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.

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.

The Effect of an eHealth Coaching Program (Smarter Pregnancy) on Attitudes and Practices Toward Periconception Lifestyle Behaviors in Women Attempting Pregnancy: Prospective Study.

BACKGROUND: Lifestyle behaviors during the periconception period contribute to achievement of a successful pregnancy. Assessment of attitudes and practices toward these modifiable behaviors can aid in identifying gaps in unhealthy lifestyle behaviors with impact on intervention effectiveness. OBJECTIVE: This study investigates the effectiveness of coaching by the eHealth program Smarter Pregnancy during the periconception period on improvement of attitudes and practices toward fruit and vegetable intake and smoking in women attempting pregnancy through assisted reproductive technology (ART) or natural conception. METHODS: Women attempting pregnancy through ART (n=1060) or natural conception (n=631) were selected during the periconception period. The intervention groups, conceived through ART or naturally, received Smarter Pregnancy coaching for 24 weeks, whereas the control group conceived through ART and did not receive coaching. Attitudes and practices at baseline and follow-up periods were obtained from self-administered online questionnaire provided by the program. Attitudes were assessed in women with unhealthy behaviors as their intention to increase their fruit and vegetable intake and to quit smoking using a yes/no question. Outcomes on practices, suggesting effectiveness, included daily fruit (pieces) and vegetable (grams) intake, and if women smoked (yes/no). Changes in attitudes and practices were compared at 12 and 24 weeks with baseline between the ART intervention and ART control groups, and within the intervention groups between ART and natural conception. Changes in practices at 12 and 24 weeks were also compared with baseline between women with negative attitude and positive attitude within the intervention groups: ART and natural conception. Analysis was performed using linear and logistic regression models adjusted for maternal confounders and baseline attitudes and practices. RESULTS: The ART intervention group showed higher vegetable intake and lower odds for negative attitudes toward vegetable intake after 12 weeks (ßadj=25.72 g, P<.001; adjusted odds ratio [ORadj] 0.24, P<.001) and 24 weeks of coaching (ßadj=23.84 g, P<.001; ORadj 0.28, P<.001) compared with ART controls. No statistically significant effect was observed on attitudes and practices toward fruit intake (12 weeks: P=.16 and .08, respectively; 24 weeks: P=.16 and .08, respectively) and smoking behavior (12 weeks: P=.87; 24 weeks: P=.92). No difference was observed for the studied attitudes and practices between the ART intervention and natural conception intervention groups. Women with persistent negative attitude toward fruit and vegetable intake at week 12 showed lower fruit and vegetable intake at week 24 compared with women with positive attitude (ßadj=-.49, P<.001; ßadj=-30.07, P<.001, respectively). CONCLUSIONS: The eHealth Smarter Pregnancy program may improve vegetable intake-related attitudes and practices in women undergoing ART treatment. Women with no intention to increase fruit and vegetable intake had less improvement in their intakes. Despite small changes, this study demonstrates again that Smarter Pregnancy can be used to improve vegetable intake, which can complemented by blended care that combines face-to-face and online care to also improve fruit intake and smoking behavior.

Human oocyte area is associated with preimplantation embryo usage and early embryo development: the Rotterdam Periconception Cohort.

PURPOSE: To investigate the association between oocyte area and fertilization rate, embryo usage, and preimplantation embryo development in order to establish if oocyte area can be a marker for optimal early embryo development. METHODS: From 2017 to 2020, 378 couples with an indication for IVF (n = 124) or ICSI (n = 254) were included preconceptionally in the Rotterdam Periconception Cohort. Resulting oocytes (n = 2810) were fertilized and submitted to time-lapse embryo culture. Oocyte area was measured at the moment of fertilization (t0), pronuclear appearance (tPNa), and fading (tPNf). Fertilization rate, embryo usage and quality, and embryo morphokinetics from 2-cell stage to expanded blastocyst stage (t2-tEB) were used as outcome measures in association with oocyte area. Oocytes were termed "used" if they were fertilized and embryo development resulted in transfer or cryopreservation, and otherwise termed "discarded". Analyses were adjusted for relevant confounders. RESULTS: Oocyte area decreased from t0 to tPNf after IVF and ICSI, and oocytes with larger area shrank faster (ß - 12.6 µm2/h, 95%CI - 14.6; - 10.5, p < 0.001). Oocytes that resulted in a used embryo were larger at all time-points and reached tPNf faster than oocytes that fertilized but were discarded (oocyte area at tPNf in used 9864 ± 595 µm2 versus discarded 9679 ± 673 µm2, p < 0.001, tPNf in used 23.6 ± 3.2 h versus discarded 25.6 ± 5.9 h, p < 0.001). Larger oocytes had higher odds of being used (oocyte area at tPNf ORused 1.669, 95%CI 1.336; 2.085, p < 0.001), were associated with faster embryo development up to the morula stage (e.g., t9 ß - 0.131 min, 95%CI - 0.237; - 0.025, p = 0.016) and higher ICM quality. CONCLUSION: Oocyte area is an informative marker for the preimplantation development of the embryo, as a larger oocyte area is associated with higher quality, faster developing embryos, and higher chance of being used. Identifying determinants associated with oocyte and embryo viability and quality could contribute to improved preconception care and subsequently healthy pregnancies.

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.

The impact of IVF culture medium on post-implantation embryonic growth and development with emphasis on sex specificity: the Rotterdam Periconceptional Cohort.

RESEARCH QUESTION: Are there (sex-specific) differences in first-trimester embryonic growth and morphological development between two culture media used for IVF and intracytoplasmic sperm injection (ICSI) treatment? DESIGN: A total of 835 singleton pregnancies from a prospective hospital-based cohort study were included, of which 153 conceived after IVF/ICSI treatment with Vitrolife G-1™ PLUS culture medium, 252 after culture in SAGE 1-Step™ and 430 were naturally conceived. Longitudinal three-dimensional ultrasound examinations were performed at 7, 9 and 11 weeks of gestation for offline biometric (crown rump length, CRL), volumetric (embryonic volume) and morphological (Carnegie stage) measurements. RESULTS: Embryos cultured in SAGE 1-Step grew faster than those cultured in Vitrolife G-1 PLUS (betaEV 0.030 3√ml [95% CI 0.008-0.052], P = 0.007). After stratification for fetal sex, male embryos cultured in SAGE 1-Step demonstrated faster growth than those cultured in Vitrolife G-1 PLUS (betaEV 0.048 3√ml [95% CI 0.015-0.081], P = 0.005). When compared with naturally conceived embryos, those cultured in SAGE 1-Step grew faster (betaEV 0.040 3√ml [95% CI 0.012-0.069], P = 0.005). This association was most pronounced in male embryos (betaEV 0.078 3√ml [95% CI 0.035-0.120], P < 0.001). CONCLUSIONS: This study shows that SAGE 1-Step culture medium accelerates embryonic growth trajectories compared with Vitrolife G-1 PLUS and naturally conceived pregnancies, especially in male embryos. Further research should focus on the impact of culture media on postnatal development and the susceptibility to non-communicable diseases.

Maternal obesity during pregnancy leads to derangements in one-carbon metabolism and the gut microbiota: implications for fetal development and offspring wellbeing.

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

Dynamic Digital Twin: Diagnosis, Treatment, Prediction, and Prevention of Disease During the Life Course.

A digital twin (DT), originally defined as a virtual representation of a physical asset, system, or process, is a new concept in health care. A DT in health care is not a single technology but a domain-adapted multimodal modeling approach incorporating the acquisition, management, analysis, prediction, and interpretation of data, aiming to improve medical decision-making. However, there are many challenges and barriers that must be overcome before a DT can be used in health care. In this viewpoint paper, we build on the current literature, address these challenges, and describe a dynamic DT in health care for optimizing individual patient health care journeys, specifically for women at risk for cardiovascular complications in the preconception and pregnancy periods and across the life course. We describe how we can commit multiple domains to developing this DT. With our cross-domain definition of the DT, we aim to define future goals, trade-offs, and methods that will guide the development of the dynamic DT and implementation strategies in health care.

Periconceptional maternal body mass index and the impact on post-implantation (sex-specific) embryonic growth and morphological development.

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

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.

The influence of frozen-thawed and fresh embryo transfer on utero-placental (vascular) development: the Rotterdam Periconception cohort.

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

Higher preconceptional maternal body mass index is associated with faster early preimplantation embryonic development: the Rotterdam periconception cohort.

BACKGROUND: Overweight and obesity affect millions of people globally, which has also serious implications for reproduction. For example, treatment outcomes after in vitro fertilisation (IVF) are worse in women with a high body mass index (BMI). However, the impact of maternal BMI on embryo quality is inconclusive. Our main aim is to study associations between preconceptional maternal BMI and morphokinetic parameters of preimplantation embryos and predicted implantation potential. In addition, associations with clinical IVF outcomes are investigated. METHODS: From a tertiary hospital, 268 women undergoing IVF or IVF with intracytoplasmic sperm injection (ICSI) were included; 143 normal weight, 79 overweight and 46 obese women. The embryos of these women were cultured in the EmbryoScope, a time-lapse incubator. The morphokinetic parameters of preimplantation embryos and predicted implantation potential, assessed by the KIDScore algorithm were longitudinally evaluated as primary and secondary outcomes, respectively. The tertiary outcomes included clinical outcomes, i.e., fertilization, implantation and live birth rate. RESULTS: After adjustment for patient- and treatment-related factors, we demonstrated in 938 embryos that maternal BMI is negatively associated with the moment of pronuclear appearance (ßtPNa -0.070 h (95%CI -0.139, -0.001), p = 0.048), pronuclear fading (ßtPNf -0.091 h (95%CI -0.180, -0.003), p = 0.043 and the first cell cleavage (ßt2 -0.111 h (95%CI -0.205, -0.016), p = 0.022). Maternal BMI was not significantly associated with the KIDScore and tertiary clinical treatment outcomes. In embryos from couples with female or combined factor subfertility, the impact of maternal BMI was even larger (ßtPNf -0.170 h (95%CI -0.293, -0.047), p = 0.007; ßt2 -0.199 h (95%CI -0.330, -0.067), p = 0.003). Additionally, a detrimental impact of BMI per point increase was observed on the KIDScore (ß -0.073 (se 0.028), p = 0.010). CONCLUSIONS: Higher maternal BMI is associated with faster early preimplantation development. In couples with female or combined factor subfertility, a higher BMI is associated with a lower implantation potential as predicted by the KIDScore. Likely due to power issues, we did not observe an impact on clinical treatment outcomes. However, an effect of faster preimplantation development on post-implantation development is conceivable, especially since the impact of maternal BMI on pregnancy outcomes has been widely demonstrated.

Prenatal growth trajectories and birth outcomes after frozen-thawed extended culture embryo transfer and fresh embryo transfer: the Rotterdam Periconception Cohort.

RESEARCH QUESTION: Are there differences in prenatal growth trajectories and birth outcomes between singleton pregnancies conceived after IVF treatment with frozen-thawed extended culture embryo transfer at day 5, fresh embryo transfer at day 3 or naturally conceived pregnancies? DESIGN: From a prospective hospital-based cohort, 859 singleton pregnancies were selected, including 133 conceived after IVF with frozen-thawed embryo transfer, 276 after fresh embryo transfer, and 450 naturally conceived pregnancies. Longitudinal 3D ultrasound scans were performed at 7, 9 and 11 weeks of gestation for offline crown-rump length (CRL) and embryonic volume measurements. Second trimester estimated fetal weight was based on growth parameters obtained during the routine fetal anomaly scan at 20 weeks of gestation. Birth outcome data were collected from medical records. RESULTS: No differences regarding embryonic growth trajectories were observed between frozen-thawed and fresh embryo transfer. Birthweight percentiles after fresh embryo transfer were lower than after frozen-thawed embryo transfer (38.0 versus 48.0; P = 0.046, respectively). The prevalence of non-iatrogenic preterm birth (PTB) was significantly lower in pregnancies resulting from fresh embryo transfer compared with frozen-thawed embryo transfer (4.7% versus 10.9%; P = 0.026, respectively). Compared with naturally conceived pregnancies, birthweight percentiles and percentage of non-iatrogenic PTB were significantly lower in pregnancies after fresh embryo transfer and gestational age at birth was significantly higher. CONCLUSIONS: This study shows that embryonic growth is comparable between singleton pregnancies conceived after fresh and frozen-thawed embryo transfer. The lower relative birthweight and PTB rate in pregnancies after fresh embryo transfer than after frozen-thawed embryo transfer and naturally conceived pregnancies warrants further investigation.

Evaluation of embryonic posture using four-dimensional ultrasound and virtual reality.

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

Effect of human embryonic morphological development on fetal growth parameters: the Rotterdam Periconceptional Cohort (Predict Study).

RESEARCH QUESTION: Is embryonic morphological development according to the Carnegie stages associated with pregnancy outcome? DESIGN: In a tertiary hospital-based cohort, 182 singleton non-malformed pregnancies were selected. Serial transvaginal three-dimensional ultrasound (3D-US) scans were carried out between 6+0 and 10+2 gestational weeks. Embryonic development was annotated according to the morphological criteria of the Carnegie classification using a virtual reality system. Second-trimester biparietal diameter, head circumference, abdominal circumference and femur length measurements were retrieved from medical records. Z-scores were calculated for mid-pregnancy estimated fetal weight (EFW) and newborn birth weight. Associations between longitudinal Carnegie stages and fetal growth parameters were investigated using linear mixed models, with subgroup analysis based on fetal gender. RESULTS: A total of 576 first-trimester 3D-US scans were analysed (median of three scans per pregnancy). Embryonic development was positively associated with EFW z-score (ß = 0.69; 95% CI 0.51 to 0.86; P < 0.001), biparietal diameter and femur length, but not with head circumference, abdominal circumference and birth weight z-score. After stratification for fetal gender, positive associations for both males and females were confirmed between embryonic development and EFW z-scores. Moreover, opposite gender-specific associations were detected between embryonic development and birth weight z-scores (males: ß = 0.37; 95% CI 0.04 to 0.70; P < 0.05; females: ß = -0.36; 95% CI -0.62 to -0.10; P < 0.01). CONCLUSIONS: Human embryonic development according to the Carnegie stages is associated with fetal growth parameters with gender-specificity of birth weight. These results emphasize the importance of the first-trimester of pregnancy, raising the morphological staging of the embryo as a new methodology for early risk assessment and improvement of subsequent fetal growth parameters.

The MOVE-trial: Monocryl® vs. Vicryl Rapide™ for skin repair in mediolateral episiotomies: a randomized controlled trial.

BACKGROUND: Previous studies have shown that complaints after episiotomy repair depend on the method and material used for repair. The objective of our study was to determine which of two frequently used suture materials, Monocryl® (poliglecaprone 25) and Vicryl Rapide™ (polyglactin 910), is superior for intracutaneous closure of the skin in mediolateral episiotomies. METHODS: In a randomized controlled trial performed in a teaching hospital in the Netherlands between 2010 and 2013 250 primiparous women with uncomplicated mediolateral episiotomies were randomly allocated to intracutaneous skin closure with either Monocryl® or Vicryl Rapide™. All other layers were sutured with Vicryl 2-0 and Vicryl 0 in both groups. Pain scores and complications were documented using questionnaires during the first three months post partum. The primary outcome was pain 10 days after delivery in sitting position established by Visual Analogous Scale (VAS). Secondary outcomes were pain scores at different time points and reported complications such as infections, dehiscence and dyspareunia one day, 10 days, six weeks and three months after delivery. RESULTS: Of 250 allocated women 54% returned questionnaires. No statistical difference was found between both groups for the primary outcome (VAS 2,8 (95% CI 2,18-3,44) vs. VAS 2,5 (95% CI 2,00-2,98), p = 0,43). With regard to secondary outcomes only self-reported dehiscence was significantly different, favouring Monocryl® (10% vs. 25%, p = 0.016). CONCLUSIONS: Use of Monocryl® 3-0 and Vicryl Rapide™ 3-0 for intracutaneous closure of the skin after mediolateral episiotomy leads to equal pain scores ten days after delivery and therefore both materials may be considered for this use. Monocryl® 3-0 might be favourable over Vicryl Rapide™ 3-0 due to less self-reported dehiscence after intracutaneous closure of the skin in mediolateral episiotomies. TRIAL REGISTRATION: The trial was retrospectively registered under trial nr. ISRCTN29869308 on 20-04-2016.

Impact of first-trimester anomaly scan on health-related quality of life and healthcare costs: a scoping review.

IMPORTANCE: The first-trimester anomaly scan (FTAS) has the potential to detect major congenital anomalies in an early stage of pregnancy. Due to this potential early detection, there is a trend to introduce FTAS in regular care. Data regarding the impact of FTAS on the patient's perspective are limited. OBJECTIVE: To provide an overview of the literature assessing the impact of the FTAS on health-related quality of life (HRQoL) and healthcare costs. EVIDENCE ACQUISITION: Literature search was performed in Embase, PubMed, Medline Ovid, Cochrane Library database, Web-of-Science, and Google Scholar were searched. All studies that reported the performance of a nuchal translucency measurement with a basic fetal assessment HRQoL or healthcare costs of FTAS were included. Studies solely describing screening of chromosomal anomalies were excluded. Three authors independently screened the studies and extracted the data. Results were combined using descriptive analysis. PROSPERO registration number: CRD42016045190. RESULTS: The search yielded 3242 articles and 16 were included. Thirteen articles (7045 pregnancies) examined the relationship between FTAS and HRQoL. Anxiety scores were raised temporarily before FTAS and returned to early pregnancy baseline following the absence of anomalies. Depression scores did not change significantly as a result of FTAS. Three articles studied healthcare costs. These studies, published before 2005, found a combination of FTAS and second-trimester anomaly scan (STAS) resulted in an increased amount of detected anomalies when compared to a STAS-only regimen. However, the combination would also be more costly. CONCLUSIONS: Women experience anxiety in anticipation of the FTAS result and following a reassuring FTAS result, anxiety returns to the baseline level. FTAS seems to be a reassuring experience. The included studies on costs showed the addition of FTAS is likely to increase the number of detected anomalies against an increase in healthcare costs per pregnancy.Review registration: PROSPERO CRD42016045190.

Discrepancies in Embryonic Staging: Towards a Gold Standard.

For over half a century, the Carnegie staging system has been used for the unification of chronology in human embryo development. Despite the system's establishment as a "universal" system, Carnegie staging reference charts display a high level of variation. To establish a clear understanding for embryologists and medical professionals, we aimed to answer the following question: does a gold standard of Carnegie staging exist, and if so, which set of proposed measures/characteristics would it include? We aimed to provide a clear overview of the variations in published Carnegie staging charts to compare and analyze these differences and propose potential explanatory factors. A review of the literature was performed, wherein 113 publications were identified and screened based on title and abstract. Twenty-six relevant titles and abstracts were assessed based on the full text. After exclusion, nine remaining publications were critically appraised. We observed consistent variations in data sets, especially regarding embryonic age, varying as large as 11 days between publications. Similarly, for embryonic length, large variations were present. These large variations are possibly attributable to sampling differences, developing technology, and differences in data collection. Based on the reviewed studies, we propose the Carnegie staging system of Prof. Hill as a gold standard amongst the available data sets in the literature.

Computational methods for the analysis of early-pregnancy brain ultrasonography: a systematic review.

BACKGROUND: Early screening of the brain is becoming routine clinical practice. Currently, this screening is performed by manual measurements and visual analysis, which is time-consuming and prone to errors. Computational methods may support this screening. Hence, the aim of this systematic review is to gain insight into future research directions needed to bring automated early-pregnancy ultrasound analysis of the human brain to clinical practice. METHODS: We searched PubMed (Medline ALL Ovid), EMBASE, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and Google Scholar, from inception until June 2022. This study is registered in PROSPERO at CRD42020189888. Studies about computational methods for the analysis of human brain ultrasonography acquired before the 20th week of pregnancy were included. The key reported attributes were: level of automation, learning-based or not, the usage of clinical routine data depicting normal and abnormal brain development, public sharing of program source code and data, and analysis of the confounding factors. FINDINGS: Our search identified 2575 studies, of which 55 were included. 76% used an automatic method, 62% a learning-based method, 45% used clinical routine data and in addition, for 13% the data depicted abnormal development. None of the studies shared publicly the program source code and only two studies shared the data. Finally, 35% did not analyse the influence of confounding factors. INTERPRETATION: Our review showed an interest in automatic, learning-based methods. To bring these methods to clinical practice we recommend that studies: use routine clinical data depicting both normal and abnormal development, make their dataset and program source code publicly available, and be attentive to the influence of confounding factors. Introduction of automated computational methods for early-pregnancy brain ultrasonography will save valuable time during screening, and ultimately lead to better detection, treatment and prevention of neuro-developmental disorders. FUNDING: The Erasmus MC Medical Research Advisor Committee (grant number: FB 379283).

A high periconceptional maternal ultra-processed food consumption impairs embryonic growth: The Rotterdam periconceptional cohort.

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