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Department of Obstetrics and Gynecology, Amsterdam Reproduction & Development, Amsterdam UMC, University of Amsterdam, Amsterdam, the NetherlandsDepartment of Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Department of Obstetrics and Gynecology, Amsterdam Reproduction & Development, Amsterdam UMC, University of Amsterdam, Amsterdam, the NetherlandsDepartment of Obstetrics and Gynecology, Amphia Hospital, Breda, the Netherlands
Department of Obstetrics and Gynecology, Amsterdam Reproduction & Development, Amsterdam UMC, University of Amsterdam, Amsterdam, the NetherlandsDepartment of Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
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 (HG) can lead to undernutrition in pregnancy. Although there is evidence that HG leads to adverse perinatal effects, aggregate evidence about children’s health after maternal HG is lacking at present.
Key findings
Meta-analysis showed that children of mothers with HG had an increased chance of developing anxiety disorder (odds ratio [OR], 1.74), sleep disorder (OR, 2.94), and possibly testicular cancer (OR, 1.60; signs of heterogeneity based on 95% prediction interval, 0.83–3.08). Narrative synthesis showed that maternal HG was associated with an increased risk of neurodevelopmental disorders in children, including autism spectrum disorder and attention deficit (hyperactivity) disorder. No consistent associations between HG during gestation and children’s cardiometabolic outcomes were found.
What does this add to what is known?
This systematic review showed that HG is associated with a small increase in neurodevelopmental disorders, mental health disorders, and possibly testicular cancer.
Introduction
Hyperemesis gravidarum (HG) is a pregnancy condition consisting of severe nausea and vomiting. Most commonly, symptoms arise in early pregnancy and usually improve before 20 weeks’ gestation, although they can persist until delivery.
In the first trimester, when organogenesis takes place, deficiencies of specific nutrients such as folic acid and vitamin K are of particular relevance because they can lead to congenital anomalies.
Folic acid supplementation for the prevention of neural tube defects: an updated evidence report and systematic review for the US Preventive Services Task Force.
In addition, there is evidence showing that specific maternal nutritional deficiencies during pregnancy, such as vitamin B12, folic acid, and iron deficiencies, can have a negative impact on children’s neurobehavioral development.
Given that HG can lead to general undernutrition and specific nutrient deficiencies with an onset in early pregnancy, it is likely that it could impact health of offspring in childhood and adulthood.
This notion is at odds with existing guidance for healthcare providers, which emphasizes the need to reassure HG patients that “hyperemesis gravidarum portends well for pregnancy outcome.”
A previous systematic review, published in 2012, found only sparse literature on health beyond the perinatal period of children born to women with HG; only 1 study was included that identified excessive nausea during pregnancy as a risk factor for developing testicular cancer in male offspring.
Recently, long-term health of children born to mothers with HG was placed in the top 10 of most urgent priorities in HG research by stakeholders, including patients.
Therefore, we aimed to update the systematic summary of the available evidence on long-term health outcomes of children born to mothers with HG.
Materials and Methods
This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) as CRD42020209560.
Search strategy
A medical information specialist (J.L.) performed a search in MEDLINE and Embase from inception to September 6, 2021. We used respectively Medical Subject Headings (MeSH) or Emtree terms and text words for the concepts: (1) hyperemesis gravidarum and (2) child, offspring, pregnancy outcomes, or long-term effects. Animal studies, reviews, case reports, editorials, and conference abstracts (Embase) were excluded. No other limitations, including date and language, were applied. Complete search strategies are detailed in Appendix A1. The search also included perinatal outcomes, which will be discussed in a separate systematic review that is currently in progress. All references were imported in EndNote (version X9.3.3; Clarivate, London, United Kingdom) and duplicates were removed. Reference lists and citing articles of identified relevant papers were checked for additional relevant studies using Web of Science.
Protocol deviations
For practical reasons, a number of deviations from the published PROSPERO protocol were necessary. We did not search the Cochrane Central Register of Controlled Trials (CENTRAL), which only contains controlled clinical trials and mainly has added value as a source for gray literature. Because we expected to find evidence from observational studies only and we excluded conference abstracts and other gray literature, we limited our search to MEDLINE and Embase. In addition, none of the relevant studies that were identified by cited reference searching before constructing the actual search were found in CENTRAL. We aimed to ensure search comprehensiveness by repeating cited reference searching after search completion. Furthermore, we decided not to use the Risk of Bias in Non-randomized Studies of Exposure (ROBINS-E) tool because it had unfortunately remained “under development” during the entire review process.
Study selection
Two reviewers (K.N. and L.J.) independently screened titles and abstracts using Rayyan (Rayyan System Inc., Cambridge, MA),
after which potentially eligible studies were obtained in full text. Two reviewers (K.N. and L.J.) independently performed a second eligibility check for studies in the full text. Any disagreements were discussed until consensus was reached or, if necessary, a third reviewer was consulted (R.P.).
Eligibility criteria were:
•
Studies reporting on long-term health outcomes of offspring born to mothers with severe nausea and vomiting in pregnancy (NVP) or HG, as reported by the authors.
•
Long-term health outcomes included: general health, growth development, cardiometabolic outcomes, cognitive development, behavioral development, neurodevelopment, mental health, and cancer.
Exclusion criteria were:
•
Case reports, case series, letters to the editor, conference abstracts, and reviews.
•
Studies not reporting a control group, unless offspring’s long-term health across the disease spectrum of severity of HG was assessed.
Data extraction
A piloted data extraction form was used to extract data by 1 reviewer (K.N.), which was critically appraised by a second reviewer (L.J.). Any disagreements were solved by consensus, and in case of persistent disagreement, a third reviewer was consulted (R.P.). Authors were contacted by email if data were unclear or missing.
Assessment of risk of bias
A quality assessment was performed independently by 2 reviewers (K.N. and L.J.). Any disagreements were discussed until consensus was reached. The Newcastle-Ottawa Scale was used, which consists of 8 questions with a maximum score of 9.
Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2014. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed October 26, 2020.
Studies scoring ≥7 were considered as good-quality, ≥5 as fair-quality, and ≤4 as poor-quality. Low quality on assessment was not a reason for exclusion.
Data synthesis
Findings were described by meta-analysis, where sufficient data were available, or otherwise described narratively. In the meta-analyses, data were presented as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Random-effects models according to the Mantel–Haenszel method were used on the basis of anticipated heterogeneity. We used I2 statistics to assess heterogeneity, with I2 values >75% considered as high heterogeneity. In those cases, we did not provide a pooled OR and we performed a sensitivity analysis, if possible. We also assessed heterogeneity by calculating 95% prediction intervals (PIs) of pooled ORs of meta-analyses that included at least 3 studies, to give an estimate of an interval in which 95% of effects might be found in future, comparable studies.
We assessed publication bias by analyzing funnel plots if at least 10 studies reported the same outcome, according to the Cochrane Handbook for Systematic Reviews of Interventions.
Higgins J.P.T. Thomas J. Chandler J. Cumpston M. Li T. Page M.J. Welch V.A. Cochrane Handbook for Systematic Reviews of Interventions. 2nd Edition. John Wiley & Sons,
Chichester, UK2019
P values below.05 were considered statistically significant. Review Manager (RevMan, version 5.4; Cochrane, London, United Kingdom) was used to conduct meta-analyses.
Strength of the evidence
Strength of the evidence of all meta-analyses was assessed by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) method according to the GRADE handbook.
Two reviewers (K.N. and L.J.) independently graded evidence using GRADEpro (Evidence Prime Inc., Ontario, Canada). Because only observational studies were included, the initial quality of evidence started at very low and was upgraded if there were: (1) a large magnitude of effect (1 level up in case of a relative risk [RR] <0.5 or >2; 2 levels up in case of a RR <0.2 or >5), (2) signs of a dose–response relationship, or (3) plausible residual confounding. Evidence was rated as very low, low, moderate, or high quality.
Results
Study selection
Our search identified 1360 unique studies. Nineteen studies were considered eligible and included in this systematic review, as shown in Figure 1.
Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: the Growing Up in Singapore Towards Healthy Outcomes study.
Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study.
were follow-up survey studies of children of the same population at the ages of 8 and 12, respectively. Both studies were included in this systematic review, but only the latter was included in meta-analysis on the basis of our ability to produce 2×2 tables and because of a longer follow-up period.
validated their results from an American cohort in a different, Danish cohort, thus these 2 study populations were described separately in this systematic review.
Self-reported: HG diagnosis with treatment with IV fluids and/or TPN/ nasogastric feeding tube
312/418
Mean age between 8 and 9 y
Neurodevelopment and mental health: ADD/ADHD, learning difficulties delays, sensory integration disorder or sensory processing disorder, social development delay or social anxiety, speech or language impairment/delay
Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study.
Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: the Growing Up in Singapore Towards Healthy Outcomes study.
Ong et al,37 and Syn et al,32 evaluated the same study population, but reported on different offspring long-term health outcomes
Singapore
Prospective cohort
2009–2010
Interviews: Severe vomiting with inability to retain meals
190/1172
1–4.5 y
Neurodevelopment and mental health: A) Social and emotional problems B) ASD C) Cognitive development D) Emotional and behavioral problems E) Intelligence test
Assessed during clinical visits: A) 1-y Infant-Toddler Social and Emotional Assessment (ITSAE) B) 1.5-y Quantitative Checklist for Autism in Toddler (Q-CHAT) C) 2-y Bayley Scales of Infant and Toddler Development (Bayley) D) 2- and 4-y Child Behavior Checklist (CBCL) E) 4.5-y Kaufman Brief Intelligence Test (KBIT)
Cancer risk Childhood cancer (including leukemia, lymphoma, cancer of the central nervous system, testis, bone, ovary, breast, adrenal and thyroid gland, nephroblastoma, hepatoblastoma, and retinoblastoma)
National cancer registries of Denmark, Norway, and Sweden (population-based database with mandatory reporting of all incident tumors)
Interviews: Severe NVP with either weight loss or prolonged disease course (>6 mo gestation)
1496/10,710
9–11 y
Neurodevelopment and mental health: A) Brain morphology B) Cognitive development C) Emotional and psychiatric problems, including anxiety, depression, ADHD, conduct disorders, oppositional defiant disorders, and somatic complaints
Assessed during clinical visits: A) Structured neuroimaging processing (MRI) B) NIH Toolbox Cognition Battery C) Child behavioral Checklist (CBCL)
Numbers displayed are from 1995 to 2012 because data about offspring’s long-term health was only available for this time period and not from the complete original Danish cohort of 1978 to 2012 including 2,092,897 offspring in total.
Numbers displayed are from 1995 to 2012 because data about offspring’s long-term health was only available for this time period and not from the complete original Danish cohort of 1978 to 2012 including 2,092,897 offspring in total.
Up to 18 y
Neurodevelopment and mental health: ADD/ADHD, ASD, childhood autism, conduct or oppositional defiant disorders, developmental disorders (including language, learning and motor skills disorders), emotional disorders
Clinical diagnosis identified from the Danish National Patient Register and Danish Psychiatric Central Research Register (ICD-10). ADHD was also diagnosed if offspring had ≥2 redeemed prescriptions for ADHD-specific medication from the National Prescription Register
ADD/ADHD, attention deficit (hyperactivity) disorder; Apo-A1/B, apolipoprotein A1 or B; ASD, autism spectrum disorder; BMI, body mass index; DBP/SBP, diastolic or systolic blood pressure; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders; HDL, high density lipoprotein; HG, hyperemesis gravidarum; HOMA-IR, Homeostatic Model Assessment for Insulin Resistance; ICD, International Classification of Diseases; IGF(BP), insulin-like growth factor (binding protein); IQ, intelligence quotient; IV, intravenous; LDL, low density lipoprotein; NVP, nausea and vomiting in pregnancy; TPN, total parenteral nutrition.
Nijsten. Hyperemesis gravidarum and children’s health. Am J Obstet Gynecol 2022.
a Total study sample size based on study participants having information on maternal HG available
Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study.
Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: the Growing Up in Singapore Towards Healthy Outcomes study.
evaluated the same study population, but reported on different offspring long-term health outcomes
c Numbers displayed are from 1995 to 2012 because data about offspring’s long-term health was only available for this time period and not from the complete original Danish cohort of 1978 to 2012 including 2,092,897 offspring in total.
Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study.
Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: the Growing Up in Singapore Towards Healthy Outcomes study.
These studies scored low on either the selection domain, because of being self-selected survey studies, and/or on the comparability domain, because of not adjusting for confounders in statistical analyses. Three studies were rated as fair-quality (2 cohort and 1 case–control study).
Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study.
Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: the Growing Up in Singapore Towards Healthy Outcomes study.
Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study.
Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: the Growing Up in Singapore Towards Healthy Outcomes study.
The NOS risk of bias assessment tool consisted of 8 items with a total maximum score of 9. A score ≥7 was considered as good-quality, a score ≥5 as fair-quality, and a score ≤4 as poor-quality.
NOS, Newcastle-Ottawa Quality Assessment Scale.
Nijsten. Hyperemesis gravidarum and children’s health. Am J Obstet Gynecol 2022.
Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study.
Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study.
Two studies reported on boys and girls separately (n=3114 children) and found contradictory findings: the first study found that girls but not boys from mothers with HG were taller at ages of 12, 18, and 24 months,
Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study.
Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study.
The 2 studies that evaluated boys and girls separately (n=3114 children) again showed conflicting findings: the first study showed that girls but not boys exposed to HG were heavier at 12, 18, and 24 months,
whereas the other study found that exposed girls were lighter (adjusted β, −0.53 SD; 95% CI, −1.03 to −0.03) and boys heavier at 5 years (adjusted β, 0.57 SD; 95% CI, 0.05–1.08).
Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study.
The third study that evaluated weight in boys and girls (n=4760 children) found that HG-exposed children weighted more than nonexposed children at age 2 (9838±1712 vs 9581±1440 g).
Four studies reported on children’s body mass index (BMI). One study (n=4760 children) found higher BMI among 6-year-old HG-exposed children than among nonexposed children (male and female: adjusted β, 0.08; 95% CI, 0.00–0.17),
whereas another study (n=1172 children) found lower BMI among 66-month-old female offspring exposed to HG (adjusted β, −0.57 SD; 95% CI, −1.09 to −0.05) but no differences among male offspring.
Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study.
Lastly, 1 study including 4760 children found that, at age 6, those born to women with HG had higher total body fat mass (adjusted β, 0.12; 95% CI, 0.03–0.20), higher android/gynoid fat mass ratio (adjusted β, 0.11; 95% CI, 0.02–0.21), and higher abdominal preperitoneal fat mass area (adjusted β, 0.10; 95% CI, 0.00–0.20) than those born to women without HG,
whereas 2 other studies (n=6540 children) did not find any differences in waist to hip ratio, android to gynoid fat mass ratio, or total body fat percentage at ages 4 to 11 and 16.
One study (n=4370 children) found that those born to women with HG had significantly higher diastolic (61.4±7.3 vs 60.5±6.7 mm Hg) and systolic blood pressures (103.8±8.8 vs 102.4±8.1 mm Hg) at the age of 6, which was not sustained after adjustments for confounders,
The difference among studies in children’s ages at assessment prohibited meta-analyses.
Cardiometabolic laboratory measures
Three studies including 8847 children reported on cardiometabolic laboratory measures. None of the studies found any differences in lipid profile measures between HG-exposed and nonexposed children.
Two of 3 studies (n=8747 children) found no differences in fasting insulin, glucose, c-peptide, or Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) levels at the ages of 6 and 16.
The third study (n=78 children, aged 4–11) found that those born to mothers with HG had significantly higher fasting insulin levels than controls (6.88 vs 5.04 mIU/L) after adjusting for confounders, including ethnicity, birthweight, birth order, age, sex, and BMI.
Because of age-specific laboratory reference intervals, these results could not be pooled for meta-analyses. Insulin sensitivity, as assessed from a 90-minute frequent-sampling intravenous glucose tolerance test, was also reported to be 20% lower in HG-exposed children than in nonexposed children.
Lastly, they reported that children of women with HG had significantly higher early-morning cortisol (256 vs 210 nmol/L), lower insulin-like growth factor (IGF) binding protein 1 (11.8 vs 19.0 ng/mL), and lower IGF-binding protein 3 levels (1955 vs 3435 ng/mL).
A narrative summary of results of included studies reporting on anthropometry and cardiometabolic health outcomes is displayed in Supplemental Table 1.
Neurodevelopment and mental health
Cognitive and motor development
Two studies (n=9696 children) found that HG-exposed children had significantly lower cognitive development scores than nonexposed children at ages of 232 and 9 to 11 years, respectively.
Two studies assessed intelligence by measuring intelligence quotient (IQ) scores: the first study (n=469 children) did not find any differences in IQ scores at age 4,
Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: the Growing Up in Singapore Towards Healthy Outcomes study.
whereas another study (n=241 children) found that HG-exposed children had significantly lower verbal, performance, and full-scale IQ scores than nonexposed children at 3.5 to 7 years of age.
Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: the Growing Up in Singapore Towards Healthy Outcomes study.
Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: the Growing Up in Singapore Towards Healthy Outcomes study.
One of them found that families with at least 1 HG-exposed child more often reported learning delays (12.3%) and speech or language impairment/delays (24.1%) than families where none of the children were exposed to HG (3.4% and 11.2%, respectively), without adjusting for possible confounders.
Another study (n=482 children at age 2) did not find any differences in language skills, measured by the Bayley-III language scale, between HG-exposed and nonexposed children in multivariable regression analysis.
Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: the Growing Up in Singapore Towards Healthy Outcomes study.
The third study (n=259 adults) did not assess associations per separate outcome, but only stated that 38% of HG-exposed offspring reported having a psychological and/or behavioral disorder (including learning disorders and speech delay), compared with 15% of nonexposed offspring (unadjusted OR, 3.57; 95% CI, 1.87–6.90; P<.001).
including 292 families and 360 children, respectively, at ages of 8 to 9 and 11 to 13. No adjustments were made for confounders, and as described earlier, it is likely that these studies partially reported on the same children. One study (N=1,109,370 children, aged up to 18) reported on developmental problems, including language, learning, and motor-skill problems, and found that they occurred more frequently in HG-exposed children than in nonexposed children (adjusted hazard ratio [HR], 1.18; 95% CI, 1.05–1.34),
Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: the Growing Up in Singapore Towards Healthy Outcomes study.
A narrative summary of results of included studies reporting on cognitive and motor development is displayed in Supplemental Table 2.
Mental health
All 8 included studies reporting on mental health found an increased risk in HG-exposed children compared with nonexposed children, as narratively summarized in Supplemental Table 3. A meta-analysis including 2 studies (n=1,109,629 offspring, including children aged up to 18 and adults) that reported on emotional problems found no significant association (OR, 1.19; 95% CI, 0.89–1.61; I2, 0%), as shown in Figure 2 (GRADE level of evidence: very low quality; Supplemental Table 4).
One study assessed affective problems as a subdomain of the Child Behavior Checklist (CBCL) and found higher scores among HG-exposed than nonexposed children at 2 and 4 years after adjustments for confounding factors.
Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: the Growing Up in Singapore Towards Healthy Outcomes study.
Four studies (n=10,490 offspring varying in age from 4 years to adulthood) found that HG-exposed offspring were at higher risk of anxiety than nonexposed offspring on the basis of CBCL subdomains
Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: the Growing Up in Singapore Towards Healthy Outcomes study.
When pooling these last 2 studies in meta-analysis, we found that HG exposure was significantly associated with anxiety disorder in offspring (OR, 1.74; 95% CI, 1.04–2.91; I2, 0%) (Figure 2) (GRADE level of evidence: very low quality; Supplemental Table 4). Two studies (n=9473 offspring) found a significant association between HG exposure and CBCL depression scores at ages 9 to 11,34 and depression rates in adulthood (unadjusted OR, 6.35).
Two studies (n=778 children, aged 8–9 and 11–13), which were likely to partially include the same children because of including follow-ups of the same original study population, found higher rates of social developmental delay or social anxiety in HG-exposed children than in nonexposed children (unadjusted OR, 5.02 and 3.58).
As shown in a narrative summary in Supplemental Table 3, all studies reporting on neurobehavioral development found an increase of neurobehavioral developmental disorders among HG-exposed offspring. Six studies (n=1,600,520 offspring, aged 1.5 years to adulthood) reporting on autism spectrum disorders (ASDs) or on autism alone found that they occurred more often in HG-exposed than in nonexposed offspring.
Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: the Growing Up in Singapore Towards Healthy Outcomes study.
A meta-analysis including 4 studies (n=1,614,559 children, aged 2–18) that reported on the association between HG exposure and ASD in children showed high heterogeneity based on an I2 of 86% (Figure 2) and a 95% PI of 0.54 to 2.95 (GRADE level of evidence: low quality; Supplemental Table 4).
Sensitivity analysis showed a significant association between HG exposure and ASD when including only the 3 studies from the United States (OR, 1.37; 95% CI, 1.19–1.57; I2, 62%; 95% PI, 0.29–6.44) (Supplemental Figure 1), but did not reveal differences when excluding studies with a poorer study design (ie, survey and case–control study) (Supplemental Figure 2). No significant association was found between HG exposure and autism alone in a meta-analysis including 2 studies (OR, 1.12; 95% CI, 0.92–1.37; I2, 0%) (Figure 2) (GRADE level of evidence: very low quality) (Supplemental Table 4).
A significant association between HG and attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) in offspring (as combined or separate diagnoses) was found in all 6 studies reporting on this topic (n=1,120,014 offspring, aged 2 years to adulthood). Pooling 2 of these studies (n=1,109,730 children, aged up to 18) in a meta-analysis that reported on ADD/ADHD combined showed substantial heterogeneity with an I2 of 81% (Figure 2) (GRADE level of evidence: very low quality) (Supplemental Table 4).
Given that only 2 studies were included, we were not able to perform a sensitivity analysis.
One study reporting on 2 different study populations (n=1,118,584 children, aged up to 18) found that conduct and oppositional defiant disorders more often occurred in HG-exposed children and that they had higher scores in corresponding CBCL subdomains than nonexposed children.
Three studies reported on sleep problems. One study (n=530 children) found increased scores in the sleep problem subdomains of the Infant-Toddler Social and Emotional Assessment and CBCL, at respectively 1 and 2 years of age, in HG-exposed children in multivariable regression analysis.
Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: the Growing Up in Singapore Towards Healthy Outcomes study.
A meta-analysis including the other 2 studies (n=619 offspring, at ages 11–13 and adults) showed increased sleep problems among HG-exposed offspring (OR, 2.94; 95% CI, 1.25–6.93; I2, 0%) (Figure 2) (GRADE level of evidence: very low quality) (Supplemental Table 4).
The effect of hyperemesis gravidarum severity and treatment on neurodevelopment and mental health in offspring
Few studies also assessed differences in children’s neurobehavioral outcomes across the disease spectrum of HG. One study (n=819 offspring with a mean age of 32) found no significant differences in autism, behavioral, emotional, sensory, and learning disorders between offspring of HG patients with and without severe weight loss (>15% of prepregnancy weight).
The second study (n=418 children, aged 8–9) found that the presence of early HG symptoms (below 5 weeks’ gestation) was significantly associated with neurodevelopmental delay in children, but found no differences between in- and outpatient care or between different medications and treatments.
Another study (n=1172 children, aged 1–4.5) found that severe NVP without admission was more often associated with reduced neurobehavioral development in children than severe NVP with admission.
Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: the Growing Up in Singapore Towards Healthy Outcomes study.
Two studies assessed associations between ASD rates and HG severity and treatments. The first study (n=360 children, aged 11–13) did not find any differences related to different treatments (antiemetics or tube feeding), in- or outpatient care, and early onset of symptoms (below 5 weeks’ gestation).
The second study (n=469,789 children, aged 2–17) found a higher ASD incidence rate among children of women diagnosed with HG in the first (adjusted HR, 1.58; 95% CI, 1.40–1.79; P<.001) or second trimester (adjusted HR, 1.36; 95% CI, 1.05–1.75; P=.02) and children of HG patients with metabolic disturbances that required rehydration or tube feeding (adjusted HR, 1.41; 95% CI, 1.05–1.90; P=.02).
Brain morphology and its association with cognitive and psychological symptoms in children
One study (n=10,710 children, aged 9–11) assessed brain morphology in children and measured the cortical area, volume, and thickness of each brain region.
They found that the total cortical volume and area were significantly smaller in children exposed to severe NVP, and that these smaller volumes and areas mediated associations between severe NVP exposure and cognitive and psychological symptoms.
Cancer risk
Data on offspring’s cancer risk was available in 5 studies (n=173,502 offspring, aged up to 40).
Meta-analysis including these 5 studies showed that HG was significantly associated with testicular cancer in male offspring (OR, 1.60; 95% CI, 1.07–2.39; I2, 0%; 95% PI, 0.83–3.08), as shown in Figure 3 (GRADE level of evidence: very low quality) (Supplemental Table 4). Sensitivity analyses showed that a significant association between HG exposure and testicular cancer in male offspring only remained after omitting the study of Vandraas et al
is a large case–control study (n=162,514 offspring) that did not find a significant association between HG exposure and testicular cancer in offspring.
However, when dividing their study population into offspring aged 1 to 10 years and 10 to 20 years, HG was significantly associated with lymphoma in offspring aged 10 to 20 years (adjusted RR, 2.08; 95% CI, 1.11–3.90).
Our systematic review identified 19 studies reporting on children’s long-term health after HG exposure in utero. We were able to conduct meta-analyses for 7 outcomes and found that maternal HG was significantly associated with anxiety disorder and sleep problems in offspring, whereas no associations were found with emotional disorders and autism. Maternal HG was also significantly associated with testicular cancer in male offspring in meta-analyses, although there were signs of heterogeneity based on the 95% PI, which is considerably wider than the CI and which crosses 1. All studies reporting on ADD/ADHD and ASD found an increased risk among children of mothers with HG, but showed high heterogeneity when pooling these results in meta-analysis. Narrative synthesis showed that most studies reported an increase in cognitive and motor problems in children of mothers with HG. One study showed that children’s brain morphology was affected, with children exposed to severe NVP having smaller total cortical volume and area than nonexposed children. Inconsistent associations were found between HG exposure and anthropometry and cardiometabolic disease risk markers. Studies reporting on the effect of HG disease severity or treatment on children’s long-term health had inconsistent findings. All evidence included in this systematic review is based on a small number of studies with evidence of meta-analyses graded to be of very low to low quality.
Strengths and limitations
This systematic review has several strengths. A research protocol was published online before conducting this review. We were able to include studies on multiple long-term health domains, including cardiometabolic health, neurodevelopment, mental health, and cancer risk. We also managed to collect additional data from corresponding authors of included studies to extend our meta-analysis. Moreover, two-thirds of included studies were rated as fair- to good-quality, and we included a relatively large group of offspring that was exposed to HG.
Limitations of this review include heterogeneity in reported outcomes and HG diagnosis. Heterogeneity in HG diagnoses is a problem that has been previously identified in a systematic review that concluded that only 2 criteria (nausea and vomiting) were commonly used in diagnosing HG.
Heterogeneity led to variances in HG rates among the included studies in our review: cohort studies diagnosing HG on the basis of self-reports or interviews reported rates between 9.7% and 21.9%, whereas cohort studies including HG patients on the basis of ICD codes reported much lower rates varying from 0.6% to 3.1%. Although ICD codes have been shown to be only valid for diagnosing women with mild HG,
Our results could have been influenced by the inclusion of mainly case-control studies, which are prone to recall bias, and by the use of different methods of disease ascertainment, which may have led to over- and underestimation of HG or disease severity.
In addition, studies reported on many different long-term health outcomes and used different methods to ascertain these. Therefore, we were not able to aggregate results in meta-analysis for most outcomes, and our results were mostly presented using narrative synthesis. Moreover, evidence of outcomes that were assessed by meta-analyses was graded as very low or low quality. Furthermore, the Diagnostic and Statistical Manual of Mental Disorders was updated in 2013, combining several disorders, including autism disorder, into 1 diagnosis: ASD.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington; 2013. Available at: https://doi.org/10.1176/appi.books.9780890425596. Accessed March 20, 2021.
This hampered us in conducting meta-analysis for ASD and autism combined because both outcomes are used interchangeably in current literature. Lastly, some of the studies included self-selected participants that self-reported offspring outcomes, plausibly leading to higher rates of adverse health outcomes and possible recall bias.
Our systematic review and meta-analysis showed that HG exposure is associated with neurodevelopmental and mental health problems and a decrease in brain volume in offspring. Thus far, only few studies have evaluated the effect of maternal undernutrition during pregnancy on children’s neurodevelopment and mental health. Research from the Dutch famine found that in-utero exposure to undernutrition led to an increased risk for developing schizoid or antisocial personality disorders,
Different mechanisms can be hypothesized to be the underlying cause, for example when interpreting our results in the context of ASD research. A recent systematic review including 36 studies found that an appropriate intake of folic acid and vitamin D could protect against ASD in offspring.
Conversely, this could mean that a reduced availability of these nutrients, potentially caused by HG, may lead to an increased ASD risk in children. Another recent systematic review and meta-analysis demonstrated that small-for-gestational-age (SGA) neonates are at increased risk of developing ASD.
Given that previous research showed that HG children are more often born SGA, an alternative explanation could be that the risk of HG-exposed children developing ASD originates in fetal growth restriction.
However, no evidence of genetic factors being involved was found in a self-reported survey study comparing HG-exposed offspring with unexposed siblings and offspring without family history of HG.
We did not find evidence of a consistent effect of HG on offspring anthropometry and cardiometabolic disease risk markers. These findings are at odds with the large body of evidence on effects of maternal undernutrition in pregnancy. Animal experiments have linked intrauterine undernutrition to adverse health outcomes in offspring in later life.
In addition, studies about the Dutch, Chinese, and Nigerian famines showed that adults exposed to maternal undernutrition in utero more often had type II diabetes mellitus, hypertension, overweight, and coronary heart diseases in later life.
This may be explained by the fact that the studies in our systematic review included children of young ages, which precludes any definitive statement about the possible effects HG may have on adult offspring. Alternatively, it could be that women included in the studies had relatively mild HG and that only women with severe HG are comparable with pregnant women during famines in terms of maternal undernutrition. Finally, it is possible that HG, despite incurring maternal undernutrition, simply does not have effects on cardiometabolic health in the next generation. Moreover, because of the presence of age-specific reference intervals for anthropometry and cardiometabolic laboratory measures, we were not able to pool results in meta-analysis. More research is warranted to draw firm conclusions about possible adverse cardiometabolic disease risks for HG-exposed children.
HG was associated with testicular cancer in male offspring, with an OR of 1.60, which has been previously hypothesized to be caused by increased estrogen levels during pregnancies complicated by HG.
Nonetheless, these results should be interpreted with caution. Although there were no signs of heterogeneity on the basis of the I2 of 0, the 95% PI suggested otherwise, estimating that in 95% of subsequent studies the true effect estimate could range from 0.83 to 3.08. In addition, only a small number of HG cases were included in most studies, and in 4 out of 5 studies HG was assessed by questionnaires or interviews long after the pregnancy occurred, which could have led to recall bias.
Importantly, the fifth and most recent large study diagnosed HG on the basis of ICD codes and did not find an association between HG and testicular cancer in offspring.
We were unable to assess whether maternal treatment interventions can have a preventive role in avoiding health sequelae among the offspring. Only 3 studies that assessed neurodevelopment and mental health,
but none of the studies on other long-term health conditions, evaluated the association with treatment interventions and showed variations in results. Sensitivity analysis showed that HG was associated with more offspring ASD only in studies from the United States, but not in Denmark. This might indicate that differences in treatment or accessibility to health care between the United States and Denmark alter offspring’s ASD disease risk, which is an important matter to be addressed in future research because it has direct implications for healthcare policy choices. Lastly, yet importantly, HG was not associated with more offspring ASD when excluding studies with a poorer study design.
Conclusions and implications
This systematic review and meta-analysis showed that there is an increased adverse long-term health risk for children exposed to HG during gestation in terms of neurodevelopmental problems and mental well-being, whereas the impact on cardiometabolic disease risk and testicular cancer remains unclear. Conclusions are based, however, on a small number of studies, with evidence from meta-analyses being graded as very low to low quality. Altogether, long-term health research in HG is still in its infancy, and more research with long-term follow-up is needed to determine the pathophysiology of these associations and to further explore the role of (early) treatment to reduce adverse long-term health effects in offspring.
Acknowledgment
We thank Rik van Eekelen, PhD, for helping us in calculating and interpreting 95% prediction intervals.
Appendix A1.
Search strategy
Search in MEDLINE (1946 to September 6, 2021)
Tabled
1
#
Searches
Results
1
hyperemesis gravidarum/
1686
2
((∗morning sickness/ and (∗vomiting/ or ∗nausea/)) or (∗vomiting/ and ∗nausea/)) and pregnancy/
472
3
(hypereme∗ adj15 (pregnanc∗ or pregnant or gestat∗ or gravidi∗ or gravidar∗ or trimester∗ or maternal or prenat∗ or pre-nat∗ or antenat∗ or ante-nat∗ or intrauterine or intra-uterine or in-utero)).tw,kf.
1804
4
((pernicious∗ or serious∗ or sever∗ or excessiv∗) adj2 (vomiting or nause∗) adj9 (gravidar∗ or gravidit∗ or gestat∗ or pregnanc∗ or pregnant or trimester∗)).tw,kf.
prenatal exposure delayed effects/ or maternal exposure/
38290
9
fetus/ or exp fetal heart/ or exp child/ or exp infant/ or puberty/ or schools/ or pediatrics/ [child /fetus]
2706830
10
child mortality/ or fetal mortality/ or exp infant mortality/
32885
11
embryo loss/ or fetal diseases/ or fetal macrosomia/ or fetal growth retardation/ or fetal hypoxia/ or fetal nutrition disorders/ or exp fetal death/ or exp fetal membranes, premature rupture/ or exp obstetric labor, premature/ or oligohydramnios/ or hydrops fetalis/ or perinatal death/ or placenta diseases/ or abruptio placentae/ or placental insufficiency/ or infant, newborn, diseases/ or asphyxia neonatorum/ or exp infant, premature, diseases/ or neonatal sepsis/ or jaundice neonatal/ or exp infant death/ [pregnancy complications/infant death]
210822
12
exp birth weight/ or fetal weight/ or cephalometry/ or crown-rump length/ or fetal distress/ or apgar score/
80637
13
child nutritional physiological phenomena/ or infant nutritional physiological phenomena/ or prenatal nutritional physiological phenomena/ or “growth and development”/ or exp human development/ or “embryonic and fetal development”/ or embryonic development/ or fetal development/ or fetal movement/ or fetal organ maturity/ or fetal viability/ or sex determination processes/ or sex differentiation/ or sexual development/ or language development/ or psychology, developmental/ or psychology, educational/ or exp education, special/ or exp child behavior/ or behavioral symptoms/ or neurobehavioral manifestations/
201303
14
adolescent health/ or child health/ or infant health/
5867
15
neurodevelopmental disorders/ or exp “attention deficit and disruptive behavior disorders”/ or exp autism spectrum disorder/ or obsessive-compulsive disorder/ or exp tic disorders/ or exp psychomotor performance/ or motor skills disorders/ or child behavior disorders/
223188
16
exp aptitude tests/ or behavior rating scale/ or neuropsychological tests/ or language tests/ or exp “memory and learning tests”/ or stroop test/ or trail making test/
124448
17
sex factors/ or sex ratio/ or sex determination analysis/
286865
18
exp testicular diseases/
39645
19
exp musculoskeletal system/ab or exp heart/ab or exp nervous system/ab or genitalia/ab or abdominal wall/ab or urinary tract/ab or kidney/ab or urinary bladder/ab or kidney diseases/cn
87954
20
exp ∗congenital abnormalities/ or exp congenital abnormalities/et, ep
516968
21
abnormalities, severe teratoid/ or exp cardiovascular abnormalities/ or exp nervous system malformations/ or hydrocephalus/ or exp musculoskeletal abnormalities/ or exp bone diseases, developmental/ or cleft lip/ or exp digestive system abnormalities/ or exp respiratory system abnormalities/ or exp urogenital abnormalities/ or exp hydronephrosis/
513447
22
((pregnancy or gestat∗) adj outcom∗).tw,kf.
27889
23
((perinat∗ or peri-nat∗ or birth∗1 or childbirth∗ or deliver∗ or labo?r∗ or obstetric∗) adj3 outcome∗).tw,kf.
34700
24
((perinat∗ or peri-nat∗) adj3 (complicat∗ or health or morbidit∗ or cancer∗ or malignan∗ or neoplas∗)).tw,kf.
9811
25
((prenat∗ or pre-nat∗ or antenat∗ or ante-nat∗ or intrauterine or intra-uterine or utero) adj18 expos∗).tw,kf.
29816
26
(maternal adj2 expos∗).tw,kf.
7898
27
((prenat∗ or pre-nat∗ or antenat∗ or ante-nat∗ or in-utero or intra-uterine or intrauterine) adj3 (factor∗ or variabl∗ or parameter∗ or circumstanc∗ or condition∗)).tw,kf.
5808
28
((prenat∗ or pre-nat∗ or antenat∗ or ante-nat∗ or intrauterine or intra-uterine or utero) adj life).tw,kf.
1940
29
(DOHAD∗ or FOAD∗ or (early adj3 origin∗)).tw,kf. or (development∗ adj3 origin∗ adj4 (health∗ or diseas∗ or adult)).tw,kf,jw.
5837
30
(offspring∗ or progeny or (born adj2 mother∗)).tw,kf.
116107
31
(f?etal or f?etus∗ or neonat∗ or neo-nat∗ or new∗born∗ or new-born∗ or child or child∗1 or children∗ or schoolchild∗ or childhood or infant∗ or infanc∗ or toddler∗ or prekindergarten∗ or kindergarten∗ or preschool∗ or school-age∗ or schoolage∗ or high-school∗ or highschool∗ or elementary school∗ or graders or puber∗ or teens or teenager∗ or youth or juvenil∗ or adolescence or adulthood or young adult∗ or adult life or older age∗ or “early life” or later-life or “later in life").tw,kf. [ child filter ]
2682682
32
(((perinat∗ or peri-nat∗ or intrauterin∗ or intra-uterin∗ or in-utero or prenat∗ or pre-nat∗ or antenat∗ or ante-nat∗) adj3 (mortalit∗ or death∗ or demise)) or stillbirth∗ or stillborn∗ or asphyx∗ or miscarriag∗ or IUFD or (spontan∗ adj3 abort∗) or ((embry∗ or pregnancy) adj2 loss∗) or liveborn∗ or (live adj3 (birth∗ or born∗))).tw,kf.
108628
33
(((intrauterin∗ or intra-uterin∗ or in-utero or prenat∗ or pre-nat∗ or antenat∗ or ante-nat∗) adj3 (growth∗ or develop∗ or brain or movement∗)) or ((intrauterin∗ or intra-uterin∗ or in-utero or prenat∗ or pre-nat∗ or antenat∗ or ante-nat∗) adj12 growth adj2 (restrict∗ or retard∗)) or FGR∗ or IUGR∗ or SFGR∗ or SIUGR∗).tw,kf.
30590
34
(placent∗ adj3 (insufficien∗ or d∗sfunct∗ or inflammat∗ or abruptio∗)).tw,kf.
8432
35
((PROM and ruptur∗ and (membran∗ or amnio∗)) or PPROM∗ or EPPROM∗1 or ((prematur∗ or pre-matur∗ or i?matur∗ or preterm∗ or pre-term∗ or pre-labo?r or prelabo?r) adj6 ruptur∗ adj4 (amnio∗ or membran∗)) or chorioamn∗ or amnionit∗ or intraamnio∗ or funisit∗).tw,kf. or (((ruptur∗ adj2 (amnio∗ or membran∗)) or ROM).tw,kf. and (pregnan∗ or gestat∗ or gravidit∗ or trimester∗ or intrauterine∗ or intra-uterin∗ or in-utero or prenat∗ or pre-nat∗ or antenat∗ or ante-nat∗).mp.)
14299
36
(prematurity or ((preterm∗ or pre-term∗ or prematur∗ or pre-matur∗) adj3 (labo?r or deliver∗ or birth∗ or childbirth∗)) or PTB or PTBs or TPTB∗ or SPTB∗ or VPTB∗ or EPTB∗ or PTL or TPTL∗ or PTD∗).tw,kf.
85358
37
(((small∗ or large∗ or deliver∗ or labo?r∗ or birth or childbirth) adj4 gestat∗ adj2 (age or ages)) or (gestat∗ adj ("at birth” or “at deliver∗")) or birth age∗ or SGA or LGA).tw,kf.
34043
38
(((birth or births or childbirth∗ or born or parturit∗ or delivery or baby or babies or postnat∗ or post-nat∗ or perinat∗ or peri-nat∗ or intrauterine or intra-uterine or in-utero) adj2 (underweight∗ or weight∗ or overweight∗ or siz∗ or length∗)) or birthweight∗ or LBW∗ or VLBW∗ or ELBW∗).tw,kf.
88258
39
((((head or cephal∗ or body or arm or arms or leg∗) adj4 (circumfer∗ or measur∗ or siz∗ or small∗ or larg∗)) or cephalometr∗ or anthropometr∗ or body mass∗ or BMI) adj9 (birth or births or childbirth∗ or parturit∗ or delivery or baby or babies or postnat∗ or post-nat∗ or perinat∗ or per-nat∗ or intrauterine or intra-uterine or in-utero)).tw,kf.
10653
40
(neurodevelop∗ or ((brain or neurol∗ or neural or sex∗ or grow∗) adj2 develop∗) or “ages and stages” or DDST or (developmental adj4 (outcome∗ or test∗ or quotient∗ or index or indices or scor∗ or scale∗)) or ((behav∗ or neurocognit∗ or cognit∗ or neurobehav∗ or neuropsychomot∗ or psychomotor∗ or psycho-motor∗ or neuromotor∗ or neuro-motor∗ or sensor?motor∗ or sensory motor∗ or visuomotor or visual motor or neuro-sensory or neurosensory) adj3 (abilit∗ or outcom∗ or problem∗ or develop∗)) or ((executive or motor) adj3 (function∗ or d#sfunc∗ or deficit∗ or problem∗)) or interference control or psychointellect∗ or intellect∗ or intelligen∗ or IQ or DQ or psycholinguist∗ or linguist∗).tw,kf.
483193
41
(((language or learning or speech or reading or memory) adj3 (skill∗ or test∗ or scale∗ or scor∗ or task∗ or cognitiv∗)) or verbal skill∗ or wording or naming or (numeric∗ adj3 memory) or 5-digit or digit-span or letter-digit).tw,kf.
114783
42
(Binet∗ or Wechsler∗ or WAIS or WASI∗ or WIAT∗ or WDD or WDR or WRR or WISC or (WISC∗ not Wisconsin∗) or WPPSI∗ or WRIT or CANTAB or complex figure or RCF or RCOF or RCFOSS or GIT-2 or FSIQ or VIQ or PIQ or (assess∗ adj2 batter∗) or ((mobile or assesment∗) adj3 ABC) or m-ABC or mABC or kABC or CELF or (mental development adj3 (index or indic∗ or scor∗)) or MDI or WJ-R or Ba?ley∗ or BSID∗ or NEPSY or Beery or Basic Concept Scale or BBCS∗ or CMS or continuous performance∗ or Serial Addition or PDI or RBMT or Stroop or CNT or PPVT∗ or Everyday Attention or TOMI or MPC or CNT or Trail Making or Brunet or LMT or LMTs or TMT or TMTs or TMTa or Achievement Test or WJ-SAT or WJ IV or WRAT∗ or sensory profil∗ or ITSP or SSP or SPNL or CBCL).tw,kf.
114014
43
(((female or male or women or men or males or ratio∗ or distribut∗ or proportion∗ or factor∗) adj3 (sex or gender∗)) or ((male or males) adj1 female∗) or girls or boys or ((deliver∗ or parturit∗ or birth or born∗) adj2 (girl∗ or boy∗ or femal∗ or male or males))).tw,kf.
317406
44
((testi∗ adj3 (cancer∗ or neoplas∗ or malignan∗ or tumo?r∗ or undescen∗ or descen∗)) or cryptorch∗).tw,kf.
35203
45
(congenit∗ or anomal∗ or malformat∗ or deformit∗ or d#smorph∗ or aplas∗ or d#splas∗ or hypoplas∗ or atres∗ or agenes∗).tw,kf.
653144
46
((prenat∗ or pre-nat∗ or antenat∗ or ante-nat∗ or perinat or peri-nat∗ or birth or anatomic∗ or morphological∗ or isolated or chromosom∗ or nonchromosom∗ or cardiac or noncardiac or extracard∗ or cardio∗ or heart or outflow tract or OFT or conotrunc∗ or cono-trunc∗ or septal or septum or endocard∗ cushion∗ or atrioventric∗ or atrio-ventr∗ or AV or musc∗skelet∗ or skelet∗ or bone or bones or osseous or spine or spinal or limb or limbs or extremit∗ or foot or feet or hand or hands or cranio∗ or orofacial or facial∗ or palat∗2 or mouth or lip or lips or (digest∗ adj2 (system or tract∗)) or GI or intestin∗ or duoden∗ or esophag∗ or oesophag∗ or trach∗esophag∗ or abdominal or respirator∗ or pulmonar∗ or lung or diaphragm∗ or hemidiaphragm∗ or sex or sexual or genit∗ or urogenit∗ or kidney∗ or uret∗ or renal or bladder or neural-tube∗ or nervous system or CNS or brain) adj3 (abnormalit∗ or defect∗1)).tw,kf.
201082
47
(Down∗ syndrome or CHD or Fallot∗ or Ebstein∗ or coarct∗ or (aort∗ adj1 arch∗) or double outlet∗ or DORV or HLHS or HLV or HRHS or univentricular or uni-ventricular or single ventricle∗ or ((common arterial or arterios∗) adj2 (trunk or truncus)) or VSD or (common adj3 (septum or septal) adj3 canal∗) or AVSD or CAVC or scimitar∗ or TAPVC∗ or PAPVC∗ or encephaloc?el∗ or cephaloc?el∗ or meningoencephaloc?el∗ or notoencephaloc?ele or craniac?el∗ or ((cereb∗ or mening∗) adj2 hernia∗) or anencephal∗ or acrani∗ or aprosencephal∗ or ((spin∗ or cranium or crania) adj2 (bifid∗ or open)) or d#sraphi∗ or rachischis∗ or crani∗-schis∗ or crani∗schis∗ or myeloc?ele∗ or mening∗myeloc?el∗ or hydrocephal∗ or hydro-cephal∗ or ventricul∗-megal∗ or ventricul∗megal∗ or holoprosencephal∗ or holo-prosencephal∗ or arhinencephal∗ or achondroplasi∗ or thanatophor∗ or osteochondrod#splas∗ or osteod#splast∗ or osteod#d#stroph∗ or chondrod#splas∗ or chondrod#stroph∗ or ((limb or limbs) adj2 reduct∗) or talipes or clubfoot or club-foot or cleft or clefts or gastro?chis∗ or gastro-schis∗ or (umbilic∗ adj2 hernia∗) or omphaloc?el∗ or exomphal∗ or ((cystic or polycyst∗ or multicyst∗) adj2 (kidney∗ or (renal adj2 (diseas∗ or disorder∗)))) or PKD or MCKD or megacystis or hydronephro∗ or Smith-Lemli-Opitz or micromelia or ectromeli∗ or (hydrops adj3 f?etalis) or hypospad∗ or hip dislocat∗).tw,kf.
250725
48
or/7-47 [ perinatal and long term offspring outcomes ]
5716019
49
6 and 48 [ HG + perinatal and long term offspring outcome]
1191
50
(editorial or “systematic review”).pt. or (editorial or reply or (case-report not case-report-survey) or two-cases or three-cases or four-cases or five-cases or 2-cases or 3-cases or 4-cases or 5-cases).ti. or cochrane.jw. or ((review.pt. or case reports/ or case report∗.jw. or (review or overview).ti. or (search∗ adj15 (literatur∗ or ((electronic∗ or medical or biomedical) adj3 database∗) or medline or pubmed or embase or psyc?info or exhaustiv∗ or systematic∗)).tw,kf,kw.) not (cohort studies/ or longitudinal studies/ or prospective studies/ or retrospective studies/ or cross-sectional studies/ or case-control studies/ or (case-control∗ or cohort∗ or retrospectiv∗ or prospectiv∗ or crosssection∗ or cross-section∗ or population-based or ((chart∗ or record∗ or retrospectiv∗) adj3 review∗)).tw,kf,kw.)) or (exp animals/ not exp humans/) or animal.jw. or (rodent∗ or rabbit∗ or mice or mouse or murine or rat or rats or (animal∗ adj3 (experiment∗ or model))).ti. [ filter for original human studies ]
10692231
51
49 not 50 [ HG + perinatal and long term offspring outcome - original human studies ]
701
52
remove duplicates from 51 [ HG + perinatal and long term offspring outcome -original human studies - duplicates removed ]
700
Nijsten. Hyperemesis gravidarum and children’s health. Am J Obstet Gynecol 2022.
Search in Embase Classic and Embase (1947 to September 6, 2021)
Tabled
1
#
Searches
Results
1
hyperemesis gravidarum/
3255
2
((∗“nausea and vomiting”/ or hyperemesis.dj. or (∗vomiting/ and ∗nausea/)) and (pregnancy/ or pregnancy complication/ or prenatal period/ or prenatal exposure/)) or ((∗vomiting/ or ∗nausea/) and (prenatal exposure/ or prenatal period/))
828
3
(hypereme∗ adj15 (pregnanc∗ or pregnant or gestat∗ or gravidi∗ or gravidar∗ or trimester∗ or maternal or prenat∗ or pre-nat∗ or antenat∗ or ante-nat∗ or intrauterine or intra-uterine or in-utero)).tw,kw.
2498
4
((pernicious∗ or serious∗ or sever∗ or excessiv∗) adj2 (vomiting or nause∗) adj9 (gravidar∗ or gravidit∗ or gestat∗ or pregnanc∗ or pregnant or trimester∗)).tw,kw.
424
5
(nausea adj2 vomit∗ adj3 pregnan∗).tw,kw.
1162
6
or/1-5 [HG]
4971
7
apgar score/ or exp birth weight/ or crown rump length/ or cephalometry/ or exp fetus maturity/ or fetus outcome/ or fetus weight/ or live birth/ or exp perinatal morbidity/ or placenta weight/ or pregnancy outcome/ ["parameters concerning the fetus, newborn and pregnancy"]
273732
8
maternal exposure/ or prenatal exposure/
28799
9
fetus/ or fetus brain/ or fetus heart/ or child/ or juvenile/ or exp infant/ or preschool child/ or school child/ or toddler/ or adolescence/ or adulthood/ or exp childhood/ or high school/ or kindergarten/ or middle school/ or primary school/ or pediatrics/ or progeny/ [fetus/child]
3547791
10
childhood mortality/ or embryo mortality/ or fetus mortality/ or infant mortality/ or exp perinatal mortality/ or prenatal mortality/ [child/fetus mortality]
69986
11
exp “immature and premature labor”/ or fetus disease/ or prenatal disorder/ or chorioamnionitis/ or dysmaturity/ or fetal malnutrition/ or fetus distress/ or fetus hypoxia/ or fetus malformation/ or exp hydramnios/ or exp intrauterine growth retardation/ or macrosomia/ or exp oligohydramnios/ or premature fetus membrane rupture/ or fetus wastage/ or spontaneous abortion/ or exp child death/ or embryo death/ or exp fetus death/ or perinatal death/ or placenta disorder/ or placenta insufficiency/ or solutio placentae/ or infant disease/ or newborn disease/ or dysmaturity/ or immaturity/ or large for gestational age/ or neonatal respiratory distress syndrome/ or neonatal stress/ or newborn apnea/ or newborn hypoxia/ or newborn infection/ or newborn sepsis/ or newborn vomiting/ or perinatal asphyxia/ or perinatal stress/ or prematurity/ or retrolental fibroplasia/ or newborn assessment/ or newborn intensive care/ or lung dysplasia/ or encephalomalacia/
453074
12
“growth, development and aging”/ or nerve cell differentiation/ or human development/ or adolescent development/ or language development/ or psychosocial development/ or speech development/ or exp postnatal development/ or prenatal development/ or embryo development/ or fetus development/ or fetal well being/ or fetus lung maturation/ or exp postnatal development/ or special education/ or exp sexual development/ or child behavior/ or neurobehavioral manifestations/ or neurodevelopment∗ outcome∗.dq.
706313
13
adolescent health/ or child health/
39074
14
behavior disorder/ or attention deficit disorder/ or congenital behavior disorder/ or exp disruptive behavior/ or oppositional defiant disorder/ or exp autism/ or exp tic/ or obsessive compulsive disorder/ or exp learning disorder/ or exp “disorders of higher cerebral function”/ or attention disturbance/ or developmental coordination disorder/ or exp intellectual impairment/ or language disability/ or exp developmental language disorder/ or developmental disorder/ or developmental delay/
1113944
15
behavior assessment/ or aptitude test/ or learning test/ or exp neuropsychological test/ or exp cognition assessment/ or developmental screening/
144565
16
“gender and sex”/ or gender/ or sex/ or sex difference/ or sex factor/ or sex ratio/ or exp sex determination/
833481
17
exp testis disease/
79045
18
exp ∗congenital disorder/ or exp congenital disorder/et, ep
973317
19
congenital malformation/ or exp “head and neck malformation”/ or exp limb malformation/ or exp cardiovascular malformation/ or severe teratoid abnormality/ or exp nervous system malformation/ or exp digestive system malformation/ or exp male genital tract malformation/ or exp musculoskeletal system malformation/ or hydronephrosis/
797608
20
((pregnancy or gestat∗) adj outcom∗).tw,kw.
41438
21
((perinat∗ or peri-nat∗ or birth∗1 or childbirth∗ or deliver∗ or labo?r∗ or obstetric∗) adj3 outcome∗).tw,kw.
52218
22
((perinat∗ or peri-nat∗) adj3 (complicat∗ or health or morbidit∗ or cancer∗ or malignan∗ or neoplas∗)).tw,kw.
14447
23
((prenat∗ or pre-nat∗ or antenat∗ or ante-nat∗ or intrauterine or intra-uterine or utero) adj18 expos∗).tw,kw.
39656
24
(maternal adj2 expos∗).tw,kw.
10434
25
((prenat∗ or pre-nat∗ or antenat∗ or ante-nat∗ or in-utero or intra-uterine or intrauterine) adj3 (factor∗ or variabl∗ or parameter∗ or circumstanc∗ or condition∗)).tw,kw.
8096
26
((prenat∗ or pre-nat∗ or antenat∗ or ante-nat∗ or intrauterine or intra-uterine or utero) adj life).tw,kw.
3478
27
(DOHAD∗ or FOAD∗ or (early adj3 origin∗)).tw,kw. or (development∗ adj3 origin∗ adj4 (health∗ or diseas∗ or adult)).tw,kw,jw.
6960
28
(offspring∗ or progeny or (born adj2 mother∗)).tw,kw.
141617
29
(f?etal or f?etus∗ or neonat∗ or neo-nat∗ or new∗born∗ or new-born∗ or child or child∗1 or children∗ or schoolchild∗ or childhood or infant∗ or infanc∗ or toddler∗ or prekindergarten∗ or kindergarten∗ or preschool∗ or school-age∗ or schoolage∗ or high-school∗ or highschool∗ or elementary school∗ or graders or puber∗ or teens or teenager∗ or youth or juvenil∗ or adolescence or adulthood or young adult∗ or adult life or older age∗ or “early life” or later-life or “later in life").tw,kw. [ child filter ]
3582830
30
(((perinat∗ or peri-nat∗ or intrauterin∗ or intra-uterin∗ or in-utero or prenat∗ or pre-nat∗ or antenat∗ or ante-nat∗) adj3 (mortalit∗ or death∗ or demise)) or stillbirth∗ or stillborn∗ or asphyx∗ or miscarriag∗ or IUFD or (spontan∗ adj3 abort∗) or ((embry∗ or pregnancy) adj2 loss∗) or liveborn∗ or (live adj3 (birth∗ or born∗))).tw,kw.
162175
31
(((intrauterin∗ or intra-uterin∗ or in-utero or prenat∗ or pre-nat∗ or antenat∗ or ante-nat∗) adj3 (growth∗ or develop∗ or brain or movement∗)) or ((intrauterin∗ or intra-uterin∗ or in-utero or prenat∗ or pre-nat∗ or antenat∗ or ante-nat∗) adj12 growth adj2 (restrict∗ or retard∗)) or FGR∗ or IUGR∗ or SFGR∗ or SIUGR∗).tw,kw.
45264
32
(placent∗ adj3 (insufficien∗ or d∗sfunct∗ or inflammat∗ or abruptio∗)).tw,kw.
13730
33
((PROM and ruptur∗ and (membran∗ or amnio∗)) or PPROM∗ or EPPROM∗1 or ((prematur∗ or pre-matur∗ or i?matur∗ or preterm∗ or pre-term∗ or pre-labo?r or prelabo?r) adj6 ruptur∗ adj4 (amnio∗ or membran∗)) or chorioamn∗ or amnionit∗ or intraamnio∗ or funisit∗).tw,kw. or (((ruptur∗ adj2 (amnio∗ or membran∗)) or ROM).tw,kw. and (pregnan∗ or gestat∗ or gravidit∗ or trimester∗ or intrauterine∗ or intra-uterin∗ or in-utero or prenat∗ or pre-nat∗ or antenat∗ or ante-nat∗).mp.)
21576
34
(prematurity or ((preterm∗ or pre-term∗ or prematur∗ or pre-matur∗) adj3 (labo?r or deliver∗ or birth∗ or childbirth∗)) or PTB or PTBs or TPTB∗ or SPTB∗ or VPTB∗ or EPTB∗ or PTL or TPTL∗ or PTD∗).tw,kw.
126669
35
(((small∗ or large∗ or deliver∗ or labo?r∗ or birth or childbirth) adj4 gestat∗ adj2 (age or ages)) or (gestat∗ adj (“at birth” or “at deliver∗”)) or birth age∗ or SGA or LGA).tw,kw.
51397
36
(((birth or births or childbirth∗ or born or parturit∗ or delivery or baby or babies or postnat∗ or post-nat∗ or perinat∗ or peri-nat∗ or intrauterine or intra-uterine or in-utero) adj2 (underweight∗ or weight∗ or overweight∗ or siz∗ or length∗)) or birthweight∗ or LBW∗ or VLBW∗ or ELBW∗).tw,kw.
123200
37
((((head or cephal∗ or body or arm or arms or leg∗) adj4 (circumfer∗ or measur∗ or siz∗ or small∗ or larg∗)) or cephalometr∗ or anthropometr∗ or body mass∗ or BMI) adj9 (birth or births or childbirth∗ or parturit∗ or delivery or baby or babies or postnat∗ or post-nat∗ or perinat∗ or per-nat∗ or intrauterine or intra-uterine or in-utero)).tw,kw.
16456
38
(neurodevelop∗ or ((brain or neurol∗ or neural or sex∗ or grow∗) adj2 develop∗) or “ages and stages” or DDST or (developmental adj4 (outcome∗ or test∗ or quotient∗ or index or indices or scor∗ or scale∗)) or ((behav∗ or neurocognit∗ or cognit∗ or neurobehav∗ or neuropsychomot∗ or psychomotor∗ or psycho-motor∗ or neuromotor∗ or neuro-motor∗ or sensor?motor∗ or sensory motor∗ or visuomotor or visual motor or neuro-sensory or neurosensory) adj3 (abilit∗ or outcom∗ or problem∗ or develop∗)) or ((executive or motor) adj3 (function∗ or d#sfunc∗ or deficit∗ or problem∗)) or interference control or psychointellect∗ or intellect∗ or intelligen∗ or IQ or DQ or psycholinguist∗ or linguist∗).tw,kw.
645254
39
(((language or learning or speech or reading or memory) adj3 (skill∗ or test∗ or scale∗ or scor∗ or task∗ or cognitiv∗)) or verbal skill∗ or wording or naming or (numeric∗ adj3 memory) or 5-digit or digit-span or letter-digit).tw,kw.
149827
40
(Binet∗ or Wechsler∗ or WAIS or WASI∗ or WIAT∗ or WDD or WDR or WRR or WISC or (WISC∗ not Wisconsin∗) or WPPSI∗ or WRIT or CANTAB or complex figure or RCF or RCOF or RCFOSS or GIT-2 or FSIQ or VIQ or PIQ or (assess∗ adj2 batter∗) or ((mobile or assesment∗) adj3 ABC) or m-ABC or mABC or kABC or CELF or (mental development adj3 (index or indic∗ or scor∗)) or MDI or WJ-R or Ba?ley∗ or BSID∗ or NEPSY or Beery or Basic Concept Scale or BBCS∗ or CMS or continuous performance∗ or Serial Addition or PDI or RBMT or Stroop or CNT or PPVT∗ or Everyday Attention or TOMI or MPC or CNT or Trail Making or Brunet or LMT or LMTs or TMT or TMTs or TMTa or Achievement Test or WJ-SAT or WJ IV or WRAT∗ or sensory profil∗ or ITSP or SSP or SPNL or CBCL).tw,kw.
154869
41
(((female or male or women or men or males or ratio∗ or distribut∗ or proportion∗ or factor∗) adj3 (sex or gender∗)) or ((male or males) adj1 female∗) or girls or boys or ((deliver∗ or parturit∗ or birth or born∗) adj2 (girl∗ or boy∗ or femal∗ or male or males))).tw,kw.
476728
42
((testi∗ adj3 (cancer∗ or neoplas∗ or malignan∗ or tumo?r∗ or undescen∗ or descen∗)) or cryptorch∗).tw,kw.
50422
43
(congenit∗ or anomal∗ or malformat∗ or deformit∗ or d#smorph∗ or aplas∗ or d#splas∗ or hypoplas∗ or atres∗ or agenes∗).tw,kw.
918817
44
((prenat∗ or pre-nat∗ or antenat∗ or ante-nat∗ or perinat or peri-nat∗ or birth or anatomic∗ or morphological∗ or isolated or chromosom∗ or nonchromosom∗ or cardiac or noncardiac or extracard∗ or cardio∗ or heart or outflow tract or OFT or conotrunc∗ or cono-trunc∗ or septal or septum or endocard∗ cushion∗ or atrioventric∗ or atrio-ventr∗ or AV or musc∗skelet∗ or skelet∗ or bone or bones or osseous or spine or spinal or limb or limbs or extremit∗ or foot or feet or hand or hands or cranio∗ or orofacial or facial∗ or palat∗2 or mouth or lip or lips or (digest∗ adj2 (system or tract∗)) or GI or intestin∗ or duoden∗ or esophag∗ or oesophag∗ or trach∗esophag∗ or abdominal or respirator∗ or pulmonar∗ or lung or diaphragm∗ or hemidiaphragm∗ or sex or sexual or genit∗ or urogenit∗ or kidney∗ or uret∗ or renal or bladder or neural-tube∗ or nervous system or CNS or brain) adj3 (abnormalit∗ or defect∗1)).tw,kw.
273256
45
(Down∗ syndrome or CHD or Fallot∗ or Ebstein∗ or coarct∗ or (aort∗ adj1 arch∗) or double outlet∗ or DORV or HLHS or HLV or HRHS or univentricular or uni-ventricular or single ventricle∗ or ((common arterial or arterios∗) adj2 (trunk or truncus)) or VSD or (common adj3 (septum or septal) adj3 canal∗) or AVSD or CAVC or scimitar∗ or TAPVC∗ or PAPVC∗ or encephaloc?el∗ or cephaloc?el∗ or meningoencephaloc?el∗ or notoencephaloc?ele or craniac?el∗ or ((cereb∗ or mening∗) adj2 hernia∗) or anencephal∗ or acrani∗ or aprosencephal∗ or ((spin∗ or cranium or crania) adj2 (bifid∗ or open)) or d#sraphi∗ or rachischis∗ or crani∗-schis∗ or crani∗schis∗ or myeloc?ele∗ or mening∗myeloc?el∗ or hydrocephal∗ or hydro-cephal∗ or ventricul∗-megal∗ or ventricul∗megal∗ or holoprosencephal∗ or holo-prosencephal∗ or arhinencephal∗ or achondroplasi∗ or thanatophor∗ or osteochondrod#splas∗ or osteod#splast∗ or osteod#d#stroph∗ or chondrod#splas∗ or chondrod#stroph∗ or ((limb or limbs) adj2 reduct∗) or talipes or clubfoot or club-foot or cleft or clefts or gastro?chis∗ or gastro-schis∗ or (umbilic∗ adj2 hernia∗) or omphaloc?el∗ or exomphal∗ or ((cystic or polycyst∗ or multicyst∗) adj2 (kidney∗ or (renal adj2 (diseas∗ or disorder∗)))) or PKD or MCKD or megacystis or hydronephro∗ or Smith-Lemli-Opitz or micromelia or ectromeli∗ or (hydrops adj3 f?etalis) or hypospad∗ or hip dislocat∗).tw,kw.
352321
46
or/7-45 [ perinatal and long term offspring outcomes ]
8528197
47
6 and 46 [ HG + perinatal and long term offspring outcome]
2586
48
editorial/ or “systematic review”/ or (editorial or conference abstract or conference review).pt. or (editorial or reply or (case-report not case-report-survey) or two-cases or three-cases or four-cases or five-cases or 2-cases or 3-cases or 4-cases or 5-cases).ti. or cochrane.jw. or ((review.pt. or review/ or case report/ or case report∗.jw. or (review or overview).ti. or (search∗ adj15 (literatur∗ or ((electronic∗ or medical or biomedical) adj3 database∗) or medline or pubmed or embase or psyc?info or exhaustiv∗ or systematic∗)).tw,kw.) not (cohort analysis/ or longitudinal study/ or prospective study/ or retrospective study/ or exp case control study/ or cross-sectional study/ or (case-control∗ or cohort∗ or retrospectiv∗ or prospectiv∗ or crosssection∗ or cross-section∗ or population-based or ((chart∗ or record∗ or retrospectiv∗) adj3 review∗)).tw,kw.)) or ((exp animal/ or animal experiment/ or exp animal model/ or nonhuman/ or exp female animal/) not human/) or exp veterinary medicine/ or animal∗.jw. or (rodent∗ or rabbit∗ or mice or mouse or murine or rat or rats or (animal∗ adj3 (experiment∗ or model))).ti. [ filter for original human studies ]
17746737
49
47 not 48 [ HG + perinatal and long term offspring outcome - original human studies ]
1248
50
Remove duplicates from 49 [ HG + perinatal and long term offspring outcome -original human studies - duplicates removed ]
1231
51
50 not medline.cr. [ HG + perinatal and long term offspring outcome - original human studies - duplicates removed - embase records only ]
1046
Nijsten. Hyperemesis gravidarum and children’s health. Am J Obstet Gynecol 2022.
Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study.
Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study.
Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study.
Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study.
Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study.
Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study.
Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: the Growing Up in Singapore Towards Healthy Outcomes study.
Presented as unadjusted means with 95% CI because of missing descriptive statistics. Severe-NVP and no-NVP group as controls are shown (mild-to-moderate–NVP group is not presented)
Presented as unadjusted means with 95% CI because of missing descriptive statistics. Severe-NVP and no-NVP group as controls are shown (mild-to-moderate–NVP group is not presented)
Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: the Growing Up in Singapore Towards Healthy Outcomes study.
Presented as unadjusted means with 95% CI because of missing descriptive statistics. Severe-NVP and no-NVP group as controls are shown (mild-to-moderate–NVP group is not presented)
Presented as unadjusted means with 95% CI because of missing descriptive statistics. Severe-NVP and no-NVP group as controls are shown (mild-to-moderate–NVP group is not presented)
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