Publications by authors named "Rebecca C Painter"

80 Publications

Long-term health and neurodevelopment in children after antenatal exposure to low-dose aspirin for the prevention of preeclampsia and fetal growth restriction: A systematic review of randomized controlled trials.

Eur J Obstet Gynecol Reprod Biol 2021 Nov 11;267:213-220. Epub 2021 Nov 11.

Amsterdam UMC, University of Amsterdam, Department of Obstetrics and Gynecology, Amsterdam Reproduction & Development Research Institute, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands.

Objective: To evaluate the long-term effects of antenatal aspirin exposure on child health and neurodevelopmental outcome beyond the perinatal period.

Study Design: PubMed, Embase.com, the Cochrane Library and Web of Science were systematically searched from inception through 5 November 2020. We performed a cited-reference search and ClinicalTrials.gov was searched on 20 October 2020 to identify trial results that were not reported elsewhere. We included randomized controlled trials reporting on health-related outcomes in children (aged > 28 days) exposed to aspirin versus placebo or no treatment during pregnancy. Studies with any dose or duration of aspirin use were included. We excluded studies evaluating other antiplatelet agents or non-steroidal inflammatory drugs. Two authors independently performed study selection, data extraction and quality assessment. Quality assessment was performed using the Cochrane RoB2 tool for the original randomized controlled trials and the QUIPS for the follow-up studies. Results are presented as relative risks (RR) with 95% confidence intervals (95%CI).

Results: The search yielded 6,907 unique records. Two studies were included, containing 4,168 children at age 12 months and 5,153 children at 18 months. Children were exposed to aspirin 50-60 mg versus placebo or no treatment. At 12 months, post-neonatal mortality was lower after allocation to aspirin (0.2% versus 0.5%; RR 0.28, 95%CI 0.08-0.99) in a single study. At 18 months, fewer children were found to have (gross and fine) motor problems (RR 0.49, 95%CI 0.26-0.91) after antenatal aspirin exposure in one study. No differences were found in mortality rate; the proportion of children with a short stature or low weight; or respiratory, hearing or visual problems at 18 months. Both included studies had a high risk of bias.

Conclusion: The two included studies showed evidence of potential benefit of antenatal low-dose aspirin on mortality and neurodevelopment up to the age of 18 months. Our findings support the current application of low-dose aspirin in pregnant women at risk for preeclampsia and fetal growth restriction. However, further follow-up research of children who were exposed to low-dose aspirin during pregnancy is of utmost importance to exclude potential long-term harm.
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http://dx.doi.org/10.1016/j.ejogrb.2021.11.010DOI Listing
November 2021

Long-term follow-up of children exposed in-utero to progesterone treatment for prevention of preterm birth: study protocol of the AMPHIA follow-up.

BMJ Open 2021 09 21;11(9):e053066. Epub 2021 Sep 21.

Department of Obstetrics and Gynaecology, Amsterdam Reproduction & Development, Amsterdam UMC Location AMC, Amsterdam, The Netherlands.

Introduction: Preterm birth is one of the main problems in obstetrics, and the most important cause of neonatal mortality, morbidity and neurodevelopmental impairment. Multiple gestation is an important risk factor for preterm birth, with up to 50% delivering before 37 weeks. Progesterone has a role in maintaining pregnancy and is frequently prescribed to prevent (recurrent) preterm birth and improve pregnancy outcomes in high-risk patients. However, little is known about its long-term effects in multiple gestations. The objective of this follow-up study is to assess long-term benefits and harms of prenatal exposure to progesterone treatment in multiple gestations on child development.

Methods And Analysis: This is a follow-up study of a multicentre, double-blind, placebo-controlled randomised trial (AMPHIA trial, ISRCTN40512715). Between 2006 and 2009 women with a multiple gestation were randomised at 16-20 weeks of gestation to weekly injections 250 mg 17α-hydroxyprogesterone caproate or placebo, until 36 weeks of gestation or delivery. The current long-term follow-up will assess all children (n=1355) born to mothers who participated in the AMPHIA trial, at 11-14 years of age, with internationally validated questionnaires, completed by themselves, their parents and their teachers.

Main Outcomes Are Child Cognition And Behaviour: Additional outcomes are death (perinatal and up to age 14), gender identity, educational performance and health-related problems. We will use intention-to-treat analyses comparing experimental and placebo group. To adjust for the correlation between twins, general linear mixed-effects models will be used.

Ethics And Dissemination: Amsterdam UMC MEC provided a waiver for the Medical Research Involving Human Subjects Act (W20_234#20.268). Results will be disseminated through peer-reviewed journals and summaries shared with stakeholders, patients and participants. This protocol is published before analysis of the results.

Trial Registration Number: NL8933.
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http://dx.doi.org/10.1136/bmjopen-2021-053066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458362PMC
September 2021

Hyperemesis gravidarum and vitamin K deficiency: a systematic review.

Br J Nutr 2021 Jul 30:1-13. Epub 2021 Jul 30.

Amsterdam University Medical Centers, University of Amsterdam, Department of Obstetrics and Gynaecology, Amsterdam Reproduction & Development Research Institute, Meibergdreef 9, Amsterdam, The Netherlands.

Hyperemesis gravidarum (HG), severe nausea and vomiting in pregnancy, can lead to vitamin deficiencies. Little is known about HG-related vitamin K deficiency. We aimed to summarise available evidence on the occurrence of HG-related vitamin K deficiency and corresponding maternal and neonatal complications. A systematic review was conducted, searching Medline and EMBASE from inception to 12 November 2020. We identified 1564 articles, of which we included fifteen in this study: fourteen case reports (n 21 women) and one retrospective cohort study (n 109 women). Nine out of twenty-one women reported in case reports had a prolonged prothrombin time (PT). The cohort study measured PT in 39/109 women with HG, of whom 10/39 women (26 %) had prolonged PT. In total, 30-50 % women received vitamin K supplementation after vitamin K deficiency had been diagnosed. Four case reports (n 4 women) reported corresponding maternal complications, all consisting of coagulopathy-related haemorrhage. Nine case reports (n 16 neonates) reported corresponding neonatal complications including intracranial haemorrhage (n 2 neonates) and embryopathy (n 14 neonates), which consisted of Binder phenotype (n 14 neonates), chondrodysplasia punctata (n 9 neonates) and grey matter heterotopia (n 3 neonates). In conclusion, vitamin K deficiency and related complications occur among women with HG. In our systematic review, we were unable to assess the incidence rate.
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http://dx.doi.org/10.1017/S0007114521002865DOI Listing
July 2021

Estimated impact of introduction of new diagnostic criteria for gestational diabetes mellitus.

World J Diabetes 2021 Jun;12(6):868-882

Department of Obstetrics and Fetal Medicine, Erasmus MC Sophia Children Hospital, Rotterdam 3015 GD, Netherlands.

Background: Implementation of new diagnostic criteria for gestational diabetes mellitus (GDM) are still a subject of debate, mostly due to concerns regarding the effects on the number of women diagnosed with GDM and the risk profile of the women newly diagnosed.

Aim: To estimate the impact of the World Health Organization (WHO) 2013 criteria compared with the WHO 1999 criteria on the incidence of gestational diabetes mellitus as well as to determine the diagnostic accuracy for detecting adverse pregnancy outcomes.

Methods: We retrospectively analyzed a single center Dutch cohort of 3338 women undergoing a 75 g oral glucose tolerance test where the WHO 1999 criteria to diagnose GDM were clinically applied. Women were categorized into four groups: non-GDM by both criteria, GDM by WHO 1999 only (excluded from GDM), GDM by WHO 2013 only (newly diagnosed) and GDM by both criteria. We compared maternal characteristics, pregnancy outcomes and likelihood ratios for adverse pregnancy outcomes.

Results: Retrospectively applying the WHO 2013 criteria increased the cohort incidence by 13.1%, from 19.3% to 32.4%. Discordant diagnoses occurred in 21.3%; 4.1% would no longer be labelled as GDM, and 17.2% were newly diagnosed. Compared to the non-GDM group, women newly diagnosed were older, had higher rates of obesity, higher diastolic blood pressure and higher rates of caesarean deliveries. Their infants were more often delivered preterm, large-for-gestational-age and were at higher risk of a 5 min Apgar score < 7. Women excluded from GDM were older and had similar pregnancy outcomes compared to the non-GDM group, except for higher rates of shoulder dystocia (4.3% 1.3%, = 0.015). Positive likelihood ratios for adverse outcomes in all groups were generally low, ranging from 0.54 to 2.95.

Conclusion: Applying the WHO 2013 criteria would result in a substantial increase in GDM diagnoses. Newly diagnosed women are at increased risk for pregnancy adverse outcomes. This risk, however, seems to be lower than those identified by the WHO 1999 criteria. This could potentially influence the treatment effect that can be achieved in this group. Evidence on treatment effects in newly diagnosed women is urgently needed.
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http://dx.doi.org/10.4239/wjd.v12.i6.868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192254PMC
June 2021

Recurrence, postponing pregnancy, and termination rates after hyperemesis gravidarum: Follow up of the MOTHER study.

Acta Obstet Gynecol Scand 2021 Sep 26;100(9):1636-1643. Epub 2021 Jun 26.

Department of Obstetrics and Gynecology, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Introduction: Hyperemesis gravidarum (HG) complicates 1% of pregnancies and has a major impact on maternal quality of life and well-being. We know very little about HG's long-term impact after an affected pregnancy, including recurrence rates in future pregnancies, which is essential information for women considering subsequent pregnancies. In this study, we aimed to prospectively measure the recurrence rate of HG and the number of postponed and terminated subsequent pregnancies due to HG. We also aimed to evaluate if there were predictive factors that could identify women at increased risk for HG recurrence, and postponing and terminating subsequent pregnancies.

Material And Methods: We conducted a prospective cohort study. A total of 215 women admitted for HG to public hospitals in the Netherlands were enrolled in the original MOTHER randomized controlled trial and associated observational cohort. Seventy-three women were included in this follow-up study. Data were collected through an online questionnaire. Recurrent HG was defined as vomiting symptoms accompanied by any of the following: multiple medication use, weight loss, admission, tube feeding or if nausea and vomiting symptoms were severe enough to affect life and/or work. Outcome measures were recurrence, postponing, and termination rates due to HG. Univariable logistic regression analysis was used to identify predictive factors associated with HG recurrence, and postponing and terminating subsequent pregnancies.

Results: Thirty-five women (48%) became pregnant again of whom 40% had postponed their pregnancy due to HG. HG recurred in 89% of pregnancies. One woman terminated and eight women (23%) considered terminating their pregnancy because of recurrent HG. Twenty-four out of 38 women did not get pregnant again because of HG in the past. Univariable logistic regression analysis identifying possible predictive factors found that having a western background was associated with having weight loss due to recurrent HG in subsequent pregnancies (odds ratio 12.9, 95% CI 1.3-130.5, p = 0.03).

Conclusions: High rates of HG recurrence and a high number of postponed pregnancies due to HG were observed. Women can be informed of a high chance of recurrence to enable informed family planning.
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http://dx.doi.org/10.1111/aogs.14197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457209PMC
September 2021

Daily stair climbing is associated with decreased risk for the metabolic syndrome.

BMC Public Health 2021 05 14;21(1):923. Epub 2021 May 14.

Department of Epidemiology and Data Science, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Background: Stair climbing can be a vigorous lifestyle physical activity, and is associated with healthier lipoprotein profiles, lower body weight and blood pressure, as well as higher aerobic fitness. The present analysis of data from a cohort of late middle-aged men and women examined the association between daily stair climbing and the metabolic syndrome.

Methods: Data from 782 (423 women) participants (mean (SD) age 58.3 (0.95) years in the Dutch Famine Birth Cohort Study (2002-2004) were used to examine the cross-sectional association between self-reported daily stair climbing and the metabolic syndrome. Stair climbing was assessed by the question 'Do you climb stairs daily?' and the metabolic syndrome was defined using the established five components relating to lipid fractions, blood glucose levels, blood pressure and abdominal obesity.

Results: Not climbing stairs daily was associated with an increased incidence of the metabolic syndrome (OR = 1.90, 95% CI = 1.23, 2.92, p = 0.004) and a greater number of its components (F = 8.48, p = 0.004): these associations were still evident after adjusting for a variety of potential confounders.

Conclusions: The most likely explanation for the current findings is that daily stair climbing may be protective against the metabolic syndrome. This result reinforces public health recommendations for increased stair climbing with evidence from physiological outcomes.
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http://dx.doi.org/10.1186/s12889-021-10965-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122558PMC
May 2021

Folate and vitamin B12 status: associations with maternal glucose and neonatal DNA methylation sites related to dysglycaemia, in pregnant women with obesity.

J Dev Orig Health Dis 2021 May 11:1-9. Epub 2021 May 11.

Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, UK.

Recent studies implicate maternal gestational diabetes mellitus (GDM) in differential methylation of infant DNA. Folate and vitamin B12 play a role in DNA methylation, and these vitamins may also influence GDM risk. The aims of this study were to determine folate and vitamin B12 status in obese pregnant women and investigate associations between folate and vitamin B12 status, maternal dysglycaemia and neonatal DNA methylation at cytosine-phosphate-guanine sites previously observed to be associated with dysglycaemia. Obese pregnant women who participated in the UK Pregnancies Better Eating and Activity Trial were included. Serum folate and vitamin B12 were measured at the oral glucose tolerance test (OGTT) visit. Cord blood DNA methylation was assessed using the Infinium MethylationEPIC BeadChip. Regression models with adjustment for confounders were used to examine associations. Of the 951 women included, 356 (37.4%) were vitamin B12 deficient, and 44 (4.6%) were folate deficient. Two-hundred and seventy-one women (28%) developed GDM. Folate and vitamin B12 concentrations were not associated with neonatal DNA methylation. Higher folate was positively associated with 1-h plasma glucose after OGTT (β = 0.031, 95% CI 0.001-0.061, p = 0.045). There was no relationship between vitamin B12 and glucose concentrations post OGTT or between folate or vitamin B12 and GDM. In summary, we found no evidence to link folate and vitamin B12 status with the differential methylation of neonatal DNA previously observed in association with dysglycaemia. We add to the evidence that folate status may be related to maternal glucose homoeostasis although replication in other maternal cohorts is required for validation.
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http://dx.doi.org/10.1017/S2040174421000246DOI Listing
May 2021

Lessons learned from 25 Years of Research into Long term Consequences of Prenatal Exposure to the Dutch famine 1944-45: The Dutch famine Birth Cohort.

Int J Environ Health Res 2021 May 5:1-15. Epub 2021 May 5.

Department of Epidemiology and Data Science, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

This paper describes the findings of a historical cohort study of men and women born around the time of the Dutch famine 1944-45. It provided the first direct evidence in humans of the lasting consequences of prenatal undernutrition. The effects of undernutrition depended on its timing during gestation, and the organs and tissues undergoing periods of rapid development at that time. Early gestation appeared to be particularly critical, with the effects of undernutrition being most apparent, even without reductions in size at birth. Undernutrition during gestation affected the structure and function of organs and tissues, altered behaviour and increased risks of chronic degenerative diseases. This demonstrates the fundamental importance of maternal nutrition during gestation as the building blocks for future health.
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http://dx.doi.org/10.1080/09603123.2021.1888894DOI Listing
May 2021

Severe metabolic ketoacidosis as a primary manifestation of SARS-CoV-2 infection in non-diabetic pregnancy.

BMJ Case Rep 2021 Apr 19;14(4). Epub 2021 Apr 19.

Obstetrics & Gynaecology, Amsterdam UMC Location AMC, Amsterdam, North Holland, The Netherlands.

We present a case of a metabolic acidosis in a term-pregnant woman with SARS-CoV-2 infection.Our patient presented with dyspnoea, tachypnoea, thoracic pain and a 2-day history of vomiting, initially attributed to COVID-19 pneumonia. Differential diagnosis was expanded when arterial blood gas showed a high anion gap metabolic non-lactate acidosis without hypoxaemia. Most likely, the hypermetabolic state of pregnancy, in combination with maternal starvation and increased metabolic demand due to infection, had resulted in metabolic ketoacidosis. Despite supportive treatment and rapid induction of labour, maternal deterioration and fetal distress during labour necessitated an emergency caesarean section. The patient delivered a healthy neonate. Postpartum, after initial improvement in metabolic acidosis, viral and bacterial pneumonia with subsequent significant respiratory compromise were successfully managed with oxygen supplementation and corticosteroids. This case illustrates how the metabolic demands of pregnancy can result in an uncommon presentation of COVID-19.
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http://dx.doi.org/10.1136/bcr-2021-241745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057576PMC
April 2021

Maternal and Neonatal Outcome after the Use of G-CSF for Cancer Treatment during Pregnancy.

Cancers (Basel) 2021 Mar 10;13(6). Epub 2021 Mar 10.

Center for Gynecological Oncology Amsterdam, Antoni van Leeuwenhoek-Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

Data on the use of Granulocyte colony-stimulating factor (G-CSF) in pregnant cancer patients are scarce. The International Network of Cancer, Infertility and Pregnancy (INCIP) reviewed data of pregnant patients treated with chemotherapy and G-CSF, and their offspring. Among 2083 registered patients, 42 pregnant patients received G-CSF for the following indications: recent chemotherapy induced febrile neutropenia (5; 12%), dose dense chemotherapy (28, 67%), poly chemotherapy (7, 17%), or prevention of neutropenia at delivery (2; 5%). Among 24 women receiving dose dense chemotherapy, three (13%) patients recovered from asymptomatic neutropenia within 5 days. One patient developed pancytopenia following polychemotherapy after which the pregnancy was complicated by chorioamnionitis and intrauterine death. Nineteen singleton livebirths (49%) were born preterm. Sixteen neonates (41%) were admitted to the Neonatal Intensive care Unit (NICU). No neonatal neutropenia occurred. Two neonates had congenital malformations. Out of 21 children in follow-up, there were four children with a motor development delay and two premature infants had a delay in cognitive development. In conclusion, the rate of maternal and neonatal complications are similar to those described in (pregnant) women treated with chemotherapy. Due to small numbers and limited follow-up, rare or delayed effects among offspring exposed to G-CSF in utero cannot be ruled out yet.
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http://dx.doi.org/10.3390/cancers13061214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001066PMC
March 2021

Cohort profile: the Dutch famine birth cohort (DFBC)- a prospective birth cohort study in the Netherlands.

BMJ Open 2021 03 4;11(3):e042078. Epub 2021 Mar 4.

Epidemiology and Data Science; Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Purpose: The Dutch famine birth cohort study was set up to investigate the effects of acute maternal undernutrition of the 1944-1945 Dutch famine during the specific stages of gestation on later health, with a particular focus on chronic cardiovascular and metabolic diseases, ageing and mental health.

Participants: The Dutch famine birth cohort consists of 2414 singletons born alive and at term in the Wilhelmina Gasthuis in Amsterdam around the time of the Dutch famine (1943-1947) whose birth records have been kept. The cohort has been traced and studied since 1994, when the first data collection started. The cohort has been interviewed and physically examined in several waves of data collection since that time, allowing repeated measures of a wide range of phenotypic information as well as the collection of biological samples (blood, urine, buccal swabs), functional testing (of heart, lungs, kidney, HPA axis) and imaging of the brain (MRI) and vasculature (ultrasound). Additionally, genetic and epigenetic information was collected. Through linkage with registries, mortality and morbidity information of the entire cohort has been obtained.

Findings To Date: Prenatal famine exposure had lasting consequences for health in later life. The effects of famine depended on its timing during the gestation and the organs and tissues developing at that time, with most effects after exposure to famine in early gestation. The effects of famine were widespread and affected the structure and function of many organs and tissues, resulted in altered behaviour and increased risks of chronic degenerative diseases and increased mortality. The effects of famine were independent of size at birth, which suggests that programming may occur without altering size at birth.

Future Plans: As the cohort ages, we will be assessing the effects of prenatal undernutrition on (brain) ageing, cognitive decline and dementia, as well as overall morbidity and mortality.

Registration: The Dutch famine birth cohort is not linked to a clinical trial.
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http://dx.doi.org/10.1136/bmjopen-2020-042078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934722PMC
March 2021

Thyroid-stimulating hormone and free thyroxine fail to predict the severity and clinical course of hyperemesis gravidarum: A prospective cohort study.

Acta Obstet Gynecol Scand 2021 08 12;100(8):1419-1429. Epub 2021 Mar 12.

Department of Obstetrics and Gynecology, Amsterdam Reproduction & Development research institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Introduction: Little is known about the pathophysiology of hyperemesis gravidarum (HG). Proposed underlying causes are multifactorial and thyroid function is hypothesized to be causally involved. In this study, we aimed to assess the utility of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) as a marker and predictor for the severity and clinical course of HG.

Material And Methods: We conducted a prospective cohort study including women admitted for HG between 5 and 20 weeks of gestation in 19 hospitals in the Netherlands. Women with a medical history of thyroid disease were excluded. TSH and FT4 were measured at study entry. To adjust for gestational age, we calculated TSH multiples of the median (MoM). We assessed HG severity at study entry as severity of nausea and vomiting (by the Pregnancy Unique Quantification of Emesis and nausea score), weight change compared with prepregnancy weight, and quality of life. We assessed the clinical course of HG as severity of nausea and vomiting and quality of life 1 week after inclusion, duration of hospital admissions, and readmissions. We performed multivariable regression analysis with absolute TSH, TSH MoMs, and FT4.

Results: Between 2013 and 2016, 215 women participated in the cohort. TSH, TSH MoM, and FT4 were available for, respectively, 150, 126, and 106 of these women. Multivariable linear regression analysis showed that lower TSH MoM was significantly associated with increased weight loss or lower weight gain at study entry (ΔKg; β = 2.00, 95% CI 0.47-3.53), whereas absolute TSH and FT4 were not. Lower TSH, not lower TSH MoM or FT4, was significantly associated with lower nausea and vomiting scores 1 week after inclusion (β = 1.74, 95% CI 0.36-3.11). TSH and FT4 showed no association with any of the other markers of the severity or clinical course of HG. Twenty-one out of 215 (9.8%) women had gestational transient thyrotoxicosis. Women with gestational transient thyrotoxicosis had a lower quality of life 1 week after inclusion than women with no gestational transient thyrotoxicosis (p = 0.03).

Conclusions: Our findings show an inconsistent role for TSH, TSH MoM, or FT4 at time of admission and provide little guidance on the severity and clinical course of HG.
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http://dx.doi.org/10.1111/aogs.14131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360038PMC
August 2021

Population Pharmacokinetics of Docetaxel, Paclitaxel, Doxorubicin and Epirubicin in Pregnant Women with Cancer: A Study from the International Network of Cancer, Infertility and Pregnancy (INCIP).

Clin Pharmacokinet 2021 06 28;60(6):775-784. Epub 2021 Jan 28.

Department of Oncology, Catholic University of Leuven, Leuven, Belgium.

Background: Based on reassuring short-term foetal and maternal safety data, there is an increasing trend to administer chemotherapy during the second and third trimesters of pregnancy. The pharmacokinetics (PK) of drugs might change as a result of several physiological changes that occur during pregnancy, potentially affecting the efficacy and safety of chemotherapy.

Objective: With this analysis, we aimed to quantitatively describe the changes in the PK of docetaxel, paclitaxel, doxorubicin and epirubicin in pregnant women compared with non-pregnant women.

Methods: PK data from 9, 20, 22 and 16 pregnant cancer patients from the International Network of Cancer, Infertility and Pregnancy (INCIP) were available for docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. These samples were combined with available PK data from non-pregnant patients. Empirical non-linear mixed-effects models were developed, evaluating fixed pregnancy effects and gestational age as covariates.

Results: Overall, 82, 189, 271, and 227 plasma samples were collected from pregnant patients treated with docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. The plasma PK data were adequately described by the respective models for all cytotoxic drugs. Typical increases in central and peripheral volumes of distribution of pregnant women were identified for docetaxel, paclitaxel, doxorubicin and epirubicin. Additionally, docetaxel, doxorubicin and paclitaxel clearance were increased in pregnant patients, resulting in lower exposure in pregnant women compared with non-pregnant patients.

Conclusion: Given the interpatient variability, the identified pregnancy-induced changes in PK do not directly warrant dose adjustments for the studied drugs. Nevertheless, these results underscore the need to investigate the efficacy of chemotherapy, when administered during pregnancy.
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http://dx.doi.org/10.1007/s40262-020-00961-4DOI Listing
June 2021

A patient-clinician James Lind Alliance partnership to identify research priorities for hyperemesis gravidarum.

BMJ Open 2021 01 15;11(1):e041254. Epub 2021 Jan 15.

Obstetrics and Gynecology, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands.

Objective: There are many uncertainties surrounding the aetiology, treatment and sequelae of hyperemesis gravidarum (HG). Prioritising research questions could reduce research waste, helping researchers and funders direct attention to those questions which most urgently need addressing. The HG priority setting partnership (PSP) was established to identify and rank the top 25 priority research questions important to both patients and clinicians.

Methods: Following the James Lind Alliance (JLA) methodology, an HG PSP steering group was established. Stakeholders representing patients, carers and multidisciplinary professionals completed an online survey to gather uncertainties. Eligible uncertainties related to HG. Uncertainties on nausea and vomiting of pregnancy and those on complementary treatments were not eligible. Questions were verified against the evidence. Two rounds of prioritisation included an online ranking survey and a 1-hour consensus workshop.

Results: 1009 participants (938 patients/carers, 118 professionals with overlap between categories) submitted 2899 questions. Questions originated from participants in 26 different countries, and people from 32 countries took part in the first prioritisation stage. 66 unique questions emerged, which were evidence checked according to the agreed protocol. 65 true uncertainties were narrowed via an online ranking survey to 26 unranked uncertainties. The consensus workshop was attended by 19 international patients and clinicians who reached consensus on the top 10 questions for international researchers to address. More patients than professionals took part in the surveys but were equally distributed during the consensus workshop. Participants from low-income and middle-income countries noted that the priorities may be different in their settings.

Conclusions: By following the JLA method, a prioritised list of uncertainties relevant to both HG patients and their clinicians has been identified which can inform the international HG research agenda, funders and policy-makers. While it is possible to conduct an international PSP, results from developed countries may not be as relevant in low-income and middle-income countries.
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http://dx.doi.org/10.1136/bmjopen-2020-041254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813320PMC
January 2021

Asymptomatic vaginal Candida colonization and adverse pregnancy outcomes including preterm birth: a systematic review and meta-analysis.

Am J Obstet Gynecol MFM 2020 08 23;2(3):100163. Epub 2020 Jun 23.

Department of Obstetrics and Gynecology, Amsterdam Reproduction and Development Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Objective: During pregnancy, vaginal colonization by Candida spp is common. Some studies suggest an association between asymptomatic vaginal Candida colonization and adverse pregnancy outcomes, but the evidence is inconsistent. This review aimed to systematically review the association between asymptomatic vaginal colonization by Candida spp and adverse pregnancy outcomes, including preterm birth.

Data Sources: We searched Ovid MEDLINE, Ovid Embase, and the Cochrane Central Register of Controlled Trials from inception to May 6, 2020 for published studies on vaginal Candida/yeast and pregnancy outcomes.

Study Eligibility Criteria: Cohort studies, case-control studies, and randomized controlled trials that included pregnant women who were tested for asymptomatic vaginal Candida colonization and reported on adverse pregnancy outcomes were eligible.

Study Appraisal And Synthesis Methods: Two reviewers independently selected and extracted the data. Critical appraisal was performed using the Newcastle-Ottawa Quality Assessment Scale for cohort and case-control studies and the revised Cochrane risk-of-bias tool for randomized controlled trials.

Results: We found no significant difference in preterm birth rate between Candida-positive and Candida-negative women (odds ratio, 1.10; 95% confidence interval, 0.99-1.22; I, 0%) in 15 studies among 33,321 women for either spontaneous preterm birth only (odds ratio, 1.13, 95% confidence interval, 0.97-1.31; I, 0%) or all preterm birth (odds ratio, 1.04; 95% confidence interval, 0.79-1.35; I, 21%). Subgroup analyses for a treatment strategy including only studies reporting on spontaneous preterm birth did not reveal any statistically significant associations either, although the odds ratio was increased for the untreated Candida-positive women (odds ratio, 1.28; 95% confidence interval, 0.90-1.81; I, 13%) in 3 studies among 5175 women. Asymptomatic vaginal Candida colonization was not associated with small for gestational age, perinatal mortality, or any other adverse pregnancy outcome.

Conclusion: Asymptomatic vaginal Candida colonization is not associated with preterm birth and other adverse pregnancy outcomes. Previous studies reported that treatment of this microorganism reduces preterm birth rate. Our results suggest that this effect is unlikely to rely on treatment of vaginal Candida.
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http://dx.doi.org/10.1016/j.ajogmf.2020.100163DOI Listing
August 2020

The chance of recurrence of hyperemesis gravidarum: A systematic review.

Eur J Obstet Gynecol Reprod Biol X 2020 Jan 20;5:100105. Epub 2019 Dec 20.

Department of Gynaecology and Obstetrics, University Medical Centres Amsterdam, Amsterdam, the Netherlands.

Around 1 % of pregnancies develop Hyperemesis Gravidarum (HG), causing high physical and psychological morbidity. Reports on HG recurrence rate in subsequent pregnancies vary widely. An accurate rate of recurrence is needed for informed reproductive decision making. Our objective is to systematically review and aggregate reported rates for HG subsequent to index pregnancies affected by HG. We searched databases from inception as per the protocol registered on PROSPERO. No language restrictions were applied. Inclusion was not restricted based on how HG was defined; reports of severe NVP were included where authors defined the condition as HG. We included descriptive epidemiological, case control and cohort study designs. Eligibility screening was performed in duplo. We extracted data on populations, study methods and outcomes of significance. A panel of patients reviewed the results and provided discussion and feedback. Quality was assessed with the JBI (2017) critical appraisal tool independently by two reviewers. We performed the searches on 1st November 2019. Our search yielded 4454 unique studies, of which five (n = 40,350 HG cases) matched eligibility criteria; One longitudinal and four population-based cohort studies from five countries. Follow-up ranged from 2 to 31 years. Definition of HG and data collection methods in all the studies created heterogeneity. Quality was low; studies lacked valid and reliable exposure, and/or follow-up was insufficient. Meta-analysis was not possible due to clinical and statistical heterogeneity. This systematic review found five heterogeneous studies reporting recurrence rates from 15 to 81%. Defining HG as hospital cases may have introduced detection bias and contribute to clinical heterogeneity. A prospective longitudinal cohort study using an internationally agreed definition of HG and outcomes meaningful to patients is required to establish the true recurrence rate of HG.
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http://dx.doi.org/10.1016/j.eurox.2019.100105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994404PMC
January 2020

Determinants of disease course and severity in hyperemesis gravidarum.

Eur J Obstet Gynecol Reprod Biol 2020 Feb 24;245:162-167. Epub 2019 Dec 24.

Department of Obstetrics and Gynecology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Objective: We aimed to identify determinants that predict hyperemesis gravidarum (HG) disease course and severity.

Study Design: For this study, we combined data of the Maternal and Offspring outcomes after Treatment of HyperEmesis by Refeeding (MOTHER) randomized controlled trial (RCT) and its associated observational cohort with non-randomised patients. Between October 2013 and March 2016, in 19 hospitals in the Netherlands, women hospitalised for HG were approached for study participation. In total, 215 pregnant women provided consent for participation. We excluded women enrolled during a readmission (n = 24). Determinants were defined as patient characteristics and clinical features, available to clinicians at first hospital admission. Patient characteristics included i.e. age, ethnicity, socio-economic status, history of mental health disease and HG and gravidity. Clinical features included weight loss compared to pre-pregnancy weight and symptom severity measured with Pregnancy Unique Quantification of Emesis (PUQE-24) questionnaire and the Nausea and Vomiting in Pregnancy specific Quality of Life questionnaire (NVPQoL). Outcome measures were measures of HG disease severity present at 1 week after hospital admission, including weight change, PUQE-24 and NVPQoL scores. Total days of admission hospital admission and readmission were also considered outcome measures.

Results: We found that high PUQE-24 and NVPQoL scores at hospital admission were associated with those 1 week after hospital admission (difference (β) 0.36, 95 %CI 0.16 to 0.57 and 0.70,95 %CI 0.45-1.1). PUQE-24 and NVPQoL scores were not associated with other outcome measures. None of the patient characteristics were associated with any of the outcome measures.

Conclusion: Our findings suggest that the PUQE-24 and NVPQoL questionnaires can identify women that maintain high symptom scores a week after admission, but that patient characteristics cannot be used as determinants of HG disease course and severity.
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http://dx.doi.org/10.1016/j.ejogrb.2019.12.021DOI Listing
February 2020

Ramadan exposure and birth outcomes: a population-based study from the Netherlands.

J Dev Orig Health Dis 2020 12 11;11(6):664-671. Epub 2019 Dec 11.

Gutenberg School of Management and Economics, Chair of Statistics and Econometrics, Johannes Gutenberg University, Mainz, Germany.

Background: Ramadan, the Islamic month of daytime fasting, is observed by many pregnant Muslims. Although pregnant women are exempt, many prefer to fast. Previous research has shown long-term adverse effects on various health outcomes among the offspring, but evidence on effects on perinatal outcomes is mixed. This study investigates effects of Ramadan during pregnancy among Muslims in the Netherlands.

Methods: Data from the Perinatal Registry of the Netherlands (Perined) on all births between 2000 and 2010 to mothers recorded as Mediterranean (i.e. of Turkish/Moroccan descent, a proxy for Muslim) (n = 139,322) or as ethnically Dutch (n = 1,481,435) were used. Ramadan exposure was defined using an intention-to-treat approach as the occurrence of a Ramadan during gestation. Muslims with versus without a Ramadan occurring during gestation were compared using difference-in-differences analyses. In these multiple linear/logistic regressions, non-Muslims were additionally included in order to take out potentially remaining confounding through seasonal effects.

Results: The occurrence of a Ramadan during pregnancy among Muslims was not associated with altered birth weight, gestational length, newborn's sex, perinatal mortality, low Apgar, or mild congenital anomalies. Odds for severe congenital anomalies were higher among the exposed (odds ratio: 1.17; 95% confidence interval: 1.00, 1.37), but this association became non-significant when adjusting for multiple testing.

Conclusions: Despite earlier research showing long-term adverse health effects of prenatal exposure to Ramadan, there seems to be little or no relation between exposure to Ramadan during pregnancy and birth outcomes.
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http://dx.doi.org/10.1017/S2040174419000837DOI Listing
December 2020

Nausea and vomiting of pregnancy and hyperemesis gravidarum.

Nat Rev Dis Primers 2019 09 12;5(1):62. Epub 2019 Sep 12.

Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Nausea and vomiting of pregnancy (NVP) is a common condition that affects as many as 70% of pregnant women. Although no consensus definition is available for hyperemesis gravidarum (HG), it is typically viewed as the severe form of NVP and has been reported to occur in 0.3-10.8% of pregnant women. HG can be associated with poor maternal, fetal and child outcomes. The majority of women with NVP can be managed with dietary and lifestyle changes, but more than one-third of patients experience clinically relevant symptoms that may require fluid and vitamin supplementation and/or antiemetic therapy such as, for example, combined doxylamine/pyridoxine, which is not teratogenic and may be effective in treating NVP. Ondansetron is commonly used to treat HG, but studies are urgently needed to determine whether it is safer and more effective than using first-line antiemetics. Thiamine (vitamin B1) should be introduced following protocols to prevent refeeding syndrome and Wernicke encephalopathy. Recent advances in the genetic study of NVP and HG suggest a placental component to the aetiology by implicating common variants in genes encoding placental proteins (namely GDF15 and IGFBP7) and hormone receptors (namely GFRAL and PGR). New studies on aetiology, diagnosis, management and treatment are under way. In the next decade, progress in these areas may improve maternal quality of life and limit the adverse outcomes associated with HG.
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http://dx.doi.org/10.1038/s41572-019-0110-3DOI Listing
September 2019

Effects of maternal lifestyle interventions on child neurobehavioral development: Follow-up of randomized controlled trials.

Scand J Psychol 2019 Dec 9;60(6):548-558. Epub 2019 Sep 9.

Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland.

Obesity is a major public health problem. Children of women who were obese before or during pregnancy are at increased risk for neurobehavioral developmental problems. Whether a maternal lifestyle intervention conducted before and during pregnancy in obese women affects child neurobehavioral development is unknown. This study reports on the follow-up of a subsample of two randomized controlled trials, the Finnish RADIEL (n = 216) and Dutch LIFEstyle (n = 305) trial. Women with a pre-pregnancy BMI ≥29 kg/m wishing to conceive or who were already pregnant (<20 weeks) were allocated to a lifestyle intervention or to care as usual. Child neurodevelopment was measured with the Ages and Stages Questionnaire and child behavioral problems were measured with the Childhood Behavior Checklist (RADIEL) or the Strengths and Difficulties Questionnaire (LIFEstyle) at age 3-6 years. We used linear and binary logistic regression analyses to assess the effects of the lifestyle interventions on children's neurobehavioral developmental scores. Follow-up data was available from 161(38%) RADIEL and 96(32%) LIFEstyle children. Child neurodevelopmental scores did not differ significantly between children in the intervention and the control group (RADIEL:median = 275 vs. 280; LIFEstyle:median = 270 vs 267). Child behavioral problem scores did not differ significantly between children in the intervention and the control group (RADIEL:median = 22 vs. 21; LIFEstyle:median = 8 vs. 8). We did not observe considerable effects of the lifestyle interventions before or during pregnancy in obese women on child neurobehavioral development. With our sample sizes, we were not able to detect subtle differences in neurobehavioral development however.
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http://dx.doi.org/10.1111/sjop.12575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899471PMC
December 2019

SUGAR-DIP trial: oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial.

BMJ Open 2019 08 18;9(8):e029808. Epub 2019 Aug 18.

Department of Obstetrics and Gynaecology, Jeroen Bosch Hospital, 's-Hertogenbosch, The Netherlands.

Introduction: In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM.

Methods: The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle.

Ethics And Dissemination: The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals.

Trial Registration Number: NTR6134; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-029808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701578PMC
August 2019

[Hyperemesis gravidarum].

Ned Tijdschr Geneeskd 2019 05 3;163. Epub 2019 May 3.

Amsterdam UMC, locatie AMC, afd. Obstetrie en Gynaecologie, Amsterdam.

Hyperemesis gravidarum Hyperemesis gravidarum (HG) is a severe form of nausea and vomiting during pregnancy, accompanied by weight loss, dehydration and electrolyte imbalances. There is no international agreement on diagnostic criteria for HG. The diagnosis of HG is only made on the basis of the clinical picture. HG has a significant impact on quality of life and is related to negative birth outcomes. The principal elements of HG treatment consist of antiemetics and intravenous rehydration. The probability that there will be a reoccurrence of HG during a subsequent pregnancy is 15-80%. If a subsequent pregnancy is desired, a preconception consultation may have added value.
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May 2019

Wernicke's encephalopathy in hyperemesis gravidarum: A systematic review.

Eur J Obstet Gynecol Reprod Biol 2019 May 12;236:84-93. Epub 2019 Mar 12.

Experimental Psychology, Helmholtz Institute, Utrecht University, the Netherlands; Korsakoff Center Slingedael, Lelie Care Group, Rotterdam, the Netherlands.

Pregnant women have an increased demand for thiamine. In hyperemesis gravidarum (HG) thiamine rapidly depletes, which can lead to Wernicke's Encephalopathy (WE). Our objective was to systematically review the signs and symptoms of WE in HG. We conducted our search from inception using Mesh terms hyperemesis, Wernicke Encephalopathy, Korsakoff's syndrome, and pregnancy. We searched Pubmed, Embase, Cochrane, Web of Science, Psychinfo, PiCarta, and Cinahl. We defined WE as mental, oculomotor, and motoric alterations and thiamine deficiency; HG was defined as severe nausea, and vomiting during pregnancy; adequate WE treatment as >500 mg/day intramuscular or intravenous. Our search yielded 146 case studies reporting on 177 cases. Pregnant WE patients became thiamine depleted between 10-15 weeks of gestation. Patients had been vomiting for a median of 7 weeks before WE, and had lost 12.1 kg. Prodromal signs of WE were nausea and vomiting (100%), double vision (37.4%), and blurred vision (27.4%). Treatment with subtherapeutic thiamin dose was common (63.6%), WE was exacerbated by intravenous glucose administration (14.1%). We found chronic cognitive disorders occurred in 65.4%, pregnancy loss in 50%, and maternal death in 5% of cases. Thiamine supplementation was insufficient or absent from treatment plans. To eradicate WE in pregnancy, it is necessary to give 100 mg of intravenous or intramuscular thiamine in HG patients with persistent or severe late onset vomiting to prevent them from developing WE.
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http://dx.doi.org/10.1016/j.ejogrb.2019.03.006DOI Listing
May 2019

The link between maternal obesity and offspring neurobehavior: A systematic review of animal experiments.

Neurosci Biobehav Rev 2019 03 3;98:107-121. Epub 2019 Jan 3.

Department of Obstetrics and Gynecology, Amsterdam UMC, location AMC, Amsterdam, the Netherlands; Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, Amsterdam, the Netherlands.

Maternal obesity in pregnancy is associated with neurobehavioral problems in the offspring. Establishing causality has been challenging in existing human studies, due to confounding by genetic and postnatal environment. Animal experiments can improve our understanding of this association. This systematic review examined the effects of maternal obesity in pregnancy on offspring neurobehavior in animal models. We included 26 studies (1047 offspring animals). Meta-analyses showed that offspring of obese mothers displayed higher levels of locomotor activity (standardized mean difference (SMD) 0.34 [0.10; 0.58]) and anxiety behavior (SMD 0.47 [0.16; 0.79]) than offspring of lean mothers, but similar memory abilities (SMD -0.06 [-0.52; 0.39]). Meta-analysis of learning abilities was not sensible due to heterogeneity. Although the evidence was heterogeneous and the quality of the included studies generally unclear, this systematic review of animal studies indicates an effect of maternal obesity on increased offspring locomotor activity and anxiety, but not on offspring memory performance. These findings may be important from a public health perspective since obesity is rapidly increasing worldwide, and warrant further research.
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http://dx.doi.org/10.1016/j.neubiorev.2018.12.023DOI Listing
March 2019

Management of severe pregnancy sickness and hyperemesis gravidarum.

BMJ 2018 Nov 30;363:k5000. Epub 2018 Nov 30.

Amsterdam UMC, University of Amsterdam, Obstetrics and Gynaecology, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1136/bmj.k5000DOI Listing
November 2018

Patient Preferences and Experiences in Hyperemesis Gravidarum Treatment: A Qualitative Study.

J Pregnancy 2018 30;2018:5378502. Epub 2018 Oct 30.

Department of Obstetrics and Gynaecology, University Medical Centers Amsterdam, University of Amsterdam, Amsterdam, Netherlands.

Introduction: Hyperemesis gravidarum (HG) medical therapies are currently of limited effect, which creates a larger role for patient preferences in the way HG care is arranged. This is the first study using in-depth interviews to investigate patients' preferences and experiences of HG treatment.

Materials And Methods: We conducted individual in-depth interviews among women who had been hospitalized for HG in North Holland at least once in the past 4 years. We asked them about their experiences, preferences, and suggestions for improvement regarding the HG treatment they received. The sample size was determined by reaching data saturation. Themes were identified from analysis of the interview transcripts.

Results And Discussion: 13 women were interviewed. Interviewees emphasized the importance of early recognition of the severity of HG, increasing caregivers' knowledge on HG, early medical intervention, and nasogastric tube feeding. They valued a single room in hospital, discussion of treatment options, more possibilities of home-treatment, psychological support during HG and after childbirth, and more uniform information and policies regarding HG treatment.

Conclusion: Further research is needed to establish whether the suggestions can lead to more (cost) effective care and improve the course of HG and outcomes for HG patients and their children.
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http://dx.doi.org/10.1155/2018/5378502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234451PMC
April 2019

Long-term effects of a preconception lifestyle intervention on cardiometabolic health of overweight and obese women.

Eur J Public Health 2019 04;29(2):308-314

Unit of General Practice and Primary Health Care, University of Helsinki, Helsinki University Hospital, Helsinki, Finland.

Background: The global prevalence of obesity in women keeps increasing. The preconception period may be a window of opportunity to improve lifestyle, reduce obesity and improve cardiometabolic health. This study assessed the effect of a preconception lifestyle intervention on long-term cardiometabolic health in two randomized controlled trials (RCTs).

Methods: Participants of the LIFEstyle and RADIEL preconception lifestyle intervention studies with a baseline body mass index (BMI) ≥29 kg/m2 were eligible for this follow-up study. Both studies randomized between a lifestyle intervention targeting physical activity, diet and behaviour modification or usual care. We assessed cardiometabolic health 6 years after randomization.

Results: In the LIFEstyle study (n = 111) and RADIEL study (n = 39), no statistically significant differences between the intervention and control groups were found for body composition, blood pressure, arterial stiffness, fasting glucose, homeostasis model assessment of insulin resistance, HbA1c, lipids and high sensitive C-reactive protein levels 6 years after randomization. Participants of the LIFEstyle study who successfully lost ≥5% bodyweight or reached a BMI <29 kg/m2 during the intervention (n = 22, [44%]) had lower weight (-8.1 kg; 99% CI [-16.6 to -0.9]), BMI (-3.3 kg/m2; [-6.5 to -0.8]), waist circumference (-8.2 cm; [-15.3 to -1.3]), fasting glucose (-0.5 mmol/L; [-1.1 to -0.0]), HbA1c (-4.1 mmol/mol; [-9.1 to -0.8]), and higher HDL-C (0.3 mmol/L; [0.1-0.5]) compared with controls.

Conclusion: We found no evidence of improved cardiometabolic health 6 years after a preconception lifestyle intervention among overweight and obese women in two RCTs. Women who successfully lost weight during the intervention had better cardiometabolic health 6 years later, emphasizing the potential of successful preconception lifestyle improvement.
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http://dx.doi.org/10.1093/eurpub/cky222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427693PMC
April 2019

A lifestyle intervention improves sexual function of women with obesity and infertility: A 5 year follow-up of a RCT.

PLoS One 2018 23;13(10):e0205934. Epub 2018 Oct 23.

Department of Obstetrics and Gynecology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Obesity and infertility are associated with poorer sexual function. We have previously shown that a lifestyle intervention in women with obesity and infertility reduced weight and improved cardiometabolic health and quality of life, which may positively affect sexual function. We now report on sexual function 5 years after randomization.

Methods And Findings: In total 577 women, between 18-39 years of age, with infertility and a BMI ≥29 kg/m2 were randomized to a six-month lifestyle intervention targeting physical activity, diet and behavior modification or prompt infertility care as usual. Intercourse frequency and sexual function were assessed with the McCoy Female Sexuality Questionnaire (MFSQ), 5.4±0.8 years after randomization. 550 women could be approached for the follow-up study, of whom 84 women in the intervention and 93 in the control group completed the MFSQ. Results were adjusted for duration of infertility, polycystic ovary syndrome and whether women were attempting to conceive. The intervention group more often reported having had intercourse in the past 4 weeks compared to the control group (aOR: 2.3 95% CI 0.96 to 5.72). Among women reporting intercourse in the past 4 weeks, the intervention group (n = 75) had intercourse more frequently (6.6±5.8 vs. 4.9±4.0 times; 95% CI 0.10 to 3.40) and had higher scores for vaginal lubrication (16.5±3.0 vs. 15.4±3.5; 95% CI 0.15 to 2.32) and total 'sexual function' score (96.5±14.2 vs. 91.4±12.8; 95% CI 0.84 to 9.35) compared to the control group (n = 72). Sexual interest, satisfaction, orgasm and sex partner scores did not differ statistically between the groups. The intervention effect on sexual function was for 21% mediated by the change in moderate to vigorous physical activity.

Conclusion: A six-month lifestyle intervention in women with obesity and infertility led to more frequent intercourse, better vaginal lubrication and overall sexual function 5 years after the intervention. (Trial Registration: NTR1530).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205934PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198949PMC
April 2019

Associations of vomiting and antiemetic use in pregnancy with levels of circulating GDF15 early in the second trimester: A nested case-control study.

Wellcome Open Res 2018 21;3:123. Epub 2018 Sep 21.

Metabolic Research Laboratories and MRC Metabolic Diseases Unit, University of Cambridge Addenbrooke's Hospital Cambridge, Cambridge, CB2 0QQ, UK.

Although nausea and vomiting are very common in pregnancy, their pathogenesis is poorly understood. We tested the hypothesis that circulating growth and differentiation factor 15 (GDF15) concentrations in early pregnancy, whose gene is implicated in hyperemesis gravidarum, are associated with nausea and vomiting. Blood samples for the measurement of GDF15 and human chorionic gonadotrophin (hCG) concentrations were obtained early in the second trimester (median 15.1 (interquartile range 14.4-15.7) weeks) of pregnancy from 791 women from the Cambridge Baby Growth Study, a prospective pregnancy and birth cohort. During each trimester participants completed a questionnaire which included questions about nausea, vomiting and antiemetic use. Associations with pre-pregnancy body mass indexes (BMI) were validated in 231 pregnant NIPTeR Study participants. Circulating GDF15 concentrations were higher in women reporting vomiting in the second trimester than in women reporting no pregnancy nausea or vomiting: 11,581 (10,977-12,219) (n=175) vs. 10,593 (10,066-11,147) (n=193) pg/mL, p=0.02). In women who took antiemetic drugs during pregnancy (n=11) the GDF15 levels were also raised 13,157 (10,558-16,394) pg/mL (p =0.04). Serum GFD15 concentrations were strongly positively correlated with hCG levels but were inversely correlated with maternal BMIs, a finding replicated in the NIPTeR Study. Week 15 serum GDF15 concentrations are positively associated with second trimester vomiting and maternal antiemetic use in pregnancy. Given GDF15's site of action in the chemoreceptor trigger zone of the brainstem and its genetic associations with hyperemesis gravidarum, these data support the concept that GDF15 may be playing a pathogenic role in pregnancy-associated vomiting.
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http://dx.doi.org/10.12688/wellcomeopenres.14818.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171563PMC
September 2018

Long-Term Effects of Oral Antidiabetic Drugs During Pregnancy on Offspring: A Systematic Review and Meta-analysis of Follow-up Studies of RCTs.

Diabetes Ther 2018 Oct 30;9(5):1811-1829. Epub 2018 Aug 30.

Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Introduction: Antidiabetic drugs (OADs) are increasingly prescribed to treat hyperglycaemia during pregnancy in women with gestational diabetes mellitus (GDM) or polycystic ovary syndrome (PCOS), even though long-term effects on offspring are unknown. This systematic review summarises the evidence of follow-up studies of randomised controlled trials (RCTs) reporting on long-term effects of prenatal exposure to OADs on offspring.

Methods: The MEDLINE, EMBASE and CENTRAL databases were searched from inception to April 2018 for the concepts antidiabetic agents and prenatal exposure (or pregnancy and offspring/child) in combination with an RCT search filter. RCTs evaluating post-neonatal health effects in offspring and comparing maternal treatment with an OAD with no treatment, placebo, an alternative OAD or insulin during pregnancy were eligible for inclusion. Two independent researchers selected, extracted and assessed the data. Meta-analyses were performed using a random effects model and the Cochrane Collaboration's risk of bias tool was used for quality assessment.

Results: Ten studies were included, with a maximal follow-up duration of 9 years, comprising 778 children of mothers with GDM or PCOS who were randomised to either metformin or insulin/placebo during pregnancy. Meta-analysis showed that children prenatally exposed to metformin were heavier compared to controls (standardised mean difference (SMD) 0.26 [95% CI 0.11-0.41]), but not taller (SMD 0.10 [95% CI -0.14-0.33]). Additionally, offspring body mass index (BMI) z scores did not differ according to metformin exposure (mean difference 0.30 [95% CI -0.01-0.61]). Individual small studies reported that prenatal exposure to metformin was associated with greater mid-upper arm, head and waist circumferences, biceps skinfolds, waist-to-height ratio, more arm fat, higher fasting glucose, ferritin and lower LDL cholesterol in offspring.

Conclusion: Prenatal exposure to metformin is associated with increased offspring weight, but not with height or BMI. Larger follow-up studies are needed to confirm and look into the implications of these findings. Plain language summary available for this article.
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http://dx.doi.org/10.1007/s13300-018-0479-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167305PMC
October 2018
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