Perinatal outcomes of infants born to mothers with hyperemesis gravidarum: A systematic review and meta-analysis.

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.

Depression, anxiety, and post-traumatic stress disorder symptoms after hyperemesis gravidarum: a prospective cohort study.

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.

Long-term health outcomes of children born to mothers with hyperemesis gravidarum: a systematic review and meta-analysis.

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 (I2>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; I2, 0%) and sleep problems in offspring (odds ratio, 2.94; 95% confidence interval, 1.25-6.93; I2, 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; I2, 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.

Hyperemesis gravidarum severity, enteral tube feeding and cardiometabolic markers in offspring cord blood.

This study aimed to investigate the association between hyperemesis gravidarum (HG) severity and early enteral tube feeding on cardiometabolic markers in offspring cord blood. We included women admitted for HG, who participated in the MOTHER randomised controlled trial (RCT) and observational cohort. The MOTHER RCT showed that early enteral tube feeding in addition to standard care did not affect symptoms/birth outcomes. Among RCT and cohort participants, we assessed how HG severity affected lipid, c-peptide, glucose and free thyroxine cord blood levels. HG severity measures were severity of vomiting at inclusion and 3 weeks after inclusion, pregnancy weight gain and 24-h energy intake at inclusion, readmissions and duration of hospital admissions. Cord blood measures were also compared between RCT participants allocated to enteral tube feeding and those receiving standard care. Between 2013-2016, 215 women were included: 115 RCT and 100 cohort participants. Eighty-one cord blood samples were available. Univariable not multivariable regression analysis showed that lower maternal weight gain was associated with higher cord blood glucose levels (ß: -0·08, 95% CI -0·16, -0·00). Lower maternal weight gain was associated with higher Apo-B cord blood levels in multivariable regression analysis (ß: -0·01, 95% CI -0·02, -0·01). No associations were found between other HG severity measures or allocation to enteral tube feeding and cord blood cardiometabolic markers. In conclusion, while lower maternal weight gain was associated with higher Apo-B cord blood levels, no other HG severity measures were linked with cord blood cardiometabolic markers, nor were these markers affected by enteral tube feeding.

Hyperemesis gravidarum and vitamin K deficiency: a systematic review.

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.

Systematic evidence map of evidence addressing the top 10 priority research questions for hyperemesis gravidarum.

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.

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

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.

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

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; ß = 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 (ß = 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.