Embryonic size and growth and adverse birth outcomes: the Rotterdam Periconception Cohort.

STUDY QUESTION: Is early embryonic size and growth in the first trimester of pregnancy associated with adverse birth outcomes? SUMMARY ANSWER: Larger embryonic crown-rump length (CRL) and embryonic volume (EV) are associated with lower odds of adverse birth outcomes, especially small for gestational age (SGA). WHAT IS ALREADY KNOWN: Preterm birth, SGA, and congenital anomalies are the most prevalent adverse birth outcomes with lifelong health consequences as well as high medical and societal costs. In the late first and second trimesters of pregnancy, fetuses at risk for adverse birth outcomes can be identified using 2-dimensional ultrasonography (US). STUDY DESIGN, SIZE, DURATION: Between 2009 and 2018, singleton pregnancies were enrolled in this ongoing prospective Rotterdam Periconception Cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included 918 pregnant women from a tertiary hospital in the Netherlands. Pregnancy dating was based on either a regular menstrual cycle (for natural pregnancies) or a conception date (for ART pregnancies). CRL and EV were measured using Virtual Reality software on 3-dimensional (3D) ultrasound scans, repeatedly performed around 7, 9, and 11 weeks of gestation. The main outcome measure was adverse birth outcome, defined as the composite of SGA (birth weight <10th percentile), preterm birth (<37th week of gestation), congenital anomalies (Eurocat criteria), stillbirth (>16th week of pregnancy), or early neonatal mortality (≤7 days of life). Reference curves for CRL and EV were constructed. Cross-sectional (CRL/EV <20th percentile at 7, 9, and 11 weeks of gestation) and longitudinal (CRL/EV growth trajectories between 6th and 13th weeks) regression analyses were performed, with adjustments for the participants' educational level, smoking, parity, age, BMI, geographical background, mode of conception, and fetal sex. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 918 pregnant women included, the median age was 32.3 years, and 404 (44%) pregnancies had been conceived via ART. In 199 (22%) pregnancies, there was an adverse birth outcome. Regression analyses showed that at 7 weeks of gestation onwards, embryos with a CRL <20th percentile had an ∼2-fold increased odds of adverse birth outcome (adjusted odds ratio (aOR) 2.03, 95% CI 1.21-3.39, P = 0.007). Similar associations were found for EV <20th percentile but were not statistically significant. These findings were mainly driven by the strong association between embryonic size and SGA (e.g. 7-week CRL: aOR 2.18 (1.16-4.09), P = 0.02; 9-week EV: aOR 2.09 (1.10-3.97, P = 0.02). Longitudinal growth trajectories of CRL, but not of EV, were associated with adverse birth outcomes. Both CRL and EV growth trajectories were associated with SGA. LIMITATIONS, REASONS FOR CAUTION: The tertiary hospital population and the availability of sophisticated 3D-ultrasound techniques limit the generalizability of this study to general populations and settings. WIDER IMPLICATIONS OF THE FINDINGS: Already very early in the first trimester of pregnancy, embryos with increased risks of an adverse birth outcome can be identified by using 3D-US and Virtual Reality. This expands the window of opportunity to enable the development of future interventions to potentially improve pregnancy outcomes and offspring health during their life-course. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by the Department of Obstetrics and Gynecology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: NL4115.

Effect of COVID-19 lockdown on maternity care and maternal outcome in the Netherlands: a national quasi-experimental study.

OBJECTIVES: The COVID-19 pandemic and associated lockdowns disrupted health care worldwide. High-income countries observed a decrease in preterm births during lockdowns, but maternal pregnancy-related outcomes were also likely affected. This study investigates the effect of the first COVID-19 lockdown (March-June 2020) on provision of maternity care and maternal pregnancy-related outcomes in the Netherlands. STUDY DESIGN: National quasi-experimental study. METHODS: Multiple linked national registries were used, and all births from a gestational age of 24+0 weeks in 2010-2020 were included. In births starting in midwife-led primary care, we assessed the effect of lockdown on provision of care. In the general pregnant population, the impact on characteristics of labour and maternal morbidity was assessed. A difference-in-regression-discontinuity design was used to derive causal estimates for the year 2020. RESULTS: A total of 1,039,728 births were included. During the lockdown, births to women who started labour in midwife-led primary care (49%) more often ended at home (27% pre-lockdown, +10% [95% confidence interval: +7%, +13%]). A small decrease was seen in referrals towards obstetrician-led care during labour (46%, -3% [-5%,-0%]). In the overall group, no significant change was seen in induction of labour (27%, +1% [-1%, +3%]). We found no significant changes in the incidence of emergency caesarean section (9%, -1% [-2%, +0%]), obstetric anal sphincter injury (2%, +0% [-0%, +1%]), episiotomy (21%, -0% [-2%, +1%]), or post-partum haemorrhage: >1000 ml (6%, -0% [-1%, +1%]). CONCLUSIONS: During the first COVID-19 lockdown in the Netherlands, a substantial increase in homebirths was seen. There was no evidence for changed available maternal outcomes, suggesting that a maternity care system with a strong midwife-led primary care system may flexibly and safely adapt to external disruptions.

Increasing trends in a low 5-min Apgar score among (near) term singletons: a Dutch nationwide cohort study.

OBJECTIVE: To investigate trends in low Apgar scores in (near) term singletons using the Dutch Perinatal Registry. METHODS: In a cohort of 1,583,188 singletons liveborn ≥35 weeks of gestation in the period 2010-2019, we studied trends in low 5-min Apgar scores (<7 and <4) using Cochrane Armitage trend tests. RESULTS: The proportion of infants with low Apgar scores <7 and <4 increased significantly between 2010-2019 (1.04-1.42% (p < 0.001), 0.17-0.19% (p = 0.009), respectively). Neonatal mortality remained unchanged. Induction of labour, epidural analgesia and planned caesarean section showed an increasing trend. Instrumental vaginal delivery and emergency caesarean section were performed less frequently over time, but these intervention subgroups showed the highest relative increase in infants with low Apgar scores. CONCLUSIONS: In the Netherlands, the risk of a low 5-min Apgar score increased over the last decade. The highest relative increase was observed in subgroups of instrumental vaginal delivery and emergency caesarean section.

Association between COVID-19 lockdown measures and the incidence of iatrogenic versus spontaneous very preterm births in the Netherlands: a retrospective study.

BACKGROUND: The COVID-19 pandemic led to regional or nationwide lockdowns as part of risk mitigation measurements in many countries worldwide. Recent studies suggest an unexpected and unprecedented decrease in preterm births during the initial COVID-19 lockdowns in the first half of 2020. The objective of the current study was to assess the effects of the two months of the initial national COVID-19 lockdown period on the incidence of very and extremely preterm birth in the Netherlands, stratified by either spontaneous or iatrogenic onset of delivery, in both singleton and multiple pregnancies. METHODS: Retrospective cohort study using data from all 10 perinatal centers in the Netherlands on very and extremely preterm births during the initial COVID-19 lockdown from March 15 to May 15, 2020. Incidences of very and extremely preterm birth were calculated using an estimate of the total number of births in the Netherlands in this period. As reference, we used data from the corresponding calendar period in 2015-2018 from the national perinatal registry (Perined). We differentiated between spontaneous versus iatrogenic onset of delivery and between singleton versus multiple pregnancies. RESULTS: The incidence of total preterm birth < 32 weeks in singleton pregnancies was 6.1‰ in the study period in 2020 versus 6.5‰ in the corresponding period in 2015-2018. The decrease in preterm births in singletons was solely due to a significant decrease in iatrogenic preterm births, both < 32 weeks (OR 0.71; 95%CI 0.53 to 0.95) and < 28 weeks (OR 0.53; 95%CI 0.29 to 0.97). For multiple pregnancies, an increase in preterm births < 28 weeks was observed (OR 2.43; 95%CI 1.35 to 4.39). CONCLUSION: This study shows a decrease in iatrogenic preterm births during the initial COVID-19-related lockdown in the Netherlands in singletons. Future studies should focus on the mechanism of action of lockdown measures and reduction of preterm birth and the effects of perinatal outcome.

Client-tailored maternity care to increase maternal empowerment: cluster randomized controlled trial protocol; the healthy pregnancy 4 All-2 program.

BACKGROUND: The postpartum period is an important period for preventive strategies as common maternal and child health risks may become manifest. Women with a lower socioeconomic status tend to have lower maternal empowerment. Increasing their risks of adverse maternal and child health outcomes. This study aims to assess the effectiveness of a primary care level intervention. Delivered to maternity care assistants, aiming to increase maternal empowerment postpartum. METHODS: This study is part of the Dutch nationwide "Healthy Pregnancy 4 All-2" (HP4All-2) program, which aims to identify vulnerable mothers and young children at risk of adverse health outcomes, and subsequently improve their care. This program targets women from deprived neighborhoods. A pragmatic cluster randomized controlled trial will be undertaken in 12 maternity care organizations. Maternity care organizations in urban municipalities (i.e. the clusters) will be randomized to either a systematic risk assessment during pregnancy with emphasis on identification of non-medical risk factors for adverse maternal and neonatal health outcomes, and subsequent adaptation of care towards a client-tailored approach during pregnancy and the postpartum period, or solely the systematic risk assessment. The primary outcome is the prevalence of a low maternal empowerment score postpartum. Secondary maternal outcomes cover health-related quality of life, postnatal depression, smoking, alcohol consumption, illicit drug use. Finally, maternal and neonatal health care utilization postpartum are recorded. All outcomes will be analyzed according to the intention-to-treat principle, using multi-level mixed effects models. DISCUSSION: The study will contribute to evidence regarding the effectiveness of client-tailored, risk-based maternity care to increase maternal empowerment postpartum. TRIAL REGISTRATION: Netherlands Trial Registry (NTR) 6311 , registered 03-27-2017.

Periodontal Disease and Pregnancy Outcomes: Overview of Systematic Reviews.

Periodontal disease is very common during pregnancy. Although it has been linked to adverse pregnancy outcomes, systematic reviews have reached discrepant conclusions on these links. Therefore, we conducted a systematic overview of systematic reviews studying the association between periodontal disease and adverse pregnancy outcomes. We searched 6 online databases up to November 2016 and hand-searched references and citations of eligible papers. Systematic reviews of studies comparing pregnancy outcomes among women with and without periodontal disease were eligible for inclusion. Primary outcomes were maternal mortality, preterm birth, and perinatal mortality. Two reviewers extracted data and assessed risk of bias of individual systematic reviews. Findings are described in tabular and narrative form. Twenty-three systematic reviews (including between 3 and 45 studies) were included. None reported the association between periodontal disease and maternal or perinatal mortality. Systematic reviews with the lowest risk of bias consistently demonstrated positive associations between periodontal disease and preterm birth (relative risk, 1.6; 95% confidence interval, 1.3 to 2.0; 17 studies, 6,741 participants), low birth weight (LBW; relative risk, 1.7; 95% CI, 1.3 to 2.1; 10 studies, 5,693 participants), preeclampsia (odds ratio, 2.2; 95% CI, 1.4 to 3.4; 15 studies, 5,111 participants), and preterm LBW (relative risk 3.4; 95% CI, 1.3 to 8.8; 4 studies, 2,263 participants). Based on these figures, estimated population-attributable fractions for periodontal disease were 5% to 38% for preterm birth, 6% to 41% for LBW, and 10% to 55% for preeclampsia. In terms of limitations, as several primary studies did not adjust for confounding, meta-analyses may have overestimated the strength of the associations under study. Due to substantial overlap in included primary studies, we could not aggregate results across reviews. Consistent evidence from systematic reviews with low risk of bias indicates that pregnant women with periodontal disease are at increased risk of developing preeclampsia and delivering a preterm and/or LBW baby (PROSPERO: CRD42015030132). Knowledge Transfer Statement: This study highlights that periodontal disease is an important risk factor for several common adverse pregnancy outcomes. Clinicians should be aware of this link to guide risk selection. Research is needed to develop novel preventive and treatment strategies.

[Tobacco control policies and perinatal health]. / Tabaksontmoediging en perinatale gezondheid.

OBJECTIVE: Study the association between the introduction of tobacco control policies in the Netherlands and changes in perinatal outcomes. DESIGN: National quasi-experimental study. METHOD: We used Netherlands Perinatal Registry data (now called Perined) for the period 2000-2011. We studied whether the introduction of smoke-free legislation in workplaces plus a tobacco tax increase and mass media campaign in January 2004, and extension of the smoke-free law to the hospitality industry accompanied by another tax increase and media campaign in July 2008, was associated with changes in perinatal outcomes. We studied all singleton births (gestational age: 24+0 to 42+6 weeks). Our primary outcome measures were: perinatal mortality, preterm birth and being small-for-gestational-age (SGA). Interrupted time series logistic regression analyses were performed to investigate changes in these outcomes occurred after the introduction of the aforementioned tobacco control policies (ClinicalTrials.gov: NCT02189265). RESULTS: Among 2,069,695 singleton births, 13,027 (0.6%) perinatal deaths, 116,043 (5.6%) preterm live-births and 187,966 (9.1%) SGA live-births were observed. The policies introduced in January 2004 were not associated with significant changes in any of the primary outcome measures. A -4.4% (95% CI: -6.4 to -2.4; p < 0.001) decrease in odds of a SGA birth was observed after the policy extension in July 2008 to include a smoke-free hospitality industry, a further tax increase and another media campaign. This translates to an estimated over 500 cases of SGA being averted per year. CONCLUSION: A reduction in SGA births, but not preterm birth or perinatal mortality, was observed in the Netherlands after extension of the smoke-free workplace law to include bars and restaurants, in conjunction with a tax increase and media campaign in 2008.

[The effects of smoking on health: growth of knowledge reveals even grimmer picture]. / De gezondheidseffecten van roken.

- In this article we give a short overview of new insights into the effects of smoking on health, both on smokers themselves and on those who are exposed to other people's tobacco smoke.- The number of diseases and conditions that are known to be caused by active smoking has now risen to over thirty.- The risk of premature death is not, as previously thought, twice as high in smokers as in non-smokers, but actually three times as high.- Passive smoking too has been shown to have a whole range of negative effects on health.- Further, the causal mechanisms of, amongst other things, the development of cancer, ischaemic heart disease and nicotine dependence under the influence of smoking have been largely unravelled.- Various issues require further investigation; these include the effect of smoking on psychological health and the effects of 'third-hand' smoke. In the meantime, a concerted campaign against this consumer product with its deleterious effects of the health of the population is overdue.

Antenatal steroids and neonatal outcome after chorioamnionitis: a meta-analysis.

BACKGROUND: There is debate concerning the safety and efficacy of antenatal steroids in preterm labour with suspected intrauterine infection (chorioamnionitis). OBJECTIVES: We performed a systematic literature review and meta-analysis aimed at evaluating the efficacy and safety of antenatal steroids in clinical and histological chorioamnionitis. SEARCH STRATEGY: MEDLINE, EMBASE, BioMed Central and the Cochrane databases were searched using the terms 'chorioamnionitis OR intrauterine infection' and '*steroids OR *corticoids'. SELECTION CRITERIA: Studies that reported selected neonatal outcome measures in preterm infants with clinical or histological chorio-amnionitis, according to antenatal steroid exposure, were eligible. DATA COLLECTION AND ANALYSIS: Study selection, data extraction and data analysis were performed by two independent investigators. The meta-analysis techniques used included: Mantel-Haenszel analysis; an assessment of study heterogeneity using the Q statistic; and Egger's regression test and funnel plots, to assess publication bias. MAIN RESULTS: Seven observational studies were included. In histological chorioamnionitis (five studies), antenatal steroids were associated with reduced mortality (OR = 0.45; 95% CI = 0.30-0.68; P = 0.0001), respiratory distress syndrome (OR = 0.53; 95% CI = 0.40-0.71; P < 0.0001), patent ductus arteriosus (OR = 0.56; 95% CI = 0.37-0.85; P = 0.007), intraventricular haemorrhage (IVH; OR = 0.35; 95% CI = 0.18-0.66; P = 0.001) and severe IVH (OR = 0.39; 95% CI = 0.19-0.82; P = 0.01). In clinical chorioamnionitis (four studies), antenatal steroids were associated with reduced severe IVH (OR = 0.29; 95% CI = 0.10-0.89; P = 0.03) and periventricular leucomalacia (OR = 0.35; 95% CI = 0.14-0.85; P = 0.02). CONCLUSIONS: Antenatal steroids may be safe and reduce adverse neonatal outcome after preterm birth associated with chorioamnionitis. There is a need for randomised clinical trials to address this issue.

Chorioamnionitis: a multiorgan disease of the fetus?

The bacterial infection of chorion and amnion is a common finding in premature delivery and is referred to as chorioamnionitis. As the mother rarely shows symptoms of a systemic inflammation, the course of chorioamnionitis is frequently asymptomatic and chronic. In contrast, the fetal inflammatory response syndrome represents a separate phenomenon, including umbilical inflammation and increased serum levels of proinflammatory cytokines in the fetus. Ascending maternal infections frequently lead to systemic fetal inflammatory reaction. Clinical studies have shown that antenatal exposure to inflammation puts the extremely immature neonates at a high risk for worsening pulmonary, neurological and other organ development. Interestingly, the presence of chorioamnionitis is associated with a lower rate of neonatal mortality in extremely immature newborns. In the following review, the pathogeneses of inflammation-associated perinatal morbidity are outlined. The concept of fetal multiorganic disease during intrauterine infection is introduced and discussed.

Histological chorioamnionitis and respiratory outcome in preterm infants.

A considerable body of human and animal experimental evidence links antenatal inflammation to both accelerated maturation and adverse development of the lung. Initial reports suggest that in preterm infants histological chorioamnionitis is associated with a decreased incidence of respiratory distress syndrome (RDS), while the incidence of bronchopulmonary dysplasia (BPD) is increased. Considerable variation exists in the findings of subsequent human studies, largely dependent on differences in inclusion and exclusion criteria. Taking these differences into account, recent studies generally seem to confirm the effect of chorioamnionitis on RDS incidence, while no effect on BPD is seen. The increased use of antenatal steroids and the diminished effects of secondary pro-inflammatory hits seem to explain part of this change. Additional research is needed to explore these complex interactions and their underlying mechanisms, and evaluate the long term pulmonary effects of antenatal inflammation.

Epidemiology of pyridoxine dependent seizures in the Netherlands.

BACKGROUND: Pyridoxine dependent epilepsy is a rare cause of seizures in childhood. The diagnosis is made on clinical criteria, that in many cases are never met. Therefore, epidemiological data on pyridoxine dependency are scarce. AIMS: To study the epidemiology of pyridoxine dependent epilepsy in the Netherlands, and to determine whether the diagnosis is based on the appropriate criteria. METHODS: Nationwide all departments of paediatrics (n = 113) and of paediatric or neonatal neurology (n = 17) were asked to report cases of pyridoxine dependent seizures. Birth incidences were calculated using national data on live births from 1991 to 2003. RESULTS: Response was received from 67% of paediatric departments, including all university hospitals and 94% of child neurology departments. Thirteen patients were reported. Four definite (31%), three probable (23%), and four possible cases (31%) were identified. Two cases (15%) did not meet criteria for either of these groups. The birth incidence was 1:396,000 for definite and probable cases and 1:252,000 when possible cases are included. CONCLUSIONS: Thus far, epidemiological data on pyridoxine dependent seizures were only available from the UK and Ireland. A higher incidence was found in the Netherlands, in accordance with earlier suggestions of a regional difference. The study shows that the diagnosis is often made without performance of a formal trial of withdrawal. The importance of confirming the diagnosis, concerning the consequences as for individual prognosis, the potential side effects of prolonged pyridoxine substitution, and the possibility of treating the mother in case of future pregnancies are emphasised.