Multivariate Growth Models

This thesis deals with models for (human) growth. We argue that growth is a multivariate phenomenon that should also be analysed as such. This is why we need multivariate growth models and multivariate reference curves. An example of a multivariate growth model is the Multivariate Superimposition by Translation And Rotation model (MSITAR), an extension of the SITAR model by Cole. In the SITAR model, there is a general, or template function for the overall growth pattern which is modelled by a spline. From this template the individual growth curves are then derived by shifting it horizontally and vertically and stretching it in the horizontal direction. Multivariate reference curves can be created by projecting the data in a large number of directions and then calculating the reference for that direction in the usual (univariate) manner. Quantile can be used to this end. Here we show that expectiles (are a generalisation of the mean in the same way that quantiles generalise the median) are an interesting alternative

Paternal Folate Status and Sperm Quality, Pregnancy Outcomes, and Epigenetics

Scope: The effectiveness of maternal folate in reducing the risk of congenital malformations during pregnancy is well established. However, the role of the paternal folate status is scarcely investigated. The aim of this study is to investigate the evidence of associations between the paternal folate status and sperm quality, sperm epigenome, and pregnancy outcomes. Methods and results: Databases are searched up to December 2017 resulting in 3682 articles, of which 23 are retrieved for full-text assessment. Four out of thirteen human and two out of four animal studies show positive associations between folate concentrations and sperm parameters. An additional meta-analysis of four randomized controlled trials in subfertile men shows that the sperm concentration increases (3.54 95% confidence interval (CI) [−1.40 to 8.48]) after 3–6 months of 5 mg folic acid use per day compared to controls. Moreover, two out of two animal and one out of three human studies show significant alterations in the overall methylation of the sperm epigenome. One animal and one human study show associations between low folate intake and an increased risk of congenital malformations. Conclusions: This systematic review and meta-analysis shows evidence of associations between paternal folate status and sperm quality, fertility, congenital malformations, and placental weight

The use of the mHealth program Smarter Pregnancy in preconception care: Rationale, study design and data collection of a randomized controlled trial

Background: Unhealthy nutrition and lifestyle contribute to the worldwide rising prevalence of non-communicable diseases. This also accounts for the reproductive population, in which unhealthy behavior affects fertility and pregnancy outcome. Maternal smoking, alcohol consumption and inadequate folic acid supplement use are strongly associated with fetal complications as small for gestational age, premature birth and congenital malformations. In the Netherlands 83% of the perinatal mortality rate is due to these complications and is relatively high compared to other European countries. In order to reduce this prevalence rate, preconception care should be focused on the promotion of health of prospective parents by identification and intervention on modifiable nutrition and lifestyle risk factors. We developed the personal mHealth program 'Smarter Pregnancy' (Dutch version available on: https://www.slimmerzwanger.nl) to provide individual coaching and information to improve nutrition and lifestyle during the preconception period in order to improve health of the reproductive population and subsequent generations. Methods: Women between 18 and 45 years of age, and trying to conceive are eligible for inclusion in a randomized controlled trial. Participants are allocated either to a general population cohort or a subfertile (IVF/ICSI) population cohort. The intervention group receives personal online coaching based on the identified nutrition and lifestyle risk factors at baseline. Coaching comprises recipes, incentives, additional questions including feedback and text and e-mail messages, with a maximum of three per week. The control group only receives one recipe per week to maintain adherence to the program and prevent drop out. Screening questionnaires are send in both groups at 6, 12, 18, and 24 weeks of the program to monitor the change in the identified risk factors. Discussion: We expect to demonstrate that the mHealth program 'Smarter Pregnancy' can effectively improve nutrition and lifestyle in couples contemplating pregnancy. By the identification and improvement of modifiable nutrition and lifestyle risk factors on a large scale, both reproductive and pregnancy outcomes can be improved and subsequent perinatal morbidity and mortality rates are expected to be reduced. The current use and rapid development of mHealth applications offers new opportunities to reach and educate large populations, which can facilitate the implementation of preconception care. Trial registration: Dutch trial register: NTR4150. (Registered 19th August 2013

Maternal Lifestyle Impairs Embryonic Growth

Previously, embryonic growth has been assumed to be uniform, but in recent years, it has become more clear that genetic and environmental factors may influence the intrauterine environment and therefore embryonic growth trajectories as well as pregnancy course and outcome. The objective of this study was to investigate associations between modifiable maternal nutrition and lifestyle factors during the periconception period and embryonic growth. We established a prospective cohort including 342 women less than 13 weeks pregnant. At enrollment, women filled out a questionnaire regarding demographic and medical data and a validated food frequency questionnaire. Participants received multiple 3-dimensional ultrasound examinations up until the 12th week of pregnancy, and crown–rump length (CRL) and embryonic volume (EV) were measured offline using V-Scope Virtual Reality software (version 1.0.0) in a Barco I-Space. Associations between maternal periconception vegetable and fruit intake, folic acid supplement use, smoking, and alcohol consumption and embryonic growth measurements were assessed by linear mixed models adjusted for potential confounders. No or postconception initiation of folic acid supplement use was significantly associated with a 0.76 mm (−7.8%) and 1.63 mm (−3.7%) smaller CRL and a 0.01 cm3 (−19.5%) and 0.86 cm3 (−12.2%) smaller EV at 7+0 and 11+0 weeks of gestation, respectively. Smoking, alcohol consumption, and inadequate fruit and vegetable intake showed weaker associations with embryonic growth parameters. These results emphasize the influence of periconceptional maternal folic acid supplement use on embryonic growth. Results regarding maternal nutrition and lifestyle factors also suggest an association with embryonic growth, but this has to be confirmed in a larger study

Are dieting and dietary inadequacy a second hit in the association with polycystic ovary syndrome severity?

Background The composition of the diet is of increasing importance for the development and maturation of the ovarian follicles. In Polycystic Ovary Syndrome (PCOS) healthy dietary interventions improve the clinical spectrum. We hypothesized that dieting and diet inadequacy in the reproductive life course is associated with impaired programming of ovarian follicles and contributes to the severity of the PCOS phenotype. Methods and Findings To determine associations between the use of a self-initiated diet and diet inadequacy and the severity of the PCOS phenotype, we performed an explorative nested case control study embedded in a periconception cohort of 1,251 patients visiting the preconception outpatient clinic. 218 patients with PCOS and 799 subfertile controls were selected from the cohort and self-administered questionnaires, anthropometric measurements and blood samples were obtained. The Preconception Dietary Risk Score (PDR score), based on the Dutch dietary guidelines, was used to determine diet inadequacy in all women. The PDR score was negatively associated to cobalamin, serum and red blood cell folate and positively to tHcy. PCOS patients (19.9%), in particular the hyperandrogenic (HA) phenotype (22.5%) reported more often the use of a self-initiated diet than controls (13.1%; p = 0.023). The use of an inadequate diet was also significantly higher in PCOS than in controls (PDR score 3.7 vs 3.5; p = 0.017) and every point increase was associated with a more than 1.3 fold higher risk of the HA phenotype (adjusted OR 1.351, 95% CI 1.09-1.68). Diet inadequacy was independently associated with the anti-Müllerian Hormone (AMH) concentration (β 0.084; p = 0.044; 95% CI 0.002 to 0.165) and free androgen index (β 0.128; p = 0.013; 95% CI 0.028 to 0.229) in PCOS patients. Conclusions The use of a self-initiated diet and diet inadequacy is associated with PCOS, in particular with the severe HA phenotype. This novel finding substantiated by the association between diet inadequacy and AMH needs further investigation

A Mobile App Lifestyle Intervention to Improve Healthy Nutrition in Women Before and During Early Pregnancy

BACKGROUND: Unhealthy nutrition contributes to the worldwide rising prevalence of noncommunicable diseases. As most adverse reproductive outcomes originate during the periconception period, effective interventions targeting this period are needed. Therefore, we developed the lifestyle intervention Smarter Pregnancy to empower women to adapt a healthy diet prior to conception and during early pregnancy and performed a randomized controlled trial. OBJECTIVE: The objectives of this trial were to investigate compliance and effectiveness in women using the Smarter Pregnancy program. METHODS: Women aged between 18 and 45 years who were contemplating pregnancy or <13 weeks pregnant and their male partners living in the urban area of Rotterdam, the Netherlands, were eligible for participation. After baseline screening, the intervention group received personal online coaching based on identified inadequate intakes of vegetables, fruits, and folic acid supplements. The sum of these risk factors was used as a dietary risk score (DRS), ranging from 0 (healthy) to 9 (unhealthy). The control group did not receive coaching. We applied an intention-to-treat principle and used a multivariable linear regression model to evaluate the change in DRS after 24 weeks. Compliance was defined as the percentage of women who completed the screening questionnaire at 24 weeks. RESULTS: Of women recruited, 81.2% (177/218) completed the program (intervention: 91/218, 83.5%; control: 86/218, 78.9%; P=.95). After 24 weeks, the reduction in DRS of women in the intervention group was significantly larger than in the control group (β=.75, 95% CI 0.18-1.34). This reduction was mainly due to increased vegetable intake (β=.55, 95% CI 0.25-0.86). CONCLUSIONS: The high compliance and the larger improvements in nutritional behaviors, especially vegetable intake, in women in the intervention group emphasizes the effectiveness of empowering women by using the lifestyle change intervention Smarter Pregnancy. TRIAL REGISTRATION: Netherlands Trial Register: NL3927; https://www.trialregister.nl/trial/3927. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s12884-017-1228-5

Propofol for endotracheal intubation in neonates: A dose-finding trial

Objective: To find propofol doses providing effective sedation without side effects in neonates of different gestational ages (GA) and postnatal ages (PNA). Design and setting: Prospective multicentere dose-finding study in 3 neonatal intensive care units. Patients: Neonates with a PNA <28 days requiring non-emergency endotracheal intubation. Interventions: Neonates were stratified into 8 groups based on GA and PNA. The first 5 neonates in every group received a dose of 1.0 mg/kg propofol. Based on sedative effect and side effects, the dose was increased or decreased in the next 5 patients until the optimal dose was found. Main outcome measures: The primary outcome was the optimal single propofol starting dose that provides effective sedation without side effects in each age group. Results: After inclusion of 91 patients, the study was prematurely terminated because the primary outcome was only reached in 13% of patients. Dose-finding was completed in 2 groups, but no optimal propofol dose was found. Effective sedation without side effects was achieved more often after a starting dose of 2.0 mg/kg (28%) than after 1.0 mg/kg (3%) and 1.5 mg/kg (9%). Propofol-induced hypotens

Periconceptional Maternal One-Carbon Biomarkers are Associated with Embryonic Development According to the Carnegie Stages

STUDY QUESTION: Is periconceptional maternal one-carbon (I-C) metabolism associated with embryonic morphological development in non-malformed ongoing pregnancies? SUMMARY ANSWER: Serum vitamin B12, red blood cell (RBC) folate and plasma total homocysteine (tHcy) are associated with embryonic development according to the Carnegie stages. WHAT IS KNOWN ALREADY: Derangements in maternal I-C metabolism affect reproductive and pregnancy outcomes, as well as future health of the offspring. STUDY DESIGN, SIZE, DURATION: Between 2010 and 2014, women with singleton ongoing pregnancies were enrolled in a prospective periconceptional cohort study. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 234 pregnancies, including 138 spontaneous or IUI pregnancies with strict pregnancy dating and 96 pregnancies derived from IVF, ICSI or cryopreserved embryo transfer (IVF/ICSI pregnancies), underwent longitudinal transvaginal three-dimensional ultrasound (3D US) scans from 6+0 up to 10+2 weeks of gestation. Carnegie stages were defined using internal and external morphologic criteria in a virtual reality system. Maternal venous blood samples were collected at enrollment for serum vitamin B12, RBC folate and plasma tHcy assessment. Associations between biomarker concentrations and longitudinal Carnegie stages were investigated using linear mixed models. MAIN RESULTS AND THE ROLE OF CHANCE: We performed a median of three 3D US scans per pregnancy (range 1-5) resulting in 600 good quality data sets for the Carnegie stage annotation (80.5%). Vitamin B12 was positively associated with embryonic development in the total study population (\u3b2 = 0.001 (95% CI: 0.000; 0.002), P < 0.05) and in the subgroup of strictly dated spontaneous pregnancies (\u3b2 = 0.002 (95% CI: 0.001; 0.003), P < 0.05). Low vitamin B12 concentrations (-2SD, 73.4 pmol/l) were associated with delayed embryonic development by 1.4 days (95% CI: 1.3-1.4) compared with high concentrations (+2SD, 563.1 pmol/l). RBC folate was positively associated with Carnegie stages only in IVF/ICSI pregnancies (\u3b2 = 0.001 (95% CI: 0.0005; 0.0015), P < 0.05). In this group, low RBC folate concentrations (-2SD, 875.4 nmol/l) were associated with a 1.8-day delay (95% CI: 1.7-1.8) in development compared with high concentrations (+2SD, 2119.9 nmol/l). tHcy was negatively associated with embryonic development in the total study population (\u3b2 = -0.08 (95% CI: -0.14; -0.02), P < 0.01), as well as in the IVF/ICSI subgroup (\u3b2 = -0.08 (95% CI: -0.15; -0.01), P < 0.05). High tHcy concentrations (+2SD, 10.4 \ub5mol/l) were associated with a delay of 1.6 days (95% CI: 1.5-1.7) in embryonic development compared with low concentrations (-2SD, 3.0 \ub5mol/l). LIMITATIONS, REASONS FOR CAUTION: The study was performed in a tertiary care center, resulting in high rates of folic acid supplement use and comorbidity that may reduce the external validity of our findings. WIDER IMPLICATIONS OF THE FINDINGS: In periconceptional care, maternal I-C biomarkers should be taken into account as predictors of embryonic morphological development. Combining embryonic size measurements with morphological assessment could better define normal embryonic development. STUDY FUNDING/COMPETING INTEREST(S): The work was funded by the Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. RPMST is CSO of the startup company Slimmere Zorg and CEO of eHealth Care Solutions. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: Not applicable

Exercise capacity in Dutch children

The Bruce treadmill protocol is suitable for children 4 years of age and older. Dutch reference values were established in 1987. We considered that children's exercise capacity has deteriorated due to changes in physical activity patterns and eating habits. We determined new reference values and evaluated determinants of exercise capacity. Healthy Dutch children (n=267) aged 6-13 years participated in this cross-sectional observational study. The maximal endurance time on the treadmill was the criterion of exercise capacity. Furthermore, we obtained data on anthropometry, smoking habits, socioeconomic status, ethnicity, sports participation, and school transport habits. The maximal endurance time for children aged up till 10 was lower (up to 1.6 and 1.4 min in girls and boys, respectively) than previously published. Body mass index was negatively, and intense sports participation was positively associated with endurance time (β=-0.412 and 0.789, respectively; P<0.001). In conclusion, exercise capacity seems to have deteriorated in Dutch children aged up till 10 years whereas the values from the older children are remarkably similar to those from the previous study

Immunoglobulin G galactosylation and sialylation are associated with pregnancy-induced improvement of rheumatoid arthritis and the postpartum flare: Results from a large prospective cohort study

Introduction: Improvement of rheumatoid arthritis (RA) during pregnancy has been causatively associated with increased galactosylation of immunoglobulin G (IgG) N-glycans. Since previous studies were small, did not include the postpartum flare and did not study sialylation, these issues were addressed in the present study.Methods: Serum from 148 RA cases and 32 healthy controls was collected at several time points before, during and after pregnancy. Improvement during pregnancy and postpartum flare were determined according to the European League Against Rheumatism (EULAR) response criteria. Galactosylation and sialylation of Immunoglobulin G (IgG) and the presence of bisecting N-acetylglucosamine (GlcNAc) were analyzed by matrix-assisted laser desorption/ionization - time of flight - mass spectrometry (MALDI-TOF-MS).Results: IgG1 and IgG2 galactosylation of the cases and controls increased during pregnancy with a maximum in the third trimester. Galactosylation decreased directly postpartum. IgG galactosylation of controls was at a higher level than cases (P < 0.001 at all time points) and a similar pattern was observed for sialylation. Moreover, there was a good association between galactosylation and sialylation. The increase in galactosylation was significantly more pronounced for cases with improvement than cases without improvement during pregnancy. The reverse was true for deteriorators and non-deteriorators postpartum. The presence of bisecting GlcNAc was not significantly influenced by pregnancy or postpartum for c