could be attributed to the neighbourhood of residence. Individual characteristics explained 38% of the neighbourhood variance, of which income and migration background were the most important contributors. An additional 6% of the variation could be explained by neighbourhood-level determinants. CONCLUSION: We found substantial neighbourhood differences in postpartum care uptake. These differences are influenced by a complex interplay between individual-level and neighbourhood-level determinants, highlighting the importance of addressing both individual and neighbourhood-level determinants to improve the uptake of postpartum care and therewith overall community health.

Does Neighborhood Crime Mediate the Relationship Between Neighborhood Socioeconomic Status and Birth Outcomes? An Application of the Mediational G-Formula.

While the link between living in a low-socioeconomic status (SES) neighborhood and higher risk of adverse birth outcomes has been well established, the underlying mechanisms remain poorly understood. Using the parametric g-formula, we assessed the role of neighborhood crime as a potential mediator of the relationship between neighborhood SES and birth outcomes using data on singleton births occurring in the Netherlands between 2010 and 2017 (n = 1,219,470). We estimated total and mediated effects of neighborhood SES on small-for-gestational-age (SGA) birth, low birth weight (LBW), and preterm birth (PTB) for 3 types of crime (violent crimes, crimes against property, and crimes against public order). The g-formula intervention settings corresponded to a hypothetical improvement in neighborhood SES. A hypothetical improvement in neighborhood SES resulted in a 6.6% (95% CI: 5.6, 7.5) reduction in the proportion of SGA birth, a 9.1% (95% CI: 7.6, 10.6) reduction in LBW, and a 5.8% (95% CI: 5.7, 6.2) decrease in PTB. Neighborhood crime jointly accounted for 28.1% and 8.6% of the total effects on SGA birth and LBW, respectively. For PTB, we found no evidence of mediation. The most relevant pathways were crimes against property and crimes against public order. The results indicate that neighborhood crime mediates a meaningful share of the relationship between neighborhood SES and birth outcomes.

Alcohol exposure before and during pregnancy is associated with reduced fetal growth: the Safe Passage Study.

BACKGROUND: Prenatal alcohol exposure (PAE) is a worldwide public health concern. While PAE is known to be associated with low birth weight, little is known about timing and quantity of PAE on fetal growth. This study investigated the association between periconceptional and prenatal alcohol exposure and longitudinal fetal growth, focusing on timing and quantity in a high exposure cohort. METHODS: The Safe Passage Study was a prospective cohort study, including 1698 pregnant women. Two-dimensional transabdominal ultrasound examinations were performed to measure fetal femur length, abdominal and head circumference, and biparietal diameter, at three time points during pregnancy. Estimated fetal weight and Z-scores of all parameters were calculated. Trimester-specific alcohol exposure was assessed using the Timeline Followback method. To investigate the associations of specific timing of PAE and fetal growth, two models were built. One with alcohol exposure as accumulative parameter over the course of pregnancy and one trimester specific model, in which PAE was separately analyzed. Linear mixed models adjusted for potential confounders were applied with repeated assessments of both alcohol exposure and fetal growth outcomes. RESULTS: This study demonstrated that periconceptional and prenatal alcohol exposure were associated with reduced fetal growth. Effect sizes are displayed as estimated differences (ED) in Z-score and corresponding 95% confidence intervals (95% CIs). When investigated as accumulative parameter, PAE was related to a smaller femur length (ED30; - 0.13 (95% CI; - 0.22; - 0.04), ED36; - 0.14 (95% CI; - 0.25; - 0.04)) and a smaller abdominal circumference (ED36; - 0.09 (95% CI; - 0.18; - 0.01)). Periconceptional alcohol exposure was associated with a smaller abdominal circumference (ED30; - 0.14 (95% CI; - 0.25; - 0.02), ED36; - 0.22 (95% CI; - 0.37; - 0.06)) and a smaller estimated fetal weight (ED36; - 0.22 (95% CI; - 0.38; - 0.05)). Second trimester alcohol exposure was associated with a smaller abdominal circumference (ED30; - 0.49 (95% CI; - 0.86; - 0.12), ED36; - 0.70 (95% CI; - 1.22; - 0.17)) and estimated fetal weight (ED30; - 0.54 (95% CI; - 0.94; - 0.14), ED36; - 0.69 (95% CI; - 1.25; - 0.14)). No additional association of binge drinking was found besides the already observed association of PAE and fetal growth. CONCLUSIONS: This study demonstrated that PAE negatively affects fetal growth, in particular when exposed during the periconception period or in second trimester. Our results indicate that potential negative consequences of PAE are detectable already before birth. Therefore, healthcare providers should actively address and discourage alcohol use during pregnancy.

Circulating maternal prorenin and oocyte and preimplantation embryo development: the Rotterdam Periconception Cohort.

STUDY QUESTION: Could circulating maternal prorenin serve as a proxy for oocyte and preimplantation embryo development, assessed by time-lapse parameters and clinical treatment outcomes? SUMMARY ANSWER: High circulating maternal prorenin concentrations after ovarian stimulation associate with a larger oocyte area, faster cleavage divisions from the five-cell stage onwards and increased chance of successful implantation. WHAT IS KNOWN ALREADY: After ovarian stimulation, circulating prorenin (renin's precursor), is largely ovary-derived. Prorenin may contribute to ovarian angiotensin synthesis, which is relevant in reproduction given its role in follicular development and oocyte maturation. STUDY DESIGN, SIZE, DURATION: Prospective observational cohort study including couples requiring fertility treatment from May 2017 as a subcohort of the ongoing Rotterdam Periconception Cohort conducted in a tertiary referral hospital. PARTICIPANTS/MATERIALS, SETTING, METHODS: Between May 2017 and July 2020, 309 couples with an indication for IVF treatment or ICSI were included. Resulting embryos (n = 1024) were submitted to time-lapse embryo culture. Time of fertilization (t0), pronuclear appearance (tPNa), and fading (tPNf) as well as the exact timing of reaching the two- to eight-cell stage (t2-t8), the start of blastulation (tSB), reaching the full (tB), and expanded blastocyst (tEB) were retrospectively recorded. Oocyte area was measured at t0, tPNa, and tPNf. Prorenin was determined at the day of embryo transfer. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for patient- and treatment-related factors, linear mixed modeling showed that higher prorenin concentrations associate with a larger oocyte area at tPNa (ß 64.45 µm2, 95% CI 3.26; 125.64, P = 0.04), and faster progression from five-cell stage onwards (e.g. ß8-cell -1.37 h, 95% CI -2.48; -0.26, P = 0.02). Prorenin associated positively with pre-transfer outcomes (e.g. ßfertilized oocytes 2.09, 95% CI 1.43; 2.75, P < 0.001) and implantation (odds ratio+ß-hCG-test: 1.79, 95% CI 1.06; 3.08, P = 0.03), but not with live birth. LIMITATIONS, REASONS FOR CAUTION: This prospective observational study provides associations and therefore residual confounding cannot be excluded and causality has to be shown in intervention studies. WIDER IMPLICATIONS OF THE FINDINGS: Theca cell-derived factors, such as prorenin, may help to clarify the underlying endocrine mechanism of oocyte maturation and embryo development, with a special focus on the (patho)physiological reproductive role of prorenin and the identification of factors influencing its secretion and activity, which is of great added value for improving embryo selection and predicting implantation and pregnancy outcomes. This will bring us to investigate which determinants of oocyte quality and embryo development should take center stage in developing preconception care strategies. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Department of Obstetrics and Gynecology of the Erasmus MC, University Medical Center, Rotterdam, the Netherlands, and the Erasmus MC Medical Research Advisor Committee's 'Health Care Efficiency Research' program (OZBS72.16080). The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Prenatal assessment of pulmonary vasculature development in fetuses with congenital diaphragmatic hernia: A literature review.

Pathophysiological studies have shown that pulmonary vascular development is impaired in fetuses with a congenital diaphragmatic hernia (CDH), leading to a simplified vascular tree and increased vascular resistance. Multiple studies have described prenatal ultrasound parameters for the assessment of the pulmonary vasculature, but none of these parameters are used in daily clinical practice. We provide a comprehensive review of the literature published between January 1990 and February 2022 describing these parameters, and aim to explain the clinical relevance of these parameters from what is known from pathophysiological studies. Prenatal detection of a smaller diameter of the contralateral (i.e. contralateral to the diaphragmatic defect) first branch of the pulmonary artery (PA), higher pulsatility indices (PI), higher peak early diastolic reverse flow values, and a lower vascularization index seem of added value for the prediction of survival and, to a lesser extent, morbidity. Integration within the routine evaluation is complicated by the lack of uniformity of the methods used. To address the main components of the pathophysiological changes, we recommend future prenatal studies in CDH with a focus on PI values, PA diameters and pulmonary vascular branching.

Piloting a complex intervention to promote a tobacco and alcohol-free pregnancy: the Smoke and Alcohol Free with EHealth and Rewards (SAFER) pregnancy study.

BACKGROUND: Tobacco smoking and alcohol consumption before and during pregnancy increase the risk of adverse health outcomes for mother and child. Interventions to address smoking and drinking before and during pregnancy have the potential to reduce early-life health inequalities. In the Smoke and Alcohol Free with EHealth and Rewards (SAFER) pilot study we aimed to evaluate the acceptability, feasibility and effectiveness of a complex intervention supporting women in smoking and alcohol cessation before and during pregnancy. METHODS: From February 2019 till March 2021, we piloted the SAFER pregnancy intervention among pregnant women and women planning pregnancy in South-West Netherlands in an uncontrolled before-after study. Participants were supported in smoking and alcohol cessation via up to six group sessions and an online platform. In addition, biochemically validated cessation was rewarded with incentives (i.e. shopping vouchers) amounting up to 185 euros. We aimed to include 66 women. The primary outcome was smoking and/or alcohol cessation at 34-38 weeks of gestation (if pregnant) or after six group sessions (if not pregnant). Quantitative data were analysed using descriptive statistics. Focus group interviews among those involved in the study were conducted at the end of the study to explore their experiences. Qualitative data was analysed using thematic analysis. RESULTS: Thirty-nine women who smoked were included; no women who consumed alcohol were referred to the study. Unemployment (51%), financial problems (36%) and a smoking partner (72%) were common. Thirteen women (33%) dropped out, often due to other problems impeding smoking cessation or 'being too busy' to participate in the group sessions. Eleven women (28%) had quit smoking at the study's endpoint. The personal and positive approach was highly valued and biochemical validation was felt to be helpful. CONCLUSION: The SAFER pregnancy intervention seems appropriate for women in need of extra support for smoking cessation before and during pregnancy. Its impact on alcohol cessation could not be studied due to recruitment issues. Recruitment and prevention of early dropout need attention in further development of this intervention. TRIAL REGISTRATION: Netherlands Trial Register: NL7493. Date registered: 04/02/2019.

Perinatal mortality and neonatal and maternal outcome per gestational week in term pregnancies: A registry-based study.

INTRODUCTION: Human pregnancy is considered term from 37+0/7 to 41+6/7 weeks. Within this range, both maternal, fetal and neonatal risks may vary considerably. This study investigates how gestational age per week is related to the components of perinatal mortality and parameters of adverse neonatal and maternal outcome at term. MATERIAL AND METHODS: A registry-based study was made of all singleton term pregnancies in the Netherlands from January 2014 to December 2017. Stillbirth and early neonatal mortality, as components of perinatal mortality, were defined as primary outcomes; adverse neonatal and maternal events as secondary outcomes. Neonatal adverse outcomes included birth trauma, 5-minute Apgar score ≤3, asphyxia, respiratory insufficiency, neonatal intensive care unit admission and composite neonatal outcome. Maternal adverse outcomes included instrumental vaginal birth, emergency cesarean section, obstetric anal sphincter injury, postpartum hemorrhage, hypertensive disorders of pregnancy and composite maternal outcome. The primary outcomes were evaluated by comparing weekly prospective risks of stillbirth and neonatal death using a fetuses-at-risk approach. Secondly, odds ratios (OR) for perinatal mortality, adverse neonatal and maternal outcome using a births-based approach were compared for each gestational week with all births occurring after that week. RESULTS: Data of 581 443 births were analyzed. At 37, 38, 39, 40, 41 and 42 weeks, the respective weekly prospective risks of stillbirth were 0.015%, 0.022%, 0.031%, 0.036%, 0.069% and 0.081%; the respective weekly prospective risks of early neonatal death were 0.051%, 0.047%, 0.032%, 0.031%, 0.039% and 0.035%. The OR for adverse neonatal outcomes were the lowest at 39 and 40 weeks. The OR for adverse maternal outcomes, including operative birth, continuously increased with each gestational week. CONCLUSIONS: The prospective risk of early neonatal death for babies born at 39 weeks is lower than the risk of stillbirth in pregnancies continuing beyond 39+6/7 weeks. Birth at 39 weeks was associated with the best combined neonatal and maternal outcome, fewer operative births and fewer maternal and neonatal adverse outcomes compared with pregnancies continuing beyond 39 weeks. This information with appropriate perspectives should be included when counseling term pregnant women.

Impact of the EURO-PERISTAT Reports on obstetric management: a difference-in-regression-discontinuity analysis.

BACKGROUND: Population health monitoring, such as perinatal mortality and morbidity rankings published by the European Perinatal Health (EURO-PERISTAT) reports may influence obstetric care providers' decision-making and professional behaviour. We investigated short-term changes in the obstetric management of singleton term deliveries in the Netherlands following publication of the EURO-PERISTAT reports in 2003, 2008 and 2013. METHODS: We used a quasi-experimental difference-in-regression-discontinuity approach. National perinatal registry data (2001-15) was used to compare obstetric management at delivery in four time windows (1, 2, 3 and 5 months) surrounding publication of each EURO-PERISTAT report. RESULTS: The 2003 EURO-PERISTAT report was associated with higher relative risks (RRs) for an assisted vaginal delivery across all time windows [RR (95% CI): 1 month: 1.23 (1.05-1.45), 2 months: 1.15 (1.02-1.30), 3 months: 1.21 (1.09-1.33) and 5 months: 1.21 (1.11-1.31)]. The 2008 report was associated with lower RRs for an assisted vaginal delivery at the 3- and 5-month time windows [0.86 (0.77-0.96) and 0.88 (0.81-0.96)]. Publication of the 2013 report was associated with higher RRs for a planned caesarean section across all time windows [1 month: 1.23 (1.00-1.52), 2 months: 1.26 (1.09-1.45), 3 months: 1.26 (1.12-1.42) and 5 months: 1.19(1.09-1.31)] and lower RRs for an assisted vaginal delivery at the 2-, 3- and 5-month time windows [0.85 (0.73-0.98), 0.83 (0.74-0.94) and 0.88 (0.80-0.97)]. CONCLUSIONS: This study showed that quasi-experimental study designs, such as the difference-in-regression-discontinuity approach, are useful to unravel the impact of population health monitoring on decision-making and professional behaviour of healthcare providers. A better understanding of the contribution of health monitoring to the behaviour of healthcare providers can help guide improvements within the (perinatal) healthcare chain.

Associations of maternal angiogenic factors during pregnancy with alterations in cardiac development in childhood at 10 years of age.

AIM: To examine whether maternal angiogenic factors in the first half of pregnancy are associated with offspring left and right cardiac development. METHODS: In a population-based prospective cohort among 2,415 women and their offspring, maternal first and second trimester plasma PlGF and sFlt-1 concentrations were measured. Cardiac MRI was performed in their offspring at 10 years. RESULTS: Maternal angiogenic factors were not associated with childhood cardiac outcomes in the total population. In children born small-for-their-gestational-age, higher maternal first trimester PlGF concentrations were associated with a lower childhood left ventricular mass  (-0.24 SDS  [95%CI -0.42, -0.05 per SDS increase in maternal PlGF]), whereas higher sFlt-1 concentrations were associated with higher childhood left ventricular mass  (0.22 SDS  [95%CI 0.09, 0.34 per SDS increase in maternal sFlt-1]). Higher second trimester maternal sFlt-1 concentrations were also associated with higher childhood left ventricular mass  (P-value <.05). In preterm born children, higher maternal first and second trimester sFlt-1/PlGF ratio were associated with higher childhood left ventricular mass  (0.30 SDS  [95%CI 0.01, 0.60], 0.22 SDS  [95%CI -0.03, 0.40]) per SDS increase in maternal sFlt-1/PlGF ratio in first and second trimester respectively). No effects on other childhood cardiac outcomes were present within these higher-risk children. CONCLUSIONS: In a low-risk population, maternal angiogenic factors are not associated with childhood cardiac ventricular structure, and function within the normal range. In children born small for their gestational age or preterm, an imbalance in maternal angiogenic factors in the first half of pregnancy was associated with higher childhood left ventricular mass only.

Tumour necrosis factor inhibitor use during pregnancy is associated with increased birth weight of rheumatoid arthritis patients' offspring.

OBJECTIVES: To study pregnancy outcomes in a closely monitored, well-defined cohort of women with rheumatoid arthritis (RA). In particular, pregnancy outcomes of women that used a TNFi during pregnancy. METHODS: Patients were derived from a prospective study on pregnancy and RA (Preconception Counseling in Active RA study) and treated according to a treatment protocol aimed at minimal disease activity. Multivariate linear regression analysis was used to describe which variables influenced birth weight. RESULTS: 188 patients were included, 92 (48.9%) patients with RA used a TNFi during pregnancy. Disease Activity Score in 28 joints C reactive protein (DAS28CRP) was low at all time points during pregnancy (DAS28CRP in the third trimester: 2.17 (SD 0.73). TNFi use was not associated with an increase of adverse pregnancy outcomes such as low birth weight (<2500 g), (emergency) caesarian section, hypertensive disorders or congenital malformations. TNFi use resulted in less children born small-for-gestational age (p=0.05), however, did not increase the risk of large-for-gestational age (p=0.73). Mean birth weight was 173 g higher in women that used a TNFi during pregnancy (3.344 kg vs 3.171 kg, p=0.03). In the multivariate analysis, maternal age (ß -0.023, 95% CI -0.040 to -0.0065, p=0.007), TNFi use (ß 0.20, 95% CI 0.066, 0.34, p=0.004), diabetes mellitus (ß 0.37, 95% CI 0.12, 0.63, p=0.004) and gestational age (ß 0.18, 95% CI 0.15, 0.2, p<0.001) were statistically significant associated with birth weight. CONCLUSIONS: This is the first study to show that TNFi use during pregnancy is associated with increased birth weight of offspring of women with well-controlled RA. The underlying mechanism of TNF-inhibition on birth weight and the long-term consequences for the offspring should be explored in future research.

Assessment of first-trimester utero-placental vascular morphology by 3D power Doppler ultrasound image analysis using a skeletonization algorithm: the Rotterdam Periconception Cohort.

STUDY QUESTION: Can three-dimensional (3D) Power Doppler (PD) ultrasound and a skeletonization algorithm be used to assess first-trimester development of the utero-placental vascular morphology? SUMMARY ANSWER: The application of 3D PD ultrasonography and a skeletonization algorithm facilitates morphologic assessment of utero-placental vascular development in the first trimester and reveals less advanced vascular morphologic development in pregnancies with placenta-related complications than in pregnancies without placenta-related complications. WHAT IS KNOWN ALREADY: Suboptimal development of the utero-placental vasculature is one of the main contributors to the periconceptional origin of placenta-related complications. The nature and attribution of aberrant vascular structure and branching patterns remain unclear, as validated markers monitoring first-trimester utero-placental vascular morphologic development are lacking. STUDY DESIGN, SIZE, DURATION: In this prospective observational cohort, 214 ongoing pregnancies were included before 10 weeks gestational age (GA) at a tertiary hospital between January 2017 and July 2018, as a subcohort of the ongoing Rotterdam Periconception Cohort study. PARTICIPANTS/MATERIALS, SETTING, METHODS: By combining 3D PD ultrasonography and virtual reality, utero-placental vascular volume (uPVV) measurements were obtained at 7, 9 and 11 weeks GA. A skeletonization algorithm was applied to the uPVV measurements to generate the utero-placental vascular skeleton (uPVS), a network-like structure containing morphologic characteristics of the vasculature. Quantification of vascular morphology was performed by assigning a morphologic characteristic to each voxel in the uPVS (end-, vessel-, bifurcation- or crossing-point) and calculating total vascular network length. A Mann-Whitney U test was performed to investigate differences in morphologic development of the first-trimester utero-placental vasculature between pregnancies with and without placenta-related complications. Linear mixed models were used to estimate trajectories of the morphologic characteristics in the first trimester. MAIN RESULTS AND THE ROLE OF CHANCE: All morphologic characteristics of the utero-placental vasculature increased significantly in the first trimester (P < 0.005). In pregnancies with placenta-related complications (n = 54), utero-placental vascular branching was significantly less advanced at 9 weeks GA (vessel points P = 0.040, bifurcation points P = 0.050, crossing points P = 0.020, total network length P = 0.023). Morphologic growth trajectories remained similar after adjustment for parity, conception mode, foetal sex and occurrence of placenta-related complications. LIMITATIONS, REASONS FOR CAUTION: The tertiary setting of this prospective observational study provides high internal, but possibly limited external, validity. Extrapolation of the study's findings should therefore be addressed with caution. WIDER IMPLICATIONS OF THE FINDINGS: The uPVS enables assessment of morphologic development of the first-trimester utero-placental vasculature. Further investigation of this innovative methodology needs to determine its added value for the assessment of (patho-) physiological utero-placental vascular development. 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).

First-trimester maternal renin-angiotensin-aldosterone system activation and fetal growth and birthweight: the Rotterdam Periconceptional Cohort.

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) (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.

Prenatal exposure to trans fatty acids and head growth in fetal life and childhood: triangulating confounder-adjustment and instrumental variable approaches.

Dietary trans fatty acids (TFAs) are primarily industrially produced and remain abundant in processed food, particularly in low- and middle-income countries. Although TFAs are a cause of adverse cardiometabolic outcomes, little is known about exposure to TFAs in relation to brain development. We aimed to investigate the effect of maternal TFA concentration during pregnancy on offspring head growth in utero and during childhood. In a prospective population-based study in Rotterdam, the Netherlands, with 6900 mother-child dyads, maternal plasma TFA concentration was assessed using gas chromatography in mid-gestation. Offspring head circumference (HC) was measured in the second and third trimesters using ultrasonography; childhood brain morphology was assessed using magnetic resonance imaging at age 10 years. We performed regression analyses adjusting for sociodemographic and lifestyle confounders and instrumental variable (IV) analyses. Our IV analysis leveraged a national policy change that led to a substantial reduction in TFA and occurred mid-recruitment. After adjusting for covariates, maternal TFA concentration during pregnancy was inversely related to fetal HC in the third trimester (mean difference per 1% wt:wt increase: - 0.33, 95% CI - 0.51, - 0.15, cm) and to fetal HC growth from the second to the third trimester (- 0.04, 95% CI - 0.06, - 0.02, cm/week). Consistent findings were obtained with IV analyses, strengthening a causal interpretation. Association between prenatal TFA exposure and HC in the second trimester or global brain volume at age 10 years was inconclusive. Our findings are of important public health relevance as TFA levels in food remain high in many countries.

Long-term association of pregnancy and maternal brain structure: the Rotterdam Study.

The peripartum period is the highest risk interval for the onset or exacerbation of psychiatric illness in women's lives. Notably, pregnancy and childbirth have been associated with short-term structural and functional changes in the maternal human brain. Yet the long-term effects of pregnancy on maternal brain structure remain unknown. We investigated a large population-based cohort to examine the association between parity and brain structure. In total, 2,835 women (mean age 65.2 years; all free from dementia, stroke, and cortical brain infarcts) from the Rotterdam Study underwent magnetic resonance imaging (1.5 T) between 2005 and 2015. Associations of parity with global and lobar brain tissue volumes, white matter microstructure, and markers of vascular brain disease were examined using regression models. We found that parity was associated with a larger global gray matter volume (ß = 0.14, 95% CI = 0.09-0.19), a finding that persisted following adjustment for sociodemographic factors. A non-significant dose-dependent relationship was observed between a higher number of childbirths and larger gray matter volume. The gray matter volume association with parity was globally proportional across lobes. No associations were found regarding white matter volume or integrity, nor with markers of cerebral small vessel disease. The current findings suggest that pregnancy and childbirth are associated with robust long-term changes in brain structure involving a larger global gray matter volume that persists for decades. Future studies are warranted to further investigate the mechanism and physiological relevance of these differences in brain morphology.

Twenty-year trends in the use of anti-seizure medication among pregnant women in the Netherlands.

BACKGROUND: Anti-seizure medications (ASMs) are used to treat conditions such as epilepsy and bipolar disorder. Some of these drugs are associated with an increased risk of congenital malformations and adverse developmental outcomes. OBJECTIVES: To examine trends in use of ASMs among pregnant women in the Netherlands according to medication safety profile. METHODS: Using population-based data from the PHARMO Perinatal Research Network, we assessed trends in use of ASMs among pregnant women in the Netherlands between 1999 and 2019, stratified by medication safety profile. Individual treatment patterns were also assessed. RESULTS: In total, 671,709 pregnancies among 446,169 women were selected, of which 2405 (3.6 per 1000) were ASM-exposed. Over the study period, a significant increase was observed for use of known safest ASMs (0.7-18.0 per 10,000 pregnancies) as well as for those with uncertain risk (5.3-13.4 per 10,000 pregnancies). Use of ASMs with higher risk of congenital malformations decreased significantly (24.8-14.5 per 10,000 pregnancies), except for topiramate (0-6.7 per 10,000 pregnancies). Switches between ASM safety risk categories before and during pregnancy were uncommon; women rather discontinued treatment or switched within the same category. There was no clear change for the proportion using polytherapy during pregnancy (12% overall), however a non-significant trend toward inclusion of known safest ASMs was observed over time (1.9-3.6%). CONCLUSIONS: Over the last two decades, there has been an increase in use of known safest ASMs among pregnant women, together with a trend toward newer ASMs with uncertain risk. Only a small proportion of women switched to a safer alternative before or during pregnancy. Altogether, this highlights the need for an expansion of ASM risk knowledge and communication to healthcare providers and women of reproductive age to improve preconception counseling.

Maternal lipid profile in pregnancy and embryonic size: a population-based prospective cohort study.

BACKGROUND: Lipids are crucial for fetal growth and development. Maternal lipid concentrations are associated with fetal growth in the second and third trimester of pregnancy and with birth outcomes. However, it is unknown if this association starts early in pregnancy or arises later during fetal development. The aim of this study was to investigate the association between the maternal lipid profile in early pregnancy and embryonic size. METHODS: We included 1474 women from the Generation R Study, a population based prospective birth cohort. Both embryonic size and the maternal lipid profile were measured between 10 weeks + 1 day and 13 weeks + 6 days gestational age. The maternal lipid profile was defined as total cholesterol, triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), remnant cholesterol, non-high-density (non-HDL-c) lipoprotein cholesterol concentrations and the triglycerides/high-density lipoprotein (TG/HDL-c) ratio. Additionally, maternal glucose concentrations were assessed. Embryonic size was assessed using crown-rump length (CRL) measurements. Associations were studied with linear regression models, adjusted for confounding factors: maternal age, pre-pregnancy body mass index (BMI), parity, educational level, ethnicity, smoking and folic acid supplement use. RESULTS: Triglycerides and remnant cholesterol concentrations are positively associated with embryonic size (fully adjusted models, 0.17 SDS CRL: 95% CI 0.03; 0.30, and 0.17 SDS: 95% CI 0.04; 0.31 per 1 MoM increase, respectively). These associations were not present in women with normal weight (triglycerides and remnant cholesterol: fully adjusted model, 0.44 SDS: 95% CI 0.15; 0.72). Associations between maternal lipid concentrations and embryonic size were not attenuated after adjustment for glucose concentrations. Total cholesterol, HDL-c, LDL-c, non-HDL-c concentrations and the TG/HDL-c ratio were not associated with embryonic size. CONCLUSIONS: Higher triglycerides and remnant cholesterol concentrations in early pregnancy are associated with increased embryonic size, most notably in overweight women. TRIAL REGISTRATION: The study protocol has been approved by the Medical Ethics Committee of the Erasmus University Medical Centre (Erasmus MC), Rotterdam (MEC-2007-413). Written informed consent was obtained from all participants.

Preconception and early-pregnancy risk prediction for birth complications: development of prediction models within a population-based prospective cohort.

BACKGROUND: Suboptimal maternal health already from preconception onwards is strongly linked to an increased risk of birth complications. To enable identification of women at risk of birth complications, we aimed to develop a prediction model for birth complications using maternal preconception socio-demographic, lifestyle, medical history and early-pregnancy clinical characteristics in a general population. METHODS: In a population-based prospective cohort study among 8340 women, we obtained information on 33 maternal characteristics at study enrolment in early-pregnancy. These characteristics covered the preconception period and first half of pregnancy (< 21 weeks gestation). Preterm birth was < 37 weeks gestation. Small-for-gestational-age (SGA) and large-for-gestational-age (LGA) at birth were gestational-age-adjusted birthweight in the lowest or highest decile, respectively. Because of their co-occurrence, preterm birth and SGA were combined into a composite outcome. RESULTS: The basic preconception model included easy obtainable maternal characteristics in the preconception period including age, ethnicity, parity, body mass index and smoking. This basic preconception model had an area under the receiver operating characteristics curve (AUC) of 0.63 (95% confidence interval (CI) 0.61 to 0.65) and 0.64 (95% CI 0.62 to 0.66) for preterm birth/SGA and LGA, respectively. Further extension to more complex models by adding maternal socio-demographic, lifestyle, medical history and early-pregnancy clinical characteristics led to small, statistically significant improved models. The full model for prediction of preterm birth/SGA had an AUC 0.66 (95% CI 0.64 to 0.67) with a sensitivity of 22% at a 90% specificity. The full model for prediction of LGA had an AUC of 0.67 (95% CI 0.65 to 0.69) with sensitivity of 28% at a 90% specificity. The developed models had a reasonable level of calibration within highly different socio-economic subsets of our population and predictive performance for various secondary maternal, delivery and neonatal complications was better than for primary outcomes. CONCLUSIONS: Prediction of birth complications is limited when using maternal preconception and early-pregnancy characteristics, which can easily be obtained in clinical practice. Further improvement of the developed models and subsequent external validation is needed.

Maternal lipid levels in early pregnancy as a predictor of childhood lipid levels: a prospective cohort study.

BACKGROUND: Maternal lipid levels in early pregnancy are associated with maternal health and foetal growth. It is however unclear if maternal lipids in early pregnancy can be used to predict childhood lipid levels. The aim of this study is to assess the association between maternal and offspring childhood lipid levels, and to investigate the influence of maternal BMI and diet on these associations. METHODS: This study included 2692 women participating in the Generation R study, an ongoing population-based prospective cohort study from early life onwards. Women with an expected delivery date between 2002 and 2006 living in Rotterdam, the Netherlands were included. Total cholesterol, triglycerides and high-density lipoprotein cholesterol (HDL-c) were measured in early pregnancy (median 13.2 weeks [90% range 10.6; 17.1]). Low-density lipoprotein cholesterol (LDL-c), remnant cholesterol and non-HDL-c were calculated. Corresponding lipid measurements were determined in 2692 children at the age of 6 (median 6.0 years [90% range 5.7; 7.5]) and 1673 children 10 years (median 9.7 years [90% range 9.5; 10.3]). Multivariate linear regression analysis was used to examine the association between maternal lipid levels in early pregnancy and the corresponding childhood lipid measurements at the ages of 6 and 10 years while adjusting for confounders. RESULTS: Maternal lipid levels in early pregnancy are positively associated with corresponding childhood lipid levels 6 and 10 years after pregnancy, independent of maternal body mass index and diet. CONCLUSIONS: Maternal lipid levels in early pregnancy may provide an insight to the lipid profile of children years later. Gestational lipid levels may therefore be used as an early predictor of children's long-term health. Monitoring of these gestational lipid levels may give a window-of-opportunity to start early interventions to decrease offspring's lipid levels and possibly diminish their cardiovascular risk later in life. Future studies are warranted to investigate the genetic contribution on maternal lipid levels in pregnancy and lipid levels of their offspring years later.

Social determinants of vulnerability in the population of reproductive age: a systematic review.

BACKGROUND: The health of an (unborn) child is largely determined by the health and social determinants of its parents. The extent to which social determinants of parents or prospective parents affect their own health depends partly on their coping or resilience abilities. Inadequate abilities allow negative effects of unfavourable social determinants to prevail, rendering them vulnerable to adverse health outcomes. Addressing these determinants in the reproductive-aged population is therefore a key approach in improving the health of the future generation. This systematic review aims to synthesise evidence on social determinants of vulnerability, i.e., inadequate coping or low resilience, in the general population of reproductive age. METHODS: The databases EMBASE, Medline, PsycINFO, CINAHL, Google Scholar, Web of Science, and Cochrane Library, were systematically searched from database inception to December 2th 2021. Observational studies examining social determinants and demographics in relation to vulnerability among the general population of reproductive age (men and women aged 18-40 years), conducted in a high-income country in Europe or North America, Australia or New Zealand were eligible for inclusion. Relevant data was extracted from each included article and findings were presented in a narrative and tabulated manner. RESULTS: We identified 40,028 unique articles, of which 78 were full text reviewed. Twenty-five studies were included, of which 21 had a cross-sectional study design (84%). Coping was the most frequently assessed outcome measure (n = 17, 68%). Thirty social determinants were identified. Overall, a younger age, lower socioeconomic attainment, lack of connection with the social environment, and adverse life events were associated with inadequate coping or low resilience. CONCLUSIONS: This review shows that certain social determinants are associated with vulnerability in reproductive-aged individuals. Knowing which factors make people more or less vulnerable carries health-related implications. More high-quality research is needed to obtain substantial evidence on the strength of the effect of these social conditions in this stage of life.