The effect of a locally tailored intervention on the uptake of preconception care in the Netherlands: a stepped-wedge cluster randomized trial (APROPOS-II study).

BACKGROUND: The preconception period provides a window of opportunity for interventions aiming to reduce unhealthy lifestyle behaviours and their negative effect on pregnancy outcomes. This study aimed to assess the effectiveness of a locally tailored preconception care (PCC) intervention in a hybrid-II effectiveness implementation design. METHODS: A stepped-wedge cluster randomized controlled trial was performed in four Dutch municipalities. The intervention contained a social marketing strategy aiming to improve the uptake (prospective parents) and the provision (healthcare providers) of PCC. Prospective parents participated by administering a questionnaire in early pregnancy recalling their preconceptional behaviours. Experiences of healthcare providers were also evaluated through questionnaires. The composite primary outcome was adherence to at least three out of four preconceptional lifestyle recommendations (early initiation of folic acid supplements, healthy nutrition, no smoking or alcohol use). Secondary outcomes were preconceptional lifestyle behaviour change, (online) reach of the intervention and improved knowledge among healthcare providers. RESULTS: A total of 850 women and 154 men participated in the control phase and 213 women and 39 men in the intervention phase. The composite primary outcome significantly improved among women participating in the municipality where the reach of the intervention was highest (Relative Risk (RR) 1.57 (95% Confidence Interval (CI) 1.11-2.22). Among women, vegetable intake had significantly improved in the intervention phase (RR 1.82 (95%CI 1.14-2.91)). The aimed online reach- and engagement rate of the intervention was achieved most of the time. Also, after the intervention, more healthcare providers were aware of PCC-risk factors (54.5% vs. 47.7%; p = 0.040) and more healthcare providers considered it easier to start a conversation about PCC (75.0% vs. 47.9%; p = 0.030). CONCLUSION: The intervention showed some tentative positive effects on lifestyle behaviours among prospective parents. Primarily on vegetable intake and the knowledge and competence of healthcare providers. The results of this study contribute to the evidence regarding successfully implementing PCC-interventions to optimize the health of prospective parents and future generations. TRIAL REGISTRATION: Dutch Trial Register: NL7784 (Registered 06/06/2019).

First-trimester utero-placental (vascular) development and embryonic and fetal growth: The Rotterdam periconception cohort.

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

The physiological effect of early pregnancy on a woman's response to a submaximal cardiopulmonary exercise test.

Given all its systemic adaptive requirements, pregnancy shares several features with physical exercise. In this pilot study, we aimed to assess the physiological response to submaximal cardiopulmonary exercise testing (CPET) in early pregnancy. In 20 healthy, pregnant women (<13 weeks gestation) and 20 healthy, non-pregnant women, we performed a CPET with stationary cycling during a RAMP protocol until 70% of the estimated maximum heart rate (HR) of each participant. Hemodynamic and respiratory parameters were non-invasively monitored by impedance cardiography (PhysioFlow® ) and a breath-by-breath analyzer (OxyconTM ). To compare both groups, we used linear regression analysis, adjusted for age. We observed a similar response of stroke volume, cardiac output (CO) and HR to stationary cycling in pregnant and non-pregnant women, but a slightly lower 1-min recovery rate of CO (-3.9 [-5.5;-2.3] vs. -6.6 [-8.2;-5.1] L min-1  min-1 ; p = .058) and HR (-38 [-47; -28] vs. -53 [-62; -44] bpm/min; p = .065) in pregnant women. We also observed a larger increase in ventilation before the ventilatory threshold (+6.2 [5.4; 7.0] vs. +3.2 [2.4; 3.9] L min-1  min-1 ; p < .001), lower PET CO2 values at the ventilatory threshold (33 [31; 34] vs. 36 [34; 38] mmHg; p = .042) and a larger increase of breathing frequency after the ventilatory threshold (+4.6 [2.8; 6.4] vs. +0.6 [-1.1; 2.3] breaths min-1  min-1 ; p = .015) in pregnant women. In conclusion, we observed a slower hemodynamic recovery and an increased ventilatory response to exercise in early pregnancy.

Undetected anomalies in foetuses with a prenatal diagnosis of isolated cleft.

The aim of this study was to determine the rate of undetected additional anomalies following a prenatal diagnosis of isolated oral cleft. Data of all infants with a prenatal diagnosis of isolated oral cleft born between 2000 and 2015 were studied retrospectively. Additional anomalies detected after birth were categorized as minor or major and included structural and chromosomal anomalies. Isolated clefts of the lip (CL), lip and alveolus (CLA) and lip, alveolus, and palate (CLAP) were diagnosed prenatally in 176 live-born infants. The type of cleft was more extensive after birth in 34/176 (19.3%) and less extensive in 16/176 (9.1%) newborns. Additional anomalies were diagnosed in 24 infants (13.6%), of which 12 (6.8%) were categorized as major. The latter included two submicroscopic chromosome anomalies and two gene mutations. Postnatal additional anomalies occurred more frequently in CLA and CLAP than in CL, and more in bilateral than in unilateral clefts. Major anomalies are still found in infants with a prenatal diagnosis of an isolated oral cleft. The prevalence of additional anomalies seems to be related to the type and bilaterality of the cleft, and this should be considered during prenatal counselling.

A compromised maternal vitamin D status is associated with congenital heart defects in offspring.

BACKGROUND: Interactions between genetic and environmental factors, including modifiable maternal nutrition and lifestyle, play a significant role in the pathogenesis of most congenital heart defects (CHD). The aim of this study was to investigate associations between periconceptional maternal vitamin D status and the prevalence of CHD in offspring. METHODS: A case-control study was performed in 345 mothers of a child with CHD and 432 mothers of a child without CHD from four tertiary hospitals in the Netherlands between 2003 and 2005. Approximately 15months after pregnancy mothers filled out questionnaires regarding general characteristics and periconceptional lifestyle. Maternal blood was obtained to determine serum 25-hydroxyvitamin D and lipid concentrations. The 25-hydroxyvitamin D concentration was stratified into a deficient <50nmol/l, moderate 50-75nmol/l and adequate >75nmol/l status. Logistic regression was performed to study associations between vitamin D status and CHD risk, adjusted for maternal age, body mass index, ethnicity, smoking and total cholesterol concentration. RESULTS: Case mothers less often had an adequate vitamin D status compared with controls (27% vs. 38%; p=0.002). The use of multivitamin supplements, ethnicity, season and body mass index were associated with vitamin D concentrations. A moderate (odds ratio 1.58, [95%CI 1.08, 2.32]) and deficient (odds ratio 2.15, [95%CI 1.44-3.19]) vitamin D status were associated with CHD in offspring. CONCLUSION: A compromised maternal vitamin D status is associated with an approximately two-fold increased prevalence of CHD in offspring. Therefore, improvement of the periconceptional maternal vitamin D status is recommended.

New imaging markers for preconceptional and first-trimester utero-placental vascularization.

INTRODUCTION: The availability of imaging makers of early placental circulation development is limited. This study aims to develop a feasible and reliable method to assess preconceptional and early first-trimester utero-placental vascular volumes using three-dimensional power Doppler (3D PD) ultrasound on two different Virtual Reality (VR) systems. METHODS: 3D PD ultrasound images of the uterine and placental vasculature were obtained in 35 women, either preconceptionally (n = 5), or during pregnancy at 7 (n = 10), 9 (n = 10) or 11 (n = 10) weeks of gestation. Preconceptional uterine vascular volume (UVV), first-trimester placental vascular volume (PVV) and embryonic vascular volume (EVV) were measured by two observers on two VR systems, i.e., a Barco I-Space and VR desktop. Intra- and inter-observer agreement and intersystem agreement were assessed by intra-class correlation coefficients (ICC) and absolute and relative differences. RESULTS: Uterine-, embryonic- and placental vascular volume measurements showed good to excellent intra- and inter-observer agreement and inter-system reproducibility with most ICC above 0.80 and relative differences of less than 20% preconceptionally and almost throughout the entire gestational age range. Inter-observer agreement of PVV at 11 weeks gestation was suboptimal (ICC 0.69, relative difference 50.1%). DISCUSSION: Preconceptional and first-trimester 3D PD ultrasound utero-placental and embryonic vascular volume measurements using VR are feasible and reliable. Longitudinal cohort studies with repeated measurements are needed to further validate this and assess their value as new imaging markers for placental vascular development and ultimately for the prediction of placenta-related pregnancy complications.

Parental perspectives on the awareness and delivery of preconception care.

BACKGROUND: The attention for Preconception Care (PCC) has grown substantially in recent years, yet the implementation of PCC appears challenging as uptake rates remain low. The objective of this study was to assess parental perspectives on how PCC should be provided. METHODS: Recruitment of participants took place among couples who received antenatal care at a Dutch community midwifery practice. Between June and September 2014, five focus group sessions were held with 29 women and one focus group session with 5 men. Thematic analysis was conducted using NVivo 10 software. RESULTS: Participants were generally unfamiliar with the concept of PCC. It was proposed to raise awareness by means of a promotional campaign, stipulating that PCC is suited for every couple with a (future) child wish. Suggestions were made to display marketing materials in both formal and informal (local community) settings. Addressing existing social networks and raising social dialogue was expected to be most efficient. It was recommended to make PCC more accessible by offering multiple forms and to involve male partners. Opportunistic offering PCC by healthcare providers was considered more acceptable when the subject was deliberately raised, for example while discussing contraceptives, lifestyle risks or drug prescriptions. GP's or midwifes were regarded the most suitable PCC providers, however provider characteristics such as experience, empathy and communication skills were considered more important. CONCLUSIONS: This study showed that from the parental perspective it is recommended to address every couple with a (future) child wish by means of enlarging the awareness and accessibility of PCC. In order to enlarge the awareness, it is recommended to address social networks, to raise the social dialogue and to conduct promotional campaigns regarding PCC. In order to improve the accessibility of PCC, it was suggested to simultaneously offer multiple forms: group sessions, individual consultations, walk-in-hours and online sessions, and to involve male partners.

Healthcare providers' views on the delivery of preconception care in a local community setting in the Netherlands.

BACKGROUND: The attention for preconception care (PCC) has grown substantially in recent years, yet PCC is far from routine in daily practice. One of the major challenges for the implementation of PCC is to identify how it can best be organized and provided within the primary care setting. The aim of this study was to identify bottlenecks and solutions for the delivery of PCC from a healthcare providers' perspective in a local community setting in the Netherlands. METHODS: Health professionals within the region of Zeist, the Netherlands, were invited for a meeting on the local implementation of PCC. Five parallel group sessions were held with 30 participants from different disciplines. The sessions were moderated based on the Nominal Group Technique, in which bottlenecks (step 1) and solutions (step 2) for the delivery of PCC were gathered, categorized and prioritized by the participants. RESULTS: Participants expressed that the provision of PCC is challenging due to lack of awareness, the absence of a costing structure and unclear allocation of responsibilities. The most pragmatic approach considered was to make interdisciplinary arrangements within the local primary care setting. Participants recommended to 1) settle a costing structure by means of third party reimbursement, 2) improve collaboration by means of a local cooperation network and an adequate referral system, 3) invest in education, tools and logistics and 4) increase uptake rates by the routine opportunistic offer of PCC and promotional campaigns. CONCLUSIONS: From a provider's perspective a tailored approach is advocated in which interdisciplinary arrangements for collaboration and referral are set up within the local primary care setting.

Effect of signal acquisition method on the fetal heart rate analysis with phase rectified signal averaging.

Phase rectified signal averaging (PRSA) is increasingly used for fetal heart rate (FHR) monitoring, both with traces acquired with external Doppler cardiotocography (D-FHR), and with transabdominal fetal electrocardiography (ta-FHR). However, it is unclear to what extend the acquisition method influences the PRSA analysis, whether results from using one acquisition method are comparable to those based on FHR acquired by the other method, and if not, which should be the preferred method. To address these questions, we applied PRSA analysis to 28 antepartum synchronous recordings of the FHR using simultaneously D-FHR and ta-FHR. The data included late-onset intrauterine growth restricted (IUGR) fetuses (n = 20) and non-IUGR fetuses (n = 8), all of them at gestation ⩾34 weeks. PRSA analysis depends on two parameters intrinsic to the algorithm, T and S. We analyzed the data using parameters that included all values adopted by other researchers previously (derived from a literature search in PubMed and Google Scholar). T and S were adjusted for the difference in acquisition techniques. We found that the correlation between PRSA analysis based on D-FHR and ta-FHR decreased with decreasing values of the PRSA parameters T and S. Therefore, the acquisition technique affects PRSA values for high resolution PRSA (low values of T and S). In conclusion, for low resolution PRSA, the results from both acquisition methods are comparable. Because ta-FHR signals provide beat to beat data and thus capture more subtle differences in the heart rate variation than D-FHR signals (pre-processed by commercial monitors), we assumed that ta-FHR may provide potentially valuable extra information compared to D-FHR. However, no parameter settings or acquisition method seemed to have a diagnostic value for identifying the late-onset IUGR babies in our dataset.

Androgen levels in women with various forms of ovarian dysfunction: associations with cardiometabolic features.

STUDY QUESTION: Are differences in androgen levels among women with various forms of ovarian dysfunction associated with cardiometabolic abnormalities? SUMMARY ANSWER: Androgen levels differed substantially between women with and without ovarian dysfunction, and increased androgen levels were associated with impaired cardiometabolic features in all women irrespective of their clinical condition. WHAT IS KNOWN ALREADY: Sex steroid hormones play important roles in the development of cardiovascular diseases (CVD). Extremes of low as well as high androgen levels have been associated with increased CVD risk in both men and women. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included 680 women with polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), natural post-menopausal women (NM), or regular menstrual cycles (RC) (170 women per group). PARTICIPANTS/MATERIALS, SETTING, METHODS: Measurements of serum testosterone, androstenedione and dehydroepiandrosterone sulfate were performed using liquid chromatography-tandem mass spectrometry. Assessments were taken of body mass index (BMI), blood pressure, lipid profiles, glucose, insulin and SHBG, and the bioactive fraction of circulating testosterone was calculated using the free androgen index (FAI). MAIN RESULTS AND THE ROLE OF CHANCE: PCOS women were hyperandrogenic [median FAI = 4.9 (IQR 3.6-7.4)], and POI women were hypoandrogenic [FAI = 1.2 (0.8-1.7)], compared with RC women [FAI = 1.7 (1.1-2.8)], after adjustment for age, ethnicity, smoking and BMI (P < 0.001). After adjustment for age, there were no significant differences in androgens between POI and NM (P = 0.15) women and between NM and RC (P = 0.27) women, the latter indicating that chronological aging rather than ovarian aging influences the differences between pre- and post-menopausal women. A high FAI was associated with elevated triglycerides (ß log FAI for PCOS: 0.45, P < 0.001, POI: 0.25, P < 0.001, NM: 0.20, P = 0.002), insulin (ß log FAI for PCOS: 0.77, POI: 0.44, NM: 0.40, all P < 0.001), HOMA-IR (ß log FAI for PCOS: 0.82, POI: 0.46, NM: 0.47, all P < 0.001) and mean arterial pressure (ß log FAI for PCOS: 0.05, P = 0.002, POI: 0.07, P < 0.001, NM: 0.04, P = 0.04) in all women; with increased glucose (ß log FAI for PCOS: 0.05, P = 0.003, NM: 0.07, P < 0.001) and decreased high-density lipoprotein (ß log FAI for PCOS: -0.23, P < 0.001, NM: -0.09, P = 0.03) in PCOS and NM women; and with increased low-density lipoprotein (ß log FAI for POI: 0.083, P = 0.041) in POI women. Adjustment for BMI attenuated the observed associations. Associations between FAI and cardiometabolic features were the strongest in PCOS women, even after adjustment for BMI. LIMITATIONS, REASONS FOR CAUTION: Associations between androgen levels and cardiometabolic features were assessed in PCOS, POI and NM women only, due to a lack of available data in RC women. Due to the cross-sectional design of the current study, the potential associations between androgen levels and actual future cardiovascular events could not be assessed. WIDER IMPLICATIONS OF THE FINDINGS: This study affirms the potent effect of androgens on cardiometabolic features, indicating that androgens should indeed be regarded as important denominators of women's health. Future research regarding the role of androgens in the development of CVD and potential modulatory effects of BMI is required. STUDY FUNDING/COMPETING INTERESTS: N.M.P.D. is supported by the Dutch Heart Foundation (grant number 2013T083). L.J. and O.H.F. work in ErasmusAGE, a center for aging research across the life course, funded by Nestlé Nutrition (Nestec Ltd), Metagenics Inc. and AXA. M.K. is supported by the AXA Research Fund. Nestlé Nutrition (Nestec Ltd), Metagenics Inc. and AXA had no role in the design and conduct of the study; the collection, management, analysis and interpretation of the data; or the preparation, review or approval of the manuscript. J.S.E.L. has received fees and grant support from the following companies (in alphabetical order): Ferring, Merck-Serono, Merck Sharpe & Dome, Organon, Schering Plough and Serono. In the last 5 years, B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order); Actavis, COGI, Euroscreen, Ferring, Finox, Genovum, Gedeon-Richter, Merck-Serono, OvaScience, Pantharei Bioscience, PregLem, Roche, Uteron and Watson laboratories. With regard to potential conflicts of interest, there is nothing further to disclose.

Biopsy techniques to study the human placental bed.

BACKGROUND: The physiologic transformation of uterine spiral arteries in the human placental bed is essential for a healthy pregnancy. Failure of this transformation due to deficient trophoblast invasion is widely believed to underlie pregnancy complications such as preeclampsia, foetal growth restriction, miscarriage and preterm labour. Understanding of invasive behaviour and remodelling properties of trophoblasts in the uterine wall is essential in elucidating the aetiology of these pregnancy complications. However, there is a lack of satisfactory specimens of the placental bed to enhance our knowledge on the mechanisms that control trophoblast invasion. Several techniques can be used to obtain biopsies from the placental bed and sample handling can be executed differently depending on the research question. METHODS: This systematic review provides an overview of all studies investigating the placental bed and sampling techniques used. Papers that described surgical techniques, specimen handling, complications and/or success rate of the placental bed biopsy procedures were included. Placental bed biopsies are an essential and feasible technique to study abnormalities in the placental bed associated with pregnancy complications. RESULTS: Depending on the technique used the likelihood of sampling a spiral artery and trophoblast from the placental bed is 51%-78% per case, without significant complications. CONCLUSIONS: Caution is needed when interpreting data if the placental bed is subjected to labour. We propose a uniform sampling technique and conservation protocol for the study of the placental bed and provide tools for selection of the appropriate technique for future placental bed collections.

[Increased risk of type II diabetes mellitus and cardiovascular disease after gestational diabetes mellitus: a systematic review]. / Verhoogd risico op diabetes mellitus type 2 en hart- en vaatziekten na diabetes gravidarum: een systematische review.

OBJECTIVE: To determine the long-term risk of developing type II diabetes (T2D) and cardiovascular disease (CVD) for women with a history of gestational diabetes mellitus. DESIGN: Systematic review and meta-analysis. METHOD: Two search strategies were used in PubMed and Embase to determine the long-term risks of developing T2D and CVD after a pregnancy complicated by gestational diabetes mellitus. After critical appraisal of the papers found, 11 papers were included, involving a total of 328,423 patients. Absolute and relative risks (RRs) were calculated. RESULTS: Eight studies (n=276,829) reported on the long-term risk of T2D and 4 (n=141,048) on the long-term risk of CVD. Follow-up ranged from 3.5 to 11.5 years for T2D and from 1.2 to 74.0 years for CVD. Women with gestational diabetes had a risk of T2D varying between 9.5% and 37.0% and a risk of CVD of between 0.28% and 15.5%. Women with gestational diabetes were at increased risk of T2D (weighted RR: 13.2; 95% CI: 8.5-20.7) and CVD (weighted RR: 2.0; 95% CI: 1.1-3.7) compared to women without gestational diabetes. CONCLUSION: Women with prior gestational diabetes mellitus have a significantly increased risk of developing T2D and CVD. It is very important that gestational diabetes is recognised as a cardiovascular risk factor in daily practice. It would be desirable to screen this group of women for the presence of hyperglycaemia and other cardiovascular risk factors. Further research is required to be able to specify the long-term risk of T2D and CVD and to demonstrate whether such screening is cost-effective.

Detection of fetal chromosomal anomalies: does nuchal translucency measurement have added value in the era of non-invasive prenatal testing?

OBJECTIVES: The objective of this study is to determine what percentage of fetal chromosomal anomalies remains undetected when first trimester combined testing is replaced by non-invasive prenatal testing for trisomies 13, 18, and 21. We focused on the added clinical value of nuchal translucency (NT) measurement. METHODS: Data on fetal karyotype, ultrasound findings, and pregnancy outcome of all pregnancies with an NT measurement ≥3.5 mm were retrospectively collected from a cohort of 25,057 singleton pregnancies in which first trimester combined testing was performed. RESULTS: Two hundred twenty-five fetuses (0.9 %) had an NT ≥3.5 mm. In 24 of these pregnancies, a chromosomal anomaly other than trisomy 13, 18, or 21 was detected. Eleven resulted in fetal demise, and ten showed fetal ultrasound anomalies. In three fetuses with normal ultrasound findings, a chromosomal anomaly was detected, of which one was a triple X. CONCLUSIONS: In three out of 25,057 pregnancies (0.01%), non-invasive prenatal testing and fetal ultrasound would have missed a chromosomal anomaly that would have been identified by NT measurement. © 2015 John Wiley & Sons, Ltd.

Human fetal growth is constrained below optimal for perinatal survival.

OBJECTIVE: The use of fetal growth charts assumes that the optimal size at birth is at the 50(th) birth-weight centile, but interaction between maternal constraints on fetal growth and the risks associated with small and large fetal size at birth may indicate that this assumption is not valid for perinatal mortality rates. The objective of this study was to investigate the distribution and timing (antenatal, intrapartum or neonatal) of perinatal mortality and morbidity in relation to birth weight and gestational age at delivery. METHODS: Data from over 1 million births occurring at 28-43 weeks' gestation from singleton pregnancies without congenital abnormalities in the period from 2002 to 2008 were collected from The Netherlands Perinatal Registry. The distribution of perinatal mortality according to birth-weight centile and gestational age at delivery was studied. RESULTS: In the 1 170 534 pregnancies studied, there were 5075 (0.43%) perinatal deaths. The highest perinatal mortality occurred in those with a birth weight below the 2.3(rd) centile (25.4/1000 births) and the lowest mortality was in those with birth weights between the 80(th) and 84(th) centiles (2.4/1000 births), according to routinely used growth charts. Antepartum deaths were lowest in those with birth weight between the 90(th) and 95(th) centiles. Data were almost identical when the analysis was restricted to infants born at ≥ 37 weeks' gestation. CONCLUSION: From an immediate survival perspective, optimal fetal growth requires a birth weight between the 80(th) and 84(th) centiles for the population. Median birth weight in the population is, by definition, substantially lower than these centiles, implying that the majority of fetuses exhibit some form of maternal constraint on growth. This finding is consistent with adaptations that have evolved in humans in conjunction with a large head and bipedalism, to reduce the risk of obstructed delivery. These data also fit remarkably well with those on long-term adult cardiovascular and metabolic health risks, which are lowest in cases with a birth weight around the 90(th) centile.

Preconception predictors of gestational diabetes: a multicentre prospective cohort study on the predominant complication of pregnancy in polycystic ovary syndrome.

STUDY QUESTION: Can we develop an adequate preconception prediction model to identify those women with polycystic ovary syndrome (PCOS) who have an increased risk of developing gestational diabetes mellitus (GDM) during subsequent pregnancy? STUDY ANSWER: The risk of developing GDM in women with PCOS can be adequately predicted prior to conception by a prediction model. WHAT IS KNOWN ALREADY: Women with PCOS are at increased risk of pregnancy complications, especially GDM. GDM has serious short-term and long-term effects on mother and baby. STUDY DESIGN, SIZE, DURATION: This study is a part of a multicentre prospective cohort study, which was conducted between April 2008 and April 2012. A total of 326 women with PCOS were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with PCOS and a wish to conceive were included prior to conception and followed until 6 weeks after delivery. Maternal, neonatal and birth complications were reported. A multivariate model was developed to predict the most common pregnancy complication, GDM, by using univariate and multivariate logistic regression of preconception patient characteristics. The area under the curve (AUC) of the receiver-operating characteristic was used to test the performance of the model. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 189 women (58%) achieved an ongoing pregnancy (8% multiples) and delivered a live-born neonate. One or two maternal complications occurred in 62 (33%) pregnant women, mainly GDM (n = 41; 22%) and pregnancy-induced hypertension (n = 14; 7%). In children, one or two complications were observed in 49 (26%) of 206 children born, e.g. premature delivery (n = 23; 12%) and small for gestational age (n = 15; 8%). The preconception prediction model for GDM performed well (AUC 0.87, 95% CI 0.81-0.93). First-degree relatives with type 2 diabetes mellitus, serum levels of fasting glucose, fasting insulin, androstenedione and sex hormone-binding globulin before conception were identified as predictors. LIMITATIONS, REASONS FOR CAUTIONS: The prediction model has not yet been externally validated in another group of patients. Also, there were missing data for some of the determinants, which were accounted for by multiple imputation. WIDER IMPLICATIONS OF THE FINDINGS: Women with PCOS who achieve a pregnancy have an increased risk of GDM. The prediction model can be used to identify women particularly at risk for GDM who should be monitored closely to enable preventative measures that may reduce the risk of developing GDM and its adverse consequences. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for the study. M.A.W., S.M.V.V., A.J.G., A.F. and M.P.H.K. have nothing to disclose. C.B.L has received fees and grant support from the following companies (in alphabetic order): Auxogen, European Society of Human Reproduction and Embryology and MSD. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gennovum, Merck-Serono, MSD, Organon, Schering Plough, Sharp & Dome and Serono. M.J.C. has received grant support from the following companies (in alphabetic order): Illumina and MSD. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order): Ferring, Ova-Science, PregLem SA, Roche and Watson Laboratories. TRIAL REGISTRATION NUMBER: NCT00821379 [Clinicaltrials.gov].

Evaluation of antenatal umbilical coiling index at 16-21 weeks of gestation as a predictor of trisomy 21 and other chromosomal defects.

OBJECTIVES: To determine whether there is an association between sonographically assessed hyper- or hypocoiling of the umbilical cord and the presence of trisomy 21, to provide reference values for the antenatal umbilical coiling index (aUCI) at a gestational age of 16-21 weeks and to determine whether these measurements are reliable and reproducible. METHODS: This was a prospective study of 737 pregnancies in which the aUCI was measured between 16 and 21 weeks of gestation by ultrasound at the time of amniocentesis. The aUCI was calculated as the reciprocal value of the mean length of one complete coil in centimeters. We created reference curves and studied the relationship with trisomy 21 and other chromosomal defects. In 30 pregnancies we studied the intra- and interobserver variation in measurements using Bland-Altman plots with associated 95% limits of agreement and intraclass correlation coefficients. RESULTS: aUCI was found to be non-linearly related to gestational age at 16-21 weeks and reference curves were created for the mean aUCI and the 2.3(rd) , 10(th) , 90(th) and 97.7(th) percentiles. There was no significant difference in aUCI values between the reference group (n = 714) and cases with trisomy 21 (n = 16) or other aneuploidies (n = 7) (one-way ANOVA, P = 0.716). There was good intra- and interobserver agreement in aUCI measurements. CONCLUSIONS: The aUCI can be measured reliably and varies according to gestational age at 16-21 weeks. The aUCI was not significantly associated with trisomy 21 or other chromosomal defects.

PP036. Cardiovascular disease risk factors among women with a history of placental abruption.

INTRODUCTION: Several studies have shown that the risk of premature cardiovascular disease (CVD) is increased after maternal placental syndromes (MPS), including hypertensive disorders and placental abruption. Although a high prevalence of CVD risk factors has been observed for women with a history of preeclampsia and pregnancy-induced hypertension, it is unclear whether patients with previous placental abruption exhibit the same cardiovascular risk profile. OBJECTIVES: To investigate the association of placental abruption with the presence of modifiable CVD risk factors that may be of potential use for prevention programs. METHODS: We performed a case-control study of 75 women with a history of placental abruption and a control group of 79 women with uneventful pregnancies. At 6-9months postpartum we measured the following CVD risk factors: blood pressure, body-mass index (BMI), fasting blood glucose levels, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and CRP. Baseline variables in the two groups with and without a previous abruption were expressed as means and standard deviations (SD). Where appropriate, means were adjusted for potential confounders using a generalized linear model. Data were further stratified for women with or without additional MPS-related complications, i.e. preeclampsia, gestational hypertension and intrauterine growth restriction. RESULTS: Women who experienced placental abruption had a significantly higher systolic and diastolic blood pressures, BMI, fasting blood glucose levels, CRP, total cholesterol, HDL-cholesterol, LDL-cholesterol and cholesterol/HDL ratio, as compared to controls. These associations remained significant in women with previous placental abruption without concomitant other MPS only for plasma lipid profile, BMI and fasting blood glucose levels, but not for diastolic and systolic blood pressure. CONCLUSION: A history of placental abruption is independently associated with increased BMI, fasting blood glucose levels, total cholesterol and LDL-cholesterol postpartum. Early detection of CVD risk factors in women with previous placental abruption offers an attractive opportunity for primary and secondary prevention.

Modeling Down syndrome screening performance using first-trimester serum markers.

OBJECTIVE: To evaluate the modeled predictive value of three current screening markers (pregnancy-associated plasma protein-A (PAPP-A), free ß-human chorionic gonadotropin (free ß-hCG), and nuchal translucency (NT)) and four potential screening markers (a disintegrin and metalloprotease 12 (ADAM12), total hCG, placental protein 13 (PP13), and placental growth factor (PlGF)) for Down syndrome using different screening strategies. METHODS: All markers were measured in stored first-trimester serum of 151 Down syndrome cases and 847 controls. All marker levels were expressed as gestational age-specific multiples of the median (MoMs) and comparisons were made using the Mann-Whitney U-test. Detection rates (DRs) for fixed false-positive rates (FPRs) were modeled using different screening strategies. RESULTS: Significantly different median MoMs for Down syndrome cases compared to controls were found for PAPP-A (0.49 vs. 1.00; P < 0.0001), free ß-hCG (1.70 vs. 1.01; P < 0.0001), ADAM12 (0.89 vs. 1.00; P < 0.0001), total hCG (1.28 vs. 1.00; P < 0.0001), PlGF (0.80 vs. 1.00; P < 0.0001) and NT (1.74 vs. 1.01; P < 0.0001). The lower PP13 MoM in Down syndrome cases (0.91 vs. 1.00) was not statistically significant (P = 0.061). Adding the four new markers to the current screening strategy (i.e. first-trimester combined test) led to an increase in DR from 77% to 80% at a 5% FPR. The modeled application of a two-sample screening strategy (with some markers assessed early and others later in the first trimester) increased the DR to 89%. In a two-step contingent screening model, using an intermediate risk range of 1 in 100 to 1 in 2000 at biochemical screening (using all markers), the overall DR was 77%, but it was predicted that only 33% of women would require referral for NT measurement. CONCLUSIONS: First-trimester Down syndrome screening may be improved by adding new markers to the current screening test and by applying different screening strategies. The application of a two-sample screening model resulted in the highest predicted DR, but this should be confirmed in population-based prospective studies.

Longitudinal trends in fetoplacental biochemical markers, uterine artery pulsatility index and maternal blood pressure during the first trimester of pregnancy.

OBJECTIVE: To assess trends in levels of biochemical markers, uterine artery (UtA) pulsatility index (PI) and maternal blood pressure changes over time and study their relationships in uncomplicated first-trimester pregnancies. METHODS: The study population comprised 86 women with singleton pregnancies. In each woman, a blood sample was collected at 6-7, 8-9, 10-11 and 12-13 weeks' gestation. At the same visit blood pressure was measured and ultrasound examination was performed to measure the crown-rump length and Doppler flow velocity waveform patterns of both UtAs. Serum concentrations of pregnancy-associated plasma protein-A (PAPP-A), free ß-human chorionic gonadotropin (ß-hCG), A disintegrin and metalloprotease domain-containing protein-12 (ADAM-12), placental protein-13 (PP-13) and placental growth factor (PlGF) levels were measured in thawed specimens using an automated time-resolved fluorescence assay. Summary curves were created to describe normal ranges and trends over time. The data were analyzed with a linear mixed model with the log-transformed marker values as dependent variables. This allowed for flexible modeling of patterns over time. RESULTS: Sixty-eight pregnancies had an uneventful outcome, with the birth of an appropriate-for-gestational-age (AGA) infant. In these pregnancies serum PAPP-A, ADAM-12, PP-13 and PlGF levels increased with gestational age. The UtA-PI decreased and the mean arterial blood pressure remained constant. There were no significant correlations between maternal age, birth-weight percentile, gender and blood pressure and any of the biochemical markers. The serum markers were highly correlated with each other except for ß-hCG. A negative correlation was found between most biomarkers and UtA-PI, especially from 10 weeks onwards. Serum concentrations of ADAM-12 and PP-13 were lower in a small-for-gestational-age (SGA) subgroup born at term (n = 6), the former statistically significantly (P = 0.031), the latter non-significantly (P = 0.054), whereas UtA-PI was significantly higher (P = 0.02). Biomarker concentrations in 12 women delivering a large-for-gestational age infant did not differ from those delivering AGA neonates. CONCLUSION: There is a relationship between biochemical markers of early placentation and downstream resistance to flow in the UtAs in low-risk uncomplicated pregnancies, indicating differences in placentation. In a small series of SGA infants born at term we could demonstrate differences as compared to normal pregnancies, with potential value for screening.

Prediction of macrosomia at birth in type-1 and 2 diabetic pregnancies with biomarkers of early placentation.

OBJECTIVE: To evaluate the value of first trimester placental biomarkers (fß-hCG, PAPP-A, ADAM12, PP13 and PlGF) and fetal nuchal translucency (NT) in the prediction of macrosomia at birth in pregestational type-1 and type-2 diabetes (PGDM). DESIGN: Nested case-control study. SETTING: Routine first-trimester combined test. POPULATION: A total of 178 PGDM and 186 control pregnancies. METHODS: ADAM12, PP13 and PlGF concentrations were measured in stored first-trimester serum, previously tested for fß-hCG and PAPP-A. All concentrations were expressed as multiples of the median (MoM). Where applicable, the median MoMs of PGDM and control pregnancies were compared in relation to birthweight centiles (≤90th centile, non-macrosomic, versus >90th centile, macrosomic). Model-predicted detection rates for fixed false-positive rates were obtained for statistically significant markers, separately and in combination. MAIN OUTCOME MEASURES: Prediction of macrosomia in diabetic pregnancies. RESULTS: In the PGDM group, median ADAM12 MoM (0.88; P = 0.007) was lower than in the controls. Subgroup analyses showed that median MoMs of PAPP-A (0.65), ADAM12 (0.85), PP13 (0.81) and PlGF (0.91) were only reduced in the PGDM non-macrosomic birthweight subgroup (n = 93) compared with other weight subgroups. In the PGDM macrosomic birthweight subgroup (n = 69), MoMs of all markers were comparable with the control birthweight subgroups. The screening performance for macrosomia at birth in the PGDM group provided a detection rate of 30% for a 5% false-positive rate (FPR) and 43% for a 10% FPR. CONCLUSIONS: Macrosomia at birth in PGDM pregnancies may be predicted by normal levels of PAPP-A, ADAM12, PP13 and PlGF already in the first trimester of pregnancy. Fetal birthweight in PGDM offspring is partially determined by placental development during the first trimester of pregnancy. The present increase in fetal macrosomia may be related to better early glycemic control and placentation.