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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. [ABSTRACT FROM AUTHOR]

Background: Advanced hybrid closed loop (AHCL) therapy can improve glycaemic control in pregnant women with type 1 diabetes. However, data are needed on the efficacy and safety of AHCL systems as these systems, such as the MiniMed 780G, are not currently approved for use in pregnant women. We aimed to investigate whether the MiniMed 780G can improve glycaemic control with less hypoglycaemia in pregnant women with type 1 diabetes., Methods: CRISTAL was a double-arm, parallel-group, open-label, randomised controlled trial conducted in secondary and tertiary care specialist endocrinology centres at 12 hospitals (11 in Belgium and one in the Netherlands). Pregnant women aged 18-45 years with type 1 diabetes were randomly assigned (1:1) to AHCL therapy (MiniMed 780G) or standard insulin therapy (standard of care) at a median of 10·1 (IQR 8·6-11·6) weeks of gestation. Randomisation was done centrally with minimisation dependent on baseline HbA 1c , insulin administration method, and centre. Participants and study teams were not masked to group allocation. The primary outcome was proportion of time spent in the pregnancy-specific target glucose range (3·5-7·8 mmol/L), measured by continuous glucose monitoring (CGM) at 14-17 weeks, 20-23 weeks, 26-29 weeks, and 33-36 weeks. Key secondary outcomes were overnight time in target range, and time below glucose range (<3·5 mmol/L) overall and overnight. Analyses were conducted on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov (NCT04520971)., Findings: Between Jan 15, 2021 and Sept 30, 2022, 101 participants were screened, and 95 were randomly assigned to AHCL therapy (n=46) or standard insulin therapy (n=49). 43 patients assigned to AHCL therapy and 46 assigned to standard insulin therapy completed the study. At baseline, 91 (95·8%) participants used insulin pumps, and the mean HbA 1c was 6·5% (SD 0·6). The mean proportion of time spent in the target range (averaged over four time periods) was 66·5% (SD 10·0) in the AHCL therapy group compared with 63·2% (12·4) in the standard insulin therapy group (adjusted mean difference 1·88 percentage points [95% CI -0·82 to 4·58], p=0·17). Overnight time in the target range was higher (adjusted mean difference 6·58 percentage points [95% CI 2·31 to 10·85], p=0·0026), and time below range overall (adjusted mean difference -1·34 percentage points [95% CI, -2·19 to -0·49], p=0·0020) and overnight (adjusted mean difference -1·86 percentage points [95% CI -2·90 to -0·81], p=0·0005) were lower with AHCL therapy than with standard insulin therapy. Participants assigned to AHCL therapy reported higher treatment satisfaction. No unanticipated safety events occurred with AHCL therapy., Interpretation: In pregnant women starting with tighter glycaemic control, AHCL therapy did not improve overall time in target range but improved overnight time in target range, reduced time below range, and improved treatment satisfaction. These data suggest that the MiniMed 780G can be safely used in pregnancy and provides some additional benefits compared with standard insulin therapy; however, it will be important to refine the algorithm to better align with pregnancy requirements., Funding: Diabetes Liga Research Fund and Medtronic., Competing Interests: Declaration of interests UZ Leuven received research support for KBen from the Diabetes Liga Research Fund (financial) and Medtronic (financial and non-financial). KU Leuven received research support for KBen from AstraZeneca (financial), Dexcom (non-financial), Eli Lilly (financial), Metagenics (financial), and Novo Nordisk (financial and non-financial). KBen reports consulting fees from AstraZeneca and Eli Lilly, and honoraria for speaking from AstraZeneca, Mundipharma, and Novo Nordisk. KBen received support for attending virtual conferences and meetings from AstraZeneca and Novo Nordisk. KBen is the recipient of a senior clinical research fellowship from FWO, the Flemish Research Council. KBeu is the recipient of a PhD fellowship strategic basic research (FWO-SB) from FWO. GV has served on the advisory board for Eli Lilly. GV reports honoraria for speaking and received support for attending (virtual) conferences and meetings from Boehringer-Ingelheim, Eli Lilly, and Novo Nordisk. YT had a fiduciary role in the Diabetes Liga (no financial compensation). YT reports consulting fees from Bayer and Eli Lilly, and honoraria for speaking from Boehringer-Ingelheim and Eli Lilly. YT received support for attending conferences and meetings from Bayer. X-PA reports honoraria for speaking from AstraZeneca, Menarini, and Novo Nordisk, and received support for attending (virtual) conferences and meetings from Novo Nordisk and Sanofi. FN is president of the Belgian Diabetes Forum, has served on advisory boards for Eli Lilly and Novo Nordisk, and received a grant from AstraZeneca to organise a symposium. FN reports honoraria for speaking from AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi. JM reports honoraria for speaking from Novo Nordisk and Sanofi; and received support for attending conferences and meetings from Novo Nordisk. DL reports honoraria for speaking from AstraZeneca, Novo Nordisk, and Sanofi. VP reports consulting fees from Abbott, Novartis, and Sanofi, and has served on the advisory board for Sanofi. SES reports honoraria for speaking from Eli Lilly and Medtronic; and has served on the advisory board for Roche (all financial compensation received by their institution and used for investigator-initiated research). RCP received governmental funding from ZonMw for research and establishing a network in the Netherlands. RCP has served on the advisory board for the stichting ZEHG and NVOG (College of Obstetrics). PG has served on the advisory board for Insulet and Ypsomed. KU Leuven received research grants for PG from Dexcom (financial and non-financial support), Medtronic, Novo Nordisk, Roche, Sanofi, and Tandem. PG reports consulting fees from Abbott, Bayer, and Medtronic, and honoraria for speaking from Abbott, Bayer, Dexcom, Insulet, Medtronic, Novo Nordisk, Vitalaire, and Ypsomed (financial compensation received by KU Leuven). PG received support for attending (virtual) conferences and meetings from Medtronic, Novo Nordisk, Roche, and Sanofi (financial compensation received by KU Leuven). PG is the recipient of a senior clinical research fellowship from FWO, the Flemish Research Council. CM has served on the advisory board for ActoBio, AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Imcyse, Insulet, Medtronic, Merck Sharp and Dohme, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Therapeutics, Vertex, and Zealand Pharma (financial compensation received by KU Leuven); and has served on the speakers' bureau for AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Novartis, Novo Nordisk, and Sanofi (financial compensation received by KU Leuven). All disclosures are unrelated to the present work. All other authors declare no competing interests., (Copyright 2024 Published by Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

We describe vaginal microbiota, including Gardnerella species and sexually transmitted infections (STIs), during pregnancy and their associations with recurrent spontaneous preterm birth (sPTB). We performed a prospective cohort study in a tertiary referral centre in the Netherlands, among pregnant women with previous sPTB <34 weeks' gestation. Participants collected three vaginal swabs in the first and second trimester. Vaginal microbiota was profiled with 16S rDNA sequencing. Gardnerella species and STI's were tested with qPCR. Standard care was provided according to local protocol, including screening and treatment for bacterial vaginosis (BV), routine progesterone administration and screening for cervical length shortening. Of 154 participants, 26 (16.9 %) experienced recurrent sPTB <37 weeks' gestation. Microbiota composition was not associated with sPTB. During pregnancy, the share of Lactobacillus iners- dominated microbiota increased at the expense of diverse microbiota between the first and second trimester. This change coincided with treatment for BV, demonstrating a similar change in microbiota composition after treatment. In this cohort of high-risk women, we did not find an association between vaginal microbiota composition and recurrent sPTB. This should be interpreted with care, as these women were offered additional preventive therapies to reduce sPTB according to national guidelines including progesterone and BV treatment. The increase observed in L. iners dominated microbiota and the decrease in diverse microbiota mid-gestation was most likely mediated by BV treatment. Our findings suggest that in recurrent sPTB occurring despite several preventive therapies, the microbe-related etiologic contribution might be limited., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:R.C. Painter, P.H.M. Savelkoul reports financial support was provided by Amsterdam Reproduction and Development. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Competing Interests: Competing interests:: Iris Grooten and Rebecca Painter are expert members for the development of the Dutch guideline on hyperemesis gravidarum and the thyroid in pregnancy, respectively. Rebecca Painter reports funding from ZonMw, participation on a data safety monitoring board for the CRISTAL study, an advisory position with Stichting ZEHG, and a board position with NVOG. No other competing interests were declared.

Aim: To investigate the association between continuous glucose monitoring (CGM) metrics and perinatal outcomes in insulin-treated diabetes mellitus in pregnancy., Materials and Methods: In a post-hoc analysis of the GlucoMOMS randomized controlled trial, we investigated the association between the metrics of an offline, intermittent CGM, glycated haemoglobin (HbA1c) and perinatal outcomes per trimester in different types of diabetes (type 1, 2 or insulin-treated gestational diabetes mellitus [GDM]). Data were analysed using multivariable binary logistic regression. Outcomes of interest were neonatal hypoglycaemia, pre-eclampsia, preterm birth, large for gestational age (LGA) and Neonatal Intensive Care Unit (NICU) admission. The glucose target range was defined as 3.5-7.8 mmol/L (63-140 mg/dL)., Results: Of the 147 participants (N = 50 type 1 diabetes, N = 94 type 2 diabetes/insulin-treated GDM) randomized to the CGM group of the GlucoMOMS trial, 115 participants had CGM metrics available and were included in the current study. We found that, in pregnancies with type 1 diabetes, a higher second trimester mean glucose was associated with LGA (odds ratio 2.6 [95% confidence interval 1.1-6.2]). In type 2 and insulin-treated gestational diabetes, an increased area under the curve above limit was associated with LGA (odds ratio 10.0 [95% confidence interval 1.4-72.8]). None of the CGM metrics were associated with neonatal hypoglycaemia, pre-eclampsia, shoulder dystocia, preterm birth and NICU admission rates for pregnancies complicated by any type of diabetes., Conclusion: In this study, in type 2 diabetes or insulin-treated GDM, the glucose increased area under the curve above limit was associated with increased LGA. In type 1 diabetes, the mean glucose was the major determinant of LGA. Our study found no evidence that other CGM metrics determined adverse pregnancy outcomes., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims/hypothesis: Glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors are novel drugs which have recently seen rapid uptake in the treatment of type 2 diabetes and obesity. The paucity of data regarding their safety during pregnancy and lactation causes a dilemma for the physician. The aim of the present study was to systematically review all available data on the offspring effects of GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation., Methods: We systematically searched PubMed, clinicaltrials.gov, FDA and EMA product information on GLP-1 agonists and SGLT2 inhibitors in pregnancy and lactation from inception up to 19 April 2022 without language restrictions. We approached both the Netherlands Pharmacovigilance Centre Lareb on January 17 th 2023 and the Teratology Information Service (TIS) of Switzerland on February 6 th 2023. Eligible studies investigating the safety (including congenital anomalies, fetal growth, perinatal demise) in animals or humans, or reporting the degree of transfer of these drugs to the fetus, breast milk or breastfed neonate. Two reviewers independently assessed and selected studies for inclusion and subsequently resolved discrepancies by discussion., Results: We included 39 records (n=9 theoretical; based on drug properties, n=7 human; n=23 animal, including 76 human offspring, and an unknown number of animal offspring as these numbers could not be retrieved from the FDA and EMA product information). In animal studies, GLP1-agonists were associated with reduced fetal weight and/or growth, delayed ossification and skeletal variants, usually associated with a reduction in maternal weight gain and decreased food consumption. Exendin-4 (GLP1-agonist) was not transported across the maternal-fetal placental interface. In human studies, exenatide (GLP1-agonist) showed a fetal-to-maternal peptide concentration ratio of ≤ 0.017 in ex vivo human placental perfusion in a single placenta. Liraglutide (GLP1-agonist) showed no significant maternal to fetal transfer at least 3.5 hours after maternal exposure in a human study with one subject. In animal studies, GLP-1 agonists were excreted in breast milk; human data on excretion were not available. In animal studies, SGLT2 inhibitors were generally safe during the first trimester but exposure during postnatal day 21 to 90 in juvenile rats, a period coinciding with the late second and third trimester of human renal development, caused dilatation of the renal pelvis and tubules. Human data consisted of a pharmaceutical database of inadvertent pregnancies during SGLT2 inhibitor use, which found an increase in miscarriages and congenital malformations. In animal studies SGLT2 inhibitors were excreted in breast milk and affected neonatal growth, but human data are not available., Conclusion/interpretation: We found evidence for adverse offspring effects of GLP-1 agonists and SGLT2 inhibitors also in human studies. Our findings broadly support the advice to discontinue GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation, and also support the ongoing registration of pregnancy outcomes in pharmacological databases since the amount of available data is scarce and mostly limited to animal studies., Registration: https://www.crd.york.ac.uk/prospero/display&#95;record.php?RecordID=219877., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Muller, Stenvers, Malekzadeh, Holleman, Painter and Siegelaar.)

Background: An effective and safe treatment for nausea and vomiting of pregnancy (NVP) is lacking., Objective: To assess the efficacy and safety of acupuncture, doxylamine-pyridoxine, and a combination of both in women with moderate to severe NVP., Design: Multicenter, randomized, double-blind, placebo-controlled, 2 × 2 factorial trial. (ClinicalTrials.gov: NCT04401384)., Setting: 13 tertiary hospitals in mainland China from 21 June 2020 to 2 February 2022., Participants: 352 women in early pregnancy with moderate to severe NVP., Intervention: Participants received daily active or sham acupuncture for 30 minutes and doxylamine-pyridoxine or placebo for 14 days., Measurements: The primary outcome was the reduction in Pregnancy-Unique Quantification of Emesis (PUQE) score at the end of the intervention at day 15 relative to baseline. Secondary outcomes included quality of life, adverse events, and maternal and perinatal complications., Results: No significant interaction was detected between the interventions ( P = 0.69). Participants receiving acupuncture (mean difference [MD], -0.7 [95% CI, -1.3 to -0.1]), doxylamine-pyridoxine (MD, -1.0 [CI, -1.6 to -0.4]), and the combination of both (MD, -1.6 [CI, -2.2 to -0.9]) had a larger reduction in PUQE score over the treatment course than their respective control groups (sham acupuncture, placebo, and sham acupuncture plus placebo). Compared with placebo, a higher risk for births with children who were small for gestational age was observed with doxylamine-pyridoxine (odds ratio, 3.8 [CI, 1.0 to 14.1])., Limitation: The placebo effects of the interventions and natural regression of the disease were not evaluated., Conclusion: Both acupuncture and doxylamine-pyridoxine alone are efficacious for moderate and severe NVP. However, the clinical importance of this effect is uncertain because of its modest magnitude. The combination of acupuncture and doxylamine-pyridoxine may yield a potentially larger benefit than each treatment alone., Primary Funding Source: The National Key R&D Program of China and the Project of Heilongjiang Province "TouYan" Innovation Team., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-2974.

Objectives: Test applicability and additional value of a consultation round after the consensus meeting in the development of core outcome sets (COSs)., Study Design and Setting: In two COS procedures (Core Outcome Set for the prevention and treatment of fetal GROwth restriction: deVeloping Endpoints (COSGROVE) and Definition and Core Outcomes on Hyperemesis Gravida (DCOHG)) that followed the Core Outcome Measures in Effectiveness Trials methodology, the first round of convergence to consensus among stakeholder groups in an online Delphi procedure was followed by a face-to-face consensus meeting during which a COS was formulated. We subsequently presented the COS to the online panel in a consultation round to confirm that the online panel agreed with the choices made at the consensus meeting, defined as 80% agreement., Participants: In the COSGROVE Study, there were eight stakeholder groups, and 83 out of 107 participants completed the consultation round. In the DCOHG Study, there were four stakeholder groups, and 96 out of 125 completed the consultation round., Interventions: Adding a consultation round after completing a modified Delphi method with a consensus meeting., Results: There was a level of agreement of 81% and 84%, respectively, in the consultation round of both procedures. This was above the preset level of agreement. The consultation round yielded additional suggestions to refine COS formulation in one of the studies., Conclusion: Our study shows that in two procedures, the online expert panel agreed with the participants of the consensus meeting in these procedures, lending validity to existing COS methodology. Future studies could evaluate whether bringing back the COS for confirmation after the consensus meeting could potentially increase the uptake of the final COS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Hyperemesis gravidarum is the severe form of nausea and vomiting during pregnancy and can lead to undernutrition and low maternal weight gain. Previous epidemiologic and animal studies have shown that undernutrition and low maternal weight gain in pregnancy can increase the risk of unfavorable perinatal outcomes, like shorter gestational age, small for gestational age and lower weight at birth., Objective: To evaluate the effect of hyperemesis gravidarum on perinatal outcomes., Search Strategy: OVID Medline and Embase were searched from inception to February 9th, 2022., Study Eligibility: Studies reporting on perinatal outcomes of infants born to mothers with hyperemesis gravidarum or severe nausea and vomiting in pregnancy were included. Case reports, case series, animal studies, reviews, editorials and conference abstracts were excluded., Data Collection and Analysis: Two reviewers independently selected and extracted data. Risk of bias was assessed by the Newcastle-Ottawa Quality Assessment Scale. We conducted meta-analyses where possible., Results: Our search yielded 1387 unique papers, of which 61 studies (n = 20,532,671 participants) were included in our systematic review. Meta-analyses showed that hyperemesis gravidarum was associated with preterm birth < 34 weeks (2 studies n = 2,882: OR 2.81, 95 %CI: 1.69-4.67), birth weight < 1500 g (2 studies, n = 489,141: OR 1.43, 95 %CI: 1.02-1.99), neonatal resuscitation (2 studies, n = 4,289,344: OR 1.07, 95 %CI: 1.05-1.10), neonatal intensive care unit admission (7 studies, n = 6,509,702: OR 1.20, 95 %CI: 1.14-1.26) and placental abruption (6 studies, n = 9,368,360: OR 1.15, 95 %CI: 1.05-1.25). Hyperemesis gravidarum was associated with reductions in birthweight > 4000 g (2 studies, n = 5,503,120: OR 0.74, 95 %CI: 0.72-0.76) and stillbirth (9 studies, n = 3,973,154: OR 0.92, 95 %CI: 0.85-0.99). Meta-analyses revealed no association between hyperemesis gravidarum and Apgar scores < 7 at 1 and 5 min; fetal loss, perinatal deaths and neonatal deaths., Conclusion: Hyperemesis gravidarum is associated with several adverse perinatal outcomes including low birth weight and preterm birth. We also found that pregnancies complicated by hyperemesis gravidarum less frequently were complicated by macrosomia and stillbirth. We were unable to investigate underlying mechanisms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Despite increasing use of continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII, insulin pumps) in type 1 diabetes (T1D) in pregnancy, achieving recommended pregnancy glycaemic targets (3.5-7.8 mmol/L or 63-140 mg/dL) remains challenging. Consequently, the risk of adverse pregnancy outcomes remains high. Outside pregnancy, hybrid closed-loop (HCL) insulin delivery systems have led to a paradigm shift in the management of T1D, with 12% higher time in glucose target range (TIR) compared to conventional CSII. However, most commercially available HCL systems are currently not approved for use in pregnancy. This study aims to evaluate the efficacy, safety and cost-effectiveness of the MiniMed™ 780G HCL system (Medtronic) in T1D in pregnancy., Methods: In this international, open-label, randomized controlled trial (RCT), we will compare the MiniMed™ 780G HCL system to standard of care (SoC) in T1D in pregnancy. Women aged 18-45 years with T1D diagnosis of at least one year, HbA1c ≤ 86 mmol/mol (≤ 10%), and confirmed singleton pregnancy up to 11 weeks 6 days will be eligible. After providing written informed consent, all participants will wear a similar CGM system (Guardian™ 3 or Guardian™ 4 CGM) during a 10-day run-in phase. After the run-in phase, participants will be randomised 1:1 to 780G HCL (intervention) or SoC [control, continuation of current T1D treatment with multiple daily injections (MDI) or CSII and any type of CGM] stratified according to centre, baseline HbA1c (< 53 vs. ≥ 53 mmol/mol or < 7 vs. ≥ 7%), and method of insulin delivery (MDI or CSII). The primary outcome will be the time spent within the pregnancy glucose target range, as measured by the CGM at four time points in pregnancy: 14-17, 20-23, 26-29, and 33-36 weeks. Prespecified secondary outcomes will be overnight TIR, time below range (TBR: <3.5 mmol/L or < 63 mg/dL), and overnight TBR. Other outcomes will be exploratory. The planned sample size is 92 participants. The study will end after postpartum discharge from hospital. Analyses will be performed according to intention-to-treat as well as per protocol., Discussion: This large RCT will evaluate a widely used commercially available HCL system in T1D in pregnancy. Recruitment began in January 2021 and was completed in October 2022. Study completion is expected in May 2023., Trial Registration: ClinicalTrials.gov: NCT04520971. Registration date: August 20, 2020. https://clinicaltrials.gov/ct2/show/NCT04520971., (© 2023. The Author(s).)

Objective: To determine the prevalence of depression, anxiety, and posttraumatic stress disorder (PTSD) years after hyperemesis gravidarum (HG) and its association with HG severity., Material and Methods: This prospective cohort study consisted of a follow-up of 215 women admitted for HG, who were eligible to participate in a randomized controlled trial and either declined or agreed to be randomized between 2013 and 2016 in 19 hospitals in the Netherlands. Participants completed the Hospital Anxiety and Depression Scale (HADS) six weeks postpartum and during follow-up and the PTSD checklist for DSM-5 (PCL-5) during follow-up. An anxiety or depression score ≥8 is indicative of an anxiety or depression disorder and a PCL-5 ≥ 31 indicative of PTSD. Measures of HG severity were symptom severity (PUQE-24: Pregnancy Unique Quantification of Emesis), weight change, duration of admissions, readmissions, and admissions after the first trimester., Results: About 54/215 participants completed the HADS six weeks postpartum and 73/215 participants completed the follow-up questionnaire, on average 4.5 years later. Six weeks postpartum, 13 participants (24.1%) had an anxiety score ≥8 and 11 participants (20.4%) a depression score ≥8. During follow-up, 29 participants (39.7%) had an anxiety score ≥8, 20 participants (27.4%) a depression score ≥8, and 16 participants (21.9%) a PCL-5 ≥ 31.Multivariable logistic regression analysis showed that for every additional point of the mean PUQE-24 three weeks after inclusion, the likelihood of having an anxiety score ≥8 and PCL-5 ≥ 31 at follow-up increased with OR 1.41 (95% CI: 1.10;1.79) and OR 1.49 (95% CI: 1.06;2.10) respectively., Conclusion: Depression, anxiety, and PTSD symptoms are common years after HG occurred.

The prevalence of obesity is increasing worldwide. Experimental animal studies demonstrate that maternal obesity during pregnancy directly affects cardiac structure and function in their offspring, which could contribute to their increased cardiovascular disease (CVD) risk. Currently, a systematic overview of the available evidence regarding maternal obesity and alterations in cardiac structure and function in human offspring is lacking. We systematically searched the electronic databases Embase, MEDLINE and NARCIS from inception to June 29, 2022 including human studies comparing cardiac structure and function from fetal life onwards in offspring of women with and without obesity. The review protocol was registered with PROSPERO International Prospective Register of Systematic Reviews (identifier: CRD42019125071). Risk of bias was assessed using a modified Newcastle-Ottawa scale. Results were expressed using standardized mean differences (SMD). The search yielded 1589 unique publications, of which thirteen articles were included. Compared to offspring of women without obesity, fetuses of women with obesity had lower left ventricular strain, indicative of reduced systolic function, that persisted in infancy (SMD -2.4, 95% confidence interval (CI) -4.4 standard deviation (SD) to -0.4 SD during fetal life and SMD -1.0, 95% CI -1.6 SD to -0.3 SD in infancy). Furthermore, infants born to women with obesity had a thicker interventricular septum (SMD 0.6 SD, 95% CI 0.0 to 1.2 SD) than children born to women without obesity. In conclusion, cardiac structure and function differs between fetuses and children of women with and without obesity. Some of these differences were present in fetal life, persisted in childhood and are consistent with increased CVD risk. Long-term follow-up research is warranted, as studies in offspring of older age are lacking., Competing Interests: The authors have no competing interests to declare that are relevant to the content of this article., (Copyright: © 2022 den Harink et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Thyroid hormone measurements are often performed in pregnant women, as hypo- and hyperthyroidism during pregnancy can severely affect the fetus. Serum free thyroxine (fT4) measurements are well known for their analytical challenges, due to low serum concentrations and the subtle equilibrium between free and bound T4 (to thyroid-binding globulin (TBG), transthyretin and albumin). Pregnant women have high TBG concentrations due to an increase in human chorionic gonadotropin (hCG) and estrogen and lower albumin concentrations which change the equilibrium and may affect the validity of fT4 measurements in their samples. As accurate serum fT4 measurements in pregnant women are important for the long-term health of the fetus, we aimed to evaluate the accuracy of several fT4 immunoassays in the serum of pregnant women., Methods: FT4 was measured in healthy controls and pregnant women using a candidate-reference method (LC-MS/MS) and five commercially available automated immunoassays (Alinity (Abbott), Atellica (Siemens), Cobas (Roche), Lumipulse (Fujirebio) and UniCel DXI (Beckman Coulter)). Method comparisons (Bland Altman plots and Passing and Bablok analyses) were performed., Results: Serum samples from both healthy controls (n = 30) and pregnant women (n = 30; mean gestational age, 24.8 weeks) were collected. The fT4 immunoassays deviated +7 to +29% more from the LC-MS/MS in serum samples of pregnant women than healthy controls (falsely high)., Conclusions: Our results indicate that immunoassays overestimate fT4 in pregnant women, which might lead to an overestimation of thyroid status. Physicians and laboratory specialists should be aware of this phenomenon to avoid drawing false conclusions about thyroid function in pregnant women.

Objective: Knowledge gaps regarding hyperemesis gravidarum (HG) are substantial. We aimed to systematically identify and map recent evidence addressing the top 10 priority questions for HG, as published in 2021 in a James Lind Alliance Priority Setting Partnership., Design: Systematic evidence map., Methods: We searched MEDLINE and EMBASE on 12 January 2021 and CINAHL on 22 February 2021 with search terms hyperemesis gravidarum, pernicious vomiting in pregnancy and their synonyms. Results were limited to 2009 onwards. Two reviewers independently screened titles and abstracts to assess whether the studies addressed a top 10 priority questions for HG. Differences were discussed until consensus was reached. Publications were allocated to one or more top 10 research questions. Study design was noted, as was patient or public involvement. Two reviewers extracted data synchronously and both cross-checked 10%. Extracted data were imported into EPPI-Reviewer software to create an evidence map., Outcome Measures: The number and design of studies in the search yield, displayed per the published 10 priority questions., Results: Searches returned 4338 results for screening; 406 publications were included in the evidence map. 136 publications addressed multiple questions. Numerous studies address the immediate and long-term outcomes or possible markers for HG (question 8 and 9, respectively 164 and 82 studies). Very few studies seek a possible cure for HG (question 1, 8 studies), preventative treatment (question 4, 2 studies) or how to achieve nutritional requirements of pregnancy (question 10, 17 studies). Case reports/series were most numerous with 125 (30.7%) included. Few qualitative studies (9, 2.2%) were identified. 25 (6.1%) systematic reviews addressed eight questions, or aspects of them. 31 (7.6%) studies included patient involvement., Conclusions: There are significant gaps and overlap in the current HG literature addressing priority questions. Researchers and funders should direct their efforts at addressing the gaps in the top 10 questions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Hyperemesis gravidarum is characterized by severe nausea and vomiting in pregnancy, frequently resulting in severe maternal nutritional deficiency. Maternal undernutrition is associated with adverse offspring health outcomes. Whether hyperemesis gravidarum permanently affects offspring health remains unclear. This review aimed to evaluate the effects of maternal hyperemesis gravidarum on offspring health., Data Sources: MEDLINE and Embase were searched from inception to September 6, 2021., Study Eligibility Criteria: Studies reporting on health at any age beyond the perinatal period of children born to mothers with hyperemesis gravidarum were included., Methods: Two reviewers independently selected studies and extracted data. The Newcastle-Ottawa Quality Assessment Scale was used to assess risk of bias. We conducted a narrative synthesis and meta-analysis where possible. In meta-analyses with high heterogeneity (I 2 >75%), we did not provide a pooled odds ratio., Results: Nineteen studies were included in this systematic review (n=1,814,785 offspring). Meta-analysis (n=619, 2 studies: 1 among adolescents and 1 among adults) showed that hyperemesis gravidarum was associated with anxiety disorder (odds ratio, 1.74; 95% confidence interval, 1.04-2.91; I 2 , 0%) and sleep problems in offspring (odds ratio, 2.94; 95% confidence interval, 1.25-6.93; I 2 , 0%). Hyperemesis gravidarum was associated with testicular cancer in male offspring aged up to 40 years on meta-analysis (5 studies, n=20,930 offspring), although heterogeneity was observed on the basis of a wide 95% prediction interval (odds ratio, 1.60; 95% confidence interval, 1.07-2.39; I 2 , 0%; 95% prediction interval, 0.83-3.08). All 6 studies reporting on attention deficit (hyperactivity) disorder and autism spectrum disorder reported an increase among children of mothers with hyperemesis gravidarum in comparison with children of unaffected mothers. Meta-analysis showed high heterogeneity, precluding us from reporting a pooled odds ratio. Most studies reporting on cognitive and motor problems found an increase among hyperemesis gravidarum-exposed children. One study investigated brain structure and found smaller cortical volumes and areas among children from hyperemesis gravidarum-affected pregnancies than among those from unaffected pregnancies. Studies evaluating anthropometry and cardiometabolic disease risk of hyperemesis gravidarum-exposed children had inconsistent findings., Conclusion: Our systematic review showed that maternal hyperemesis gravidarum is associated with small increases in adverse health outcomes among children, including neurodevelopmental disorders, mental health disorders, and possibly testicular cancer, although evidence is based on few studies of low quality., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Pregnancy and liver cirrhosis is a rare but increasing combination. Liver cirrhosis can raise the chance of maternal and fetal mortality and morbidity, although the exact risks remain unclear., Objective: To provide a systematic literature review and meta-analysis on maternal, fetal and obstetric complications among pregnant women with liver cirrhosis., Search Strategy: We performed a systematic literature search in the databases PubMed/MEDLINE and EMBASE (Ovid) from inception through 25 January 2021., Selection Criteria: Studies including pregnancies with liver cirrhosis and controls were eligible., Data Collection and Analysis: Two reviewers independently evaluated study eligibility. We used the random effects model for meta-analysis., Main Results: Our search yielded 3118 unique papers. We included 11 studies, including 2912 pregnancies in women with cirrhosis from 1982-2020. Seven studies were eligible for inclusion in the meta-analysis. The overall maternal mortality rate was 0.89%. Maternal mortality and variceal haemorrhage were lower in recent than in older studies. Most cases of maternal mortality due to variceal haemorrhage (70%) occurred during vaginal delivery. Pregnant women with liver cirrhosis had a higher chance of preterm delivery (OR 6.7, 95% CI 5.1-9.1), caesarean section (OR 2.6, 95% CI 1.7-3.9), pre-eclampsia (OR 3.8, 95% CI 2.2-6.5) and small-for-gestational-age neonates (OR 2.6, 95% CI 1.6-4.2) compared with the general obstetric population. Subgroup analyses could not be conducted., Conclusions: Liver cirrhosis in pregnant women is associated with increases in maternal mortality and obstetric and fetal complications. Large international prospective studies are needed to identify risk factors for unfavourable outcome., Tweetable Abstract: Systematic review and meta-analysis: higher risks that pregnant women with liver cirrhosis face are quantified., (© 2022 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Introduction: The use of low-dose aspirin by pregnant women to prevent preterm pre-eclampsia is gradually increasing. The administration of aspirin during pregnancy improves perinatal outcome, which could translate into improved child outcome in the long term. However, antenatal exposure to aspirin could have adverse effects on child development that may manifest later in life. The aim of this follow-up study is to assess the long-term effects of antenatal exposure to low-dose aspirin compared with placebo on survival, (neuro)development, behaviour and general health at 4 years corrected age., Methods and Analysis: This is a follow-up study of the Dutch double-blind randomised controlled APRIL trial which assessed the effectiveness of treatment with aspirin (80 mg daily) compared with placebo for the prevention of preterm birth in women with a previous spontaneous preterm birth. Treatment was initiated before 16 weeks of gestation and continued until 36 weeks or birth. We aim to follow-up all 379 children born to women who participated in the APRIL trial and survived the neonatal period, at the corrected age of 4 years. The main outcomes are (neuro)development as assessed by the Ages and Stages Questionnaire, and behaviour as assessed by the Strength and Difficulties Questionnaire. Additional outcomes include mortality, growth and general health from birth up to 4 years, and a composite outcome including mortality, abnormal (neuro)development and problem behaviour. Analyses will be performed by intention-to-treat using a superiority design., Ethics and Dissemination: Institutional Review Board approval was obtained from the Medical Research Ethics Committee from Amsterdam Medical Center (no. W20 289#20.325). The results will be published in a peer-reviewed journal and presented at conferences., Trial Registration Number: The APRIL trial (NTR5675, NL5553; EudraCT number 2015-003220-31) and the APRIL follow-up study (NL8950) are registered in the Dutch trial register. The study is funded by the Amsterdam Reproduction & Development research institute., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Hazardous working conditions increase the risk of adverse pregnancy outcomes. In this study, we examine adherence to legislation and guidelines aimed at improving working conditions in pregnancy., Methods: Between 2014 and 2016, we recruited a prospective cohort of low-risk nulliparous pregnant women in paid employment or self-employed in 16 community midwifery practices in The Netherlands. Participants completed two questionnaires concerning demographics, education, general health and working conditions between 10-16 and 20-24 weeks of pregnancy. We calculated the proportion of participants with work-related risk factors not in accordance with legislation and/or guidelines., Results: Of 269 participants included, 214 (80%) completed both questionnaires. At 10-16 weeks 110 (41%) participants and at 20-24 weeks 129 (63%) participants continued to work under circumstances that did not meet recommendations. Employers provided mandated information on work adjustment to 37 (15%) participants and 96 (38%) participants received no information about the potential hazards while working with biological and chemical hazards. Participants with lower educational attainment (aOR 2.2 95%CI 1.3-3.9), or employment in healthcare (aOR 4.5, 95%CI 2.2-9.0), education/childcare and social service (aOR 2.6, 95%CI 1.1-6.0 2),, catering (aOR 3.6, 95%CI 1.1-12) and industry, construction and cleaning (aOR 3.3, 95%CI 1.1-10.3) more often continued work which did not meet recommendations., Conclusion: There is poor adherence to national legislation and guidelines for safe working in pregnancy in The Netherlands: 50% of the pregnant women worked under hazardous conditions. Given the impact on adverse pregnancy outcomes as well as on the public purse, action to improve compliance must be taken by all stakeholders., (© 2022. The Author(s).)

Background: Improving maternal lifestyle before conception may prevent the adverse effects of maternal obesity on their children's future cardiovascular disease (CVD) risk. In the current study, we examined whether a preconception lifestyle intervention in women with obesity could alter echocardiographic indices of cardiovascular health in their children., Methods: Six years after a randomized controlled trial comparing the effects of a 6-month preconception lifestyle intervention in women with obesity and infertility prior to fertility care to prompt fertility care, 315 of the 341 children conceived within 24 months after randomization were eligible for this study. The intervention was aimed at weight loss (≥5% or until BMI < 29 kg/m 2 ). Children underwent echocardiographic assessment of cardiac structure and function, conducted by a single pediatric cardiologist, blinded to group allocation. Results were adjusted for multiple variables including body surface area, age, and sex in linear regression analyses., Results: Sixty children (32 girls, 53%) were included, mean age 6.5 years (SD 1.09). Twenty-four children (40%) were born to mothers in the intervention group. Children of mothers from the intervention group had a lower end-diastolic interventricular septum thickness (-0.88 Z-score, 95%CI -1.18 to -0.58), a lower left ventricle mass index (-8.56 g/m 2 , 95%CI -13.09 to -4.03), and higher peak systolic and early diastolic annular velocity of the left ventricle (1.43 cm/s 95%CI 0.65 to 2.20 and 2.39 cm/s 95%CI 0.68 to 4.11, respectively) compared to children of mothers from the control group., Conclusions: Children of women with obesity, who underwent a preconception lifestyle intervention, had improved cardiac structure and function; a thinner interventricular septum, lower left ventricle mass, and improved systolic and diastolic tissue Doppler velocities. Despite its high attrition rates, our study provides the first experimental human evidence suggesting that preconception lifestyle interventions may present a method of reducing CVD risk in the next generation., Clinical Trial Registration: LIFEstyle study: Netherlands Trial Register: NTR1530 ( https://www.trialregister.nl/trial/1461 ). This follow-up study was approved by the medical ethics committee of the University Medical Centre Groningen (METC code: 2008/284)., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: Spontaneous preterm birth (sPTB) is a major contributor to neonatal morbidity and mortality worldwide. The pathophysiology of sPTB is poorly understood, in particular among nulliparous women without apparent medical or obstetric risk factors. Therefore, we aimed to identify risk factors for sPTB in healthy nulliparous women., Material and Methods: We performed a prospective cohort study. Recruitment took place from February 2014 to December 2016 in 16 community midwifery centers in the Netherlands. Eligibility criteria were: ≥18 years, no previous pregnancy >16 weeks of gestation, healthy singleton pregnancy, and antenatal booking <24 weeks of gestation. At study inclusion, participants completed a questionnaire, including details on lifestyle, work, and medical history. Cervical length was measured by vaginal ultrasound at the second-trimester anomaly scan. Detailed information concerning pregnancy and birth was collected via antenatal charts. We calculated the adjusted odds ratio (aOR) and 95% confidence intervals (CI) for various risk factors with correction for socioeconomic status (SES) using logistic regression and Firth's correction., Results: We included 363 women of whom pregnancy outcomes were available in 349 (96.1%) participants. The cervical length measurement was available for 225 (62.0%) participants. sPTB occurred in 26 women (7.5%). SES was associated with sPTB (OR: 3.7, 95%  CI: 1.6-8.5) in univariate analysis. First or second trimester vaginal bleeding (aOR: 3.6, 95% CI: 1.4-9.0) and urinary tract infection during pregnancy (aOR: 4.9, 95% CI: 1.7-13.9) were associated with sPTB in multivariate analysis., Conclusions: This prospective cohort confirms established risk factors for sPTB in nulliparous women deemed at low risk of sPTB., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Background: Immunoglobulin A (IgA) plays an important role in maintaining a healthy intestinal microbiome, but little is known about the interaction between local immunoglobulins and the vaginal microbiome. We assessed immunoglobulins (unbound and bound to bacteria), their association with vaginal microbiota composition and the changes over time in 25 healthy women of reproductive age., Results: In both Lactobacillus crispatus-dominated and non-L. crispatus-dominated microbiota, IgA and IgG (unbound and bound to bacteria) were higher during menses (T = 1) compared to day 7‑11 (T = 2) and day 17‑25 (T = 3) after menses onset. The majority of vaginal bacteria are coated with IgA and/or IgG. Women with L. crispatus-dominated microbiota have increased IgA coating of vaginal bacteria compared to women with other microbiota compositions, but contained less IgA per bacterium. Presence of a dominantly IgA-coated population at T = 2 and/or T = 3 was also strongly associated with L. crispatus-dominated microbiota. In women with non-L. crispatus-dominated microbiota, more bacteria were uncoated. Unbound IgA, unbound IgG, and bound IgG levels were not associated with microbiota composition., Conclusions: In conclusion, L. crispatus-dominated vaginal microbiota have higher levels of bacterial IgA coating compared to non-L. crispatus-dominated vaginal microbiota. Similar to its regulating function in the intestinal tract, we hypothesize that IgA is involved in maintaining L. crispatus-dominated microbiota in the female genital tract. This may play a role in L. crispatus-associated health benefits. Video abstract., (© 2022. The Author(s).)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

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% vs 1.3%, P = 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., Competing Interests: Conflict-of-interest statement: The authors declare that there is no duality of interest associated with this manuscript., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

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 1,780  = 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.

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 2 , 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 2 , 0%) or all preterm birth (odds ratio, 1.04; 95% confidence interval, 0.79-1.35; I 2 , 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 2 , 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., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest None declared. Completed disclosure of interests form available to view online as supporting information., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., Competing Interests: There are no conflicts of interest to declare., (© 2019 The Author(s).)

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.

Purpose: To identify demographic, (bio)physical, behavioral, and psychological determinants of successful lifestyle change and program completion by performing a secondary analysis of the intervention arm of a randomized-controlled trial, investigating a preconception lifestyle intervention., Methods: The 6-month lifestyle intervention consisted of dietary counseling, physical activity, and behavioral modification, and was aimed at 5-10% weight loss. We operationalized successful lifestyle change as successful weight loss (≥ 5% weight/BMI ≤ 29 kg/m 2 ), weight loss in kilograms, a reduction in energy intake, and an increase in physical activity during the intervention program. We performed logistic and mixed-effect regression analyses to identify baseline factors that were associated with successful change or program completion., Results: Women with higher external eating behavior scores had higher odds of successful weight loss (OR 1.10, 95% CI 1.05-1.16). Women with the previous dietetic support lost 0.94 kg less during the intervention period (95% CI 0.01-1.87 kg). Women with higher self-efficacy reduced energy intake more than women with lower self-efficacy (p < 0.01). Women with an older partner had an increased energy intake (6 kcal/year older, 95% CI 3-13). A high stage of change towards physical activity was associated with a higher number of daily steps (p = 0.03). A high stage of change towards weight loss was associated with completion of the intervention (p = 0.04)., Conclusions: Determinants of lifestyle change and program completion were: higher external eating behavior, not having received previous dietetic support, high stage of change. This knowledge can be used to identify women likely to benefit from lifestyle interventions and develop new interventions for women requiring alternative support., Trial Registration: The LIFEstyle study was registered at the Dutch trial registry (NTR 1530; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1530 ).

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.

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.

Background: 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. Methods: 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. Results: 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. Conclusions: 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., Competing Interests: No competing interests were disclosed.

Nausea and occasional vomiting in early pregnancy (NVP) are common. When vomiting is severe or protracted, it is referred to as hyperemesis gravidarum (HG). HG affects up to 3% of pregnancies and is characterized by weight loss, dehydration, electrolyte imbalance, and the need for hospital admission. HG has significant consequences for maternal well-being, is associated with adverse birth outcomes, and leads to major health care costs. Treatment options are symptomatic, hampered by the lack of evidence-based options including studies on nutritional interventions. One of the reasons for this lack of evidence is the use of a broad range of definitions and outcome measures. An internationally accepted definition and the formulation of core outcomes would facilitate meta-analysis of trial results and implementation of evidence in guidelines to ultimately improve patient care.

Background: Corticosteroids (CCS) are effective in reducing chemotherapy-induced nausea and vomiting, but it is unknown whether CCS are effective in treating hyperemesis gravidarum (HG)., Methods: We searched PubMed and ClinicalTrials.gov from inception to May 15, 2015, for randomized controlled trials examining the effects of CCS in HG., Results: We identified five trials (n = 310) examining the effects of CCS in women with HG. Meta-analysis was possible for one outcome (n = 214) and showed no significant effect of CCS on readmission rates (odds ratio, 0.37; 95% confidence internal: 0.1-1.35). Two small studies (n = 104) reported a reduction of vomiting episodes, and one (n = 24) found improvement of well-being, but no effect on other outcomes. None of the studies that investigated perinatal outcome (n = 173) found an effect of CCS and were underpowered to investigate teratogenic effects. We found evidence of publication bias., Conclusion: Meta-analysis yielded no effect of CCS therapy on readmission rates. Single small studies indicated possible beneficial effects on other outcomes. Future high-quality trials are necessary and would benefit from consensus on HG definition and core outcomes of HG therapy.

Background: Energy restriction in prenatal life has detrimental effects on later life health and longevity. Studies in rats have shown that the shortening of telomeres in key tissues plays an important role in this association., Objective: The aim of the current study was to investigate leukocyte telomere length in relation to prenatal famine exposure., Design: The Dutch famine birth cohort consists of 2414 term singleton men and women who were born between 1943 and 1947 in Amsterdam around the time of the famine. At a mean age of 68 y, telomere length and the percentage of short telomeres was assessed in a subsample of 131 cohort members, of whom 45 were born before the famine (control), 41 were exposed to famine during early gestation, and 45 were conceived after the famine (control). Median telomere length was determined in peripheral blood leukocytes by a high-throughput quantitative fluorescent in situ hybridization-based technology., Results: Leukocyte telomere length and the percentage of short telomeres did not differ between those exposed to famine during early gestation and those unexposed during gestation. A lower socioeconomic status at birth, frequent consumption of alcohol (specifically consumption of spirits), a history of cancer, and a lower self-reported health status were significantly associated with shorter leukocyte telomere length (all P ≤ 0.03). Currently having a job was significantly associated with a smaller percentage of short telomeres (P = 0.04)., Conclusion: The results of the current study suggest that prenatal exposure to famine is not associated with the shortening of telomeres in peripheral blood leukocytes at age 68 y., (© 2015 American Society for Nutrition.)

The effects of artificial reproductive techniques and subfertility on cardiovascular and metabolic profiles of children aged 5-6 years were investigated using data from the Amsterdam Born Children and their Development study. Of the 2577 children, 34 were conceived through ovulation induction, 51 through artificial insemination and 28 through IVF or intracytoplasmic sperm injection (ICSI). Two hundred and twenty children were born to couples who conceived after more than 12 months and 2244 were born to couples who conceived within 12 months of unprotected intercourse ('subfertile' and 'fertile', respectively). At the age of 5-6 years, fasting glucose levels were higher among children conceived through ovulation induction and IVF-ICSI compared with those of children of fertile couples (adjusted difference: ovulation induction: 0.4 mmol/l, 95% CI 0.2 to 0.6; IVF-ICSI: 0.2 mmol/l, 95% CI 0.0 to 0.5). Blood pressure was higher in children of subfertile couples compared with that of children of fertile couples (adjusted difference systolic blood pressure: 0.8 mmHg, 95% CI -0.2 to 1.8; diastolic blood pressure: 1.4 mmHg, 95% CI 0.6 to 2.3). Subfertility and conception through ovulation induction and IVF-ICSI each contributed to aspects of an adverse cardiovascular and metabolic profile in childhood., (Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Maternal undernutrition during gestation is associated with an increase in cardiovascular risk factors in the offspring in adult life. The effect of famine exposure during different stages of gestation on adult microalbuminuria (MA) was studied. MA was measured in 724 people, aged 48 to 53, who were born as term singletons in a university hospital in Amsterdam, the Netherlands, around the time of the Dutch famine 1944 to 1945. Twelve percent of people who were exposed to famine in mid gestation had MA (defined as albumin/creatinine ratio >/=2.5) compared with 7% of those who were not prenatally exposed to famine (odds ratio 2.1; 95% confidence interval 1.0 to 4.3). Correcting for BP, diabetes, and other influences that affect MA did not attenuate this association (adjusted odds ratio 3.2; 95% confidence interval 1.4 to 7.7). The effect of famine was independent of size at birth. Midgestation is a period of rapid increase in nephron number, which is critical in determining nephron endowment at birth. Fetal undernutrition may lead to lower nephron endowment with consequent MA in adult life.