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Lack of catch-up in weight gain may intermediate between pregnancies with hyperemesis gravidarum and reduced fetal growth: the Japan Environment and Children’s Study

Abstract

Background

Women with nausea and vomiting of pregnancy (NVP) have higher birth weight infants, while those with hyperemesis gravidarum, a severe manifestation of NVP, have lower birth weight infants. We aimed to investigate the associations between maternal weight loss (a consequence of hyperemesis gravidarum), NVP, and infant birth weight.

Methods

This study was a secondary analysis of a nationwide birth cohort in Japan. Singleton pregnancies delivered at 28–41 weeks of gestation were included in the analysis. Women were categorized based on their weight change in the 1st trimester (as a proportion to their pre-pregnancy weight: >  + 3%, > 0 to + 3%, > -3 to 0%, > -5 to -3%, ≤ -5%) and severity of NVP (no nausea, only nausea, vomiting but able to eat, vomiting and unable to eat). The effects of weight change and severity of NVP on infant birth weight and small for gestational age (SGA) were assessed using regression models. We further examined how these effects could be modified by maternal weight gain up to the 2nd trimester.

Results

Among 91,313 women, 5,196 (5.7%) lost ≥ 5% of their pre-pregnancy weight and 9,983 (10.9%) experienced vomiting and were unable to eat in the 1st trimester. Women with weight loss ≥ 5% in the 1st trimester had infants 66 (95% CI: 53, 78) g lighter and higher odds of SGA (aOR: 1.29; 95% CI: 1.14, 1.47) than women who gained > 3% during the same period. However, when adjusting for weight gain up to the 2nd trimester, women with weight loss ≥ 5% in the 1st trimester had infants 150 (95% CI: 135, 165) g heavier and lower odds of SGA (aOR: 0.39; 95% CI: 0.33, 0.46) than those who gained > 3% during the same period. In contrast, women with more severe NVP tended to have infants with larger birth weight and lower odds of SGA compared to women without NVP. These trends were strengthened when adjusting for weight gain up to the 2nd trimester.

Conclusions

Our study suggests the possibility that reduced fetal growth in pregnancies with hyperemesis gravidarum may be caused by the lack of catch-up in gestational weight gain up to the 2nd trimester.

Peer Review reports

Background

Nausea and vomiting of pregnancy (NVP), commonly experienced by 35–91% of pregnant women typically in the 1st trimester, is characterized by nausea and vomiting [1,2,3,4]. Hyperemesis gravidarum is a severe manifestation of NVP and is described as involving severe nausea and vomiting, which may lead to a loss of more than 5% of the pregnant woman’s pre-pregnancy weight, dehydration, electrolyte imbalances, and antenatal hospital admission [5,6,7]. This condition reportedly affects 0.3%-3.6% of pregnant women [2, 8,9,10].

The potential adverse effects of hyperemesis gravidarum on fetal growth have been reported, and a systematic review and large population-based study have confirmed this association [11, 12]. However, another meta-analysis and large observational study also showed that women who experienced NVP gave birth to heavier infants than those who did not [13, 14]. Given that hyperemesis gravidarum is a severe manifestation of NVP, the apparently contradictory association with fetal growth invites inquiry. There are also studies that have focused on the adverse impact of insufficient gestational weight gain [15,16,17] and weight gain in early pregnancy [18, 19] on fetal growth. The lack of definite diagnostic criteria for hyperemesis gravidarum may have confused the situation and made research synthesis challenging [6, 7]. Nonetheless, few studies have investigated the mechanism underlying this paradoxical phenomenon.

In this study, we focused on “maternal weight change”, as maternal weight loss is one of the major consequences of hyperemesis gravidarum. We aimed to investigate 1) the association between maternal weight change in the 1st trimester and birth weight of infants, 2) the association between the severity of NVP symptoms and birth weight of infants; and 3) how these associations change after adjusting for differences in maternal weight gain up to the 2nd trimester.

Methods

Study design, setting, and study sample

We used data collected from the Japan Environment and Children’s Study (JECS), a nationwide prospective cohort study of pregnant women, their spouses, and their children in Japan. The Review Board on Epidemiological Studies of the Ministry of the Environment and the ethics committees of all participating institutions approved the JECS protocol. Written informed consent was obtained from all participants. The study was conducted in accordance with the relevant national and institutional guidelines as well as the Declaration of Helsinki.

The detailed methodology of this cohort has been previously reported [20, 21]. In brief, pregnant women were recruited through 1) the first antenatal visit at participating health care institutions, and 2) the local government offices issuing the Mother–Child Health Handbook from January 2011 to March 2014 in 15 study regions throughout Japan. During pregnancy, participating women were asked to fill out two questionnaires: one administered at recruitment and another administered at mid-pregnancy, which captured their demographics, lifestyle, behaviors, and medical history. Birth characteristics and medical information were transcribed separately from medical records.

In total, 104,102 births were born among the recruited women. For this study, we used the dataset of the birth characteristics “jecs-ag-20160424” which was created in April 2016 and revised in October 2016. Among 99,744 singleton pregnancies in the study, we excluded miscarriages and births (including stillbirths) before 28 weeks (n = 1,537), post-term births more than or equal to 42 weeks (n = 226), and births with missing background characteristics (n = 6,158). We also excluded births from severely obese women with body mass index (BMI) over 35 (n = 510) because they were considered as outliers of the study sample (+ 4.18 standard deviation) and may include unreliable measurements/records. Thus, we based our analysis on 91,313 (92%) subjects (Fig. 1).

Fig. 1
figure 1

Population flow chart. Legends: BMI, body mass index; GA, gestational age

Variable definitions

Our primary variable of interest was maternal weight change during the 1st trimester. Weight change in the 1st trimester, as well as weight gain up to the 2nd trimester and gestational weight gain, were calculated using weight measurements in the 1st trimester (7–14 weeks), 2nd trimester (20–28 weeks), and at delivery, which were collected from the medical records. Weight change was calculated by subtracting the self-reported pre-pregnancy weight from these values and categorizing them by proportion to pre-pregnancy weight, with cutoffs created based on both interpretability and distribution of the data (> + 3%, > 0 to + 3%, > -3 to 0%, > -5 to -3%, ≤ -5%).

The severity of NVP symptoms was assessed by a single question in the 2nd trimester questionnaire: “Did you have morning sickness from conception to week 12 of your pregnancy?” (no nausea = 1, only nausea = 2, vomiting but able to eat = 3, vomiting and unable to eat = 4). We categorized other maternal socio-demographic data from the responses to questions (which was also included in the second questionnaire) as follows: annual household income (< 2 million yen, 2 to < 4 million yen, 4 to < 6 million yen, 6 to < 8 million yen, ≥ 8 million yen, no answer), maternal education (university graduate or higher, 2-year college, vocational school, high school or less), smoking status (never smoked, previously smoked but stopped before pregnancy, previously smoked but stopped because of pregnancy, current smoker). Pre-pregnancy BMI was calculated from height and pre-pregnancy weight and categorized as under 18.5 kg/m2, 18.5 to < 25 kg/m2, and 25 kg/m2 or higher.

Data on maternal age, parity, and birth outcomes (gestational age, birth weight, and placental weight) were obtained from medical records. We categorized maternal age and parity as follows: maternal age (< 25, 25–34, 35 ≤) and parity (0 and 1 or more). We defined small for gestational age (SGA) as a birth weight below the 10th percentile of the normal population at each day of gestation and stratified by sex and parity using the Japanese birth weight reference [22]. The same reference was used to calculate the birth weight z-score for each infant.

Statistical analysis

We first summarized participants’ background characteristics and assessed their association with weight change in the 1st trimester. We also assessed the severity of NVP symptoms, gestational weight gain, birth outcomes, and their association with weight change in the 1st trimester.

Next, we used linear and logistic regression to estimate the effect of weight change in the 1st trimester as well as the severity of NVP symptoms, on birth outcomes. We created two models, one with and the other without weight gain up to the 2nd trimester as a variable.

We considered maternal age, parity, education, household income, pre-pregnancy BMI, height, smoking status, and infant sex as confounders for the multivariate analysis. All variables were considered to be independent. Among the 91,313 subjects, weight at 7–14 weeks (n = 10,828; 11.9% of the sample), measurement timing of weight at 7–14 weeks (n = 9,741; 10.7%), weight at 20–28 weeks (n = 9,182; 10.1%), and measurement timing of weight at 20–28 weeks (n = 9,041; 9.9%), weight at delivery (n = 1,801; 2.0%), and placental weight (n = 3,562; 3.9%) were missing. Therefore, we used multiple imputations (30 imputations) to estimate the missing values from other background characteristics, birth characteristics, and existing weight measurements.

A sensitivity analysis limiting the sample to term deliveries was also conducted to ensure that the findings were not driven by differences in preterm deliveries. The analyses were repeated using categorization by actual changes in weight (≥ + 3 kg, + 1 to <  + 3 kg, 0 to <  + 1 kg, -2 to < 0 kg, < -2 kg) rather than by changes in proportion to pre-pregnancy weight to ensure the robustness of our findings.

All statistical analyses were conducted using the statistical software package Stata 13 (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP.), and a p-value < 0.05 was considered statistically significant when performing hypothesis tests.

Results

Table 1 shows the background characteristics of the study participants. Of the 91,313 women, 5,196 (5.7%) had a weight loss ≥ 5% in the 1st trimester. The background characteristics according to weight change in the 1st trimester are presented in Additional File 1. A higher proportion of women with weight loss ≥ 5% were observed among women with pre-pregnancy BMI ≥ 25 kg/m2 and women who never smoked. Current smokers and women who had continued smoking until they were aware of their pregnancy had a lower proportion of weight loss ≥ 5%.

Table 1 Background characteristics of study participants (91,313 singleton pregnancies)

The severity of NVP symptoms and weight change in the 1st trimester were closely correlated: 73% of women who did not experience nausea gained weight, and 71% of women who vomited and were unable to eat lost weight. In the latter group, 25% had a weight loss ≥ 5%. Although more weight gain was observed in the 2nd trimester among women with weight loss ≥ 5% in the 1st trimester, their average weight gain was 6.6 kg less at 20–28 weeks (95% confidence interval [CI]: 6.5, 6.7), and 6.2 kg less at delivery (95% CI: 6.1, 6.3), than in women with weight gain > 3% in the 1st trimester (Table 2). Weight gain up to the 2nd trimester and up to delivery were all substantially lower in women with weight loss ≥ 5% in the 1st trimester, although the rate of weight gain from the 1st to 2nd trimester was similar to that noted in women without weight loss ≥ 5% in the 1st trimester (Fig. 2).

Table 2 Nausea and vomiting of pregnancy, gestational weight gain, and birth outcomes by weight change in 1st trimester
Fig. 2
figure 2

Weight gain during pregnancy among women with weight loss < 5% and ≥ 5% in 1st trimester. Legends: Multiple imputation was used to impute the following missing values: weight at 7–14 weeks (n = 10,840; 11.9% of the sample), weight at 20–28 weeks (n = 9,189; 10.1%), and weight at delivery (n = 1,801; 2.0%)

Birth weight, birth weight z-score, and placental weight were lower, and the odds of SGA were higher for women who lost more weight in the 1st trimester. Women with weight loss ≥ 5% in the 1st trimester had infants with lower birth weight and higher odds of SGA than women who gained weight > 3% during the same period. This association was not attenuated, instead was strengthened after adjusting for maternal characteristics. However, after adjusting for differences in weight gain up to the 2nd trimester, the association was inverted; birth weight, birth weight z-score, and placental weight were increased, and the odds of SGA were decreased for women who gained less weight in the 1st trimester. This made the infants from women with weight loss ≥ 5% in the 1st trimester to have, on average, 150 g higher birth weight (95% CI: 135, 165) and lower odds of SGA (adjusted odds ratio [aOR]: 0.39, 95% CI: 0.33, 0.46) than those from women who gained > 3% during the same period (Fig. 3, numbers presented in Additional File 2).

Fig.3
figure 3

Association between weight change in 1st trimester in proportion to pre-pregnancy weight and birth outcomes. Legends: Linear regressions were used for continuous outcomes (birth weight, grams; birth weight, SD; placental weight, grams), and logistic regression was used for a categorical outcome (SGA risk, odds ratio). All analyses were adjusted for maternal age, height, pre-pregnancy body mass index, household income, education, smoking status, and infant sex. Multiple imputation was used to impute the following missing values: weight at 7–14 weeks (n = 10,840; 11.9% of the sample), measurement timing at 7–14 weeks (n = 9,752; 10.7%), weight at 20–28 weeks (n = 9,189; 10.1%), measurement timing at 20–28 weeks (n = 9,048; 9.9%), weight at delivery (n = 1,801; 2.0%), and placental weight (n = 3,562; 3.9%). Weight change in the 1st trimester was calculated from pre-pregnancy weight and weight at the 1st trimester visit (at 7–14 weeks). Weight gain up to the 2nd trimester was calculated from pre-pregnancy weight and weight at the 2nd trimester visit (at 20–28 weeks). SD, standard deviation; SGA, small for gestational age

On the other hand, women with more severe NVP symptoms tended to have larger birth weight, birth weight z-score, placental weight, and lower odds of SGA. This association was strengthened after adjusting for differences in weight gain up to the 2nd trimester (Fig. 4, numbers presented in Additional File 3).

Fig. 4
figure 4

Association between severity of nausea and vomiting of pregnancy symptoms and birth outcomes. Legends: Linear regressions were used for continuous outcomes (birth weight, grams; birth weight, SD; placental weight, grams), and logistic regression was used for a categorical outcome (SGA risk, odds ratio). All analyses were adjusted for maternal age, height, pre-pregnancy body mass index, household income, education, smoking status, and infant sex. Multiple imputation was used to impute the following missing values: weight at 7–14 weeks (n = 10,840; 11.9% of the sample), measurement timing at 7–14 weeks (n = 9,752; 10.7%), weight at 20–28 weeks (n = 9,189; 10.1%), measurement timing at 20–28 weeks (n = 9,048; 9.9%), weight at delivery (n = 1,801; 2.0%), and placental weight (n = 3,562; 3.9%). Weight change in the 1st trimester was calculated from pre-pregnancy weight and weight at the 1st trimester visit (at 7–14 weeks). Weight gain up to the 2nd trimester was calculated from pre-pregnancy weight and weight at the 2nd trimester visit (at 20–28 weeks). SD, standard deviation; SGA, small for gestational age

When the analysis was limited to term infants, this association persisted (Additional Files 2 and 3). A similar association was observed between weight change in the 1st trimester and birth outcomes when analysis was conducted using kg measurements of weight gain instead of percentage to pre-pregnancy weight (Additional File 4).

Discussion

This study found that women who lost more weight in the 1st trimester tended to have infants with lower birth weight. On the other hand, women with more severe NVP symptoms tended to have infants with larger birth weight. When maternal weight gain up to the 2nd trimester was accounted for, both women who lost more weight in the 1st trimester as well as those with more severe NVP symptoms tended to have infants with larger birth weight.

There has been a controversy regarding the effects of NVP and hyperemesis gravidarum on fetal growth in previous studies [11,12,13,14]. The same kind of controversy was also found in our study results. The only difference was that our study focused on maternal weight change in the 1st trimester, while previous studies included various definitions of hyperemesis gravidarum. Based on our results as well as previous studies, it can be said that NVP symptoms themselves do not have adverse effects on fetal growth, rather it is maternal weight loss, or the condition that causes maternal weight loss (e.g., malnutrition) that contributes to reduced fetal growth. This finding is consistent with recent studies that have focused on the importance of maternal weight change in early pregnancy [18, 19].

More importantly, the association between increased weight loss during the 1st trimester and reduced fetal growth was inverted after adjusting for weight gain up to the 2nd trimester. These results suggest that the adverse effects of maternal weight loss in the 1st trimester on fetal growth may stem from the inability of those women to gain enough weight later in pregnancy to make up for their 1st trimester loss, rather than from the direct influence of the severe NVP symptoms and/or weight loss in the 1st trimester themselves. This decrease in total weight gain may result in malnutrition and suboptimal fetal growth. A similar argument was made by Dodds et al., who found that hyperemesis gravidarum increased the risk of SGA only if total gestational weight gain was below 7 kg, but not if weight gain exceeded 7 kg [23]. By using a larger database with longitudinal measurements of weight over the course of a pregnancy and a two-stage analytical approach adjusting for weight change persisting into mid-pregnancy, we were able to corroborate this hypothesis.

The implications of our results may potentially be significant from a preventive perspective. The adverse effects of hyperemesis gravidarum on birth outcomes, if mediated by reduced weight gain, may be reversible by increasing weight gain later in pregnancy after nausea and vomiting have resolved. This implication is relevant to the 10th research priority for hyperemesis gravidarum (i.e., nutritional requirements of the first, second, and third trimesters for people with hyperemesis gravidarum), which was identified by the patient–clinician James Lind Alliance partnership [24]. Understanding the nutritional status of women with hyperemesis gravidarum, as well as effective approaches to improve it, is of great importance [25,26,27,28]. While our study has limitations inherent to its observational approach, we believe it provides insights for future interventional studies, suggesting that educational or nutritional approaches aimed at improving mid-pregnancy weight gain among women with hyperemesis gravidarum may improve birth outcomes.

The main strengths of our study include its large sample size, completeness in longitudinal measurements of weight over the course of a pregnancy, and its two-stage analytical approach hypothesizing that gestational weight gain acted as a mediator in the association between experiencing hyperemesis gravidarum and giving birth to infants with lower birth weight.

However, the limitations of the present study should be acknowledged. First, pre-pregnancy weight was self-reported and may have included a certain degree of misclassification. As such measurement error is likely to be randomly distributed across the participants, it may have led to a bias towards the null of the estimates. Second, the severity of NVP was self-rated by participants in the 2nd trimester without using validated assessment tools. Detailed information related to the severity of NVP (e.g., medical interventions) was not assessed. This may have jeopardized the reliability of the data. However, the correlation between the severity of NVP symptoms and weight change in the 1st trimester was high (test for linear trend: p < 0.001). Third, as an observational study, a true causal interpretation cannot be made, and the question of whether birth outcomes can be modified by weight gain later in pregnancy needs to be pursued by future intervention studies. In particular, information related to NVP symptoms after 12 weeks was not collected or assessed in the present study. We should address the possibility that NVP symptoms after 12 weeks may have caused residual confounding. In addition, each country has its own food culture, and we did not assess the diet quality or nutritional status of the participants, which may have been involved in the association between maternal weight change and birth weight. Lastly, this study was based on a cohort in Japan where women are generally thinner [29, 30], gain less weight during pregnancy [29,30,31], and have higher rates of hyperemesis gravidarum compared to women in other countries [1, 8, 9]. Therefore, the generalizability of our findings should be assessed in studies conducted in other populations.

Conclusions

In conclusion, our study results suggest the possibility that the reduced fetal growth observed in pregnancies with hyperemesis gravidarum may be caused by the lack of catch-up in gestational weight gain later in pregnancy. Educational and nutritional interventions aimed at improving mid-pregnancy weight gain may improve birth outcomes in women with hyperemesis gravidarum.

Availability of data and materials

The JECS data are not publicly available because of the ethical restrictions and legal framework of Japan. All inquiries about access to the data should be sent to the JECS Programme Office, National Institute for Environmental Studies (jecs-en@nies.go.jp).

Abbreviations

aOR:

Adjusted odds ratio

BMI:

Body mass index

CI:

Confidence interval

JECS:

Japan Environment and Children’s Study

NVP:

Nausea and vomiting of pregnancy

SD:

Standard deviation

SGA:

Small for gestational age

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Acknowledgements

We would like to express our gratitude to all participants in this study and all the individuals involved in data collection. We would also like to thank the following members of the JECS (principal investigator, Toshihiro Kawamoto) as of 2017: Hirohisa Saito (National Center for Child Health and Development, Tokyo, Japan), Reiko Kishi (Hokkaido University, Sapporo, Japan), Nobuo Yaegashi (Tohoku University, Sendai, Japan), Koichi Hashimoto (Fukushima Medical University, Fukushima, Japan), Chisato Mori (Chiba University, Chiba, Japan), Shuichi Ito (Yokohama City University, Yokohama, Japan), Zentaro Yamagata (University of Yamanashi, Chuo, Japan), Hidekuni Inadera (University of Toyama, Toyama, Japan), Michihiro Kamijima (Nagoya City University, Nagoya, Japan), Toshio Heike (Kyoto University, Kyoto, Japan), Hiroyasu Iso (Osaka University, Suita, Japan), Masayuki Shima (Hyogo College of Medicine, Nishinomiya, Japan), Yasuaki Kawai (Tottori University, Yonago, Japan), Narufumi Suganuma (Kochi University, Nankoku, Japan), Koichi Kusuhara (University of Occupational and Environmental Health, Kitakyushu, Japan), and Takahiko Katoh (Kumamoto University, Kumamoto, Japan). We also thank Kevin Y. Urayama for his valuable comments and editing, as well as James R. Valera for his editorial support.

Funding

The JECS is conducted by Japan’s Ministry of the Environment. The present study was supported by Japan’s Ministry of Education, Culture, Sports, Science and Technology (JP24119004 to SM), RIKEN Healthcare and Medical Data Platform Project to SM, and Japan Society for the Promotion of Science (JP16H01880, JP16K13072 to SM, and JP26870889 to NM). The findings and conclusions of this article are solely the responsibility of the authors and do not represent the official views of the government. The funding sources were not involved in the study design, collection, analysis and interpretation of the data, writing of the manuscript, or the decision to submit it for publication.

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NM and SM initiated the study concept and designed the analysis protocol. NM analyzed the data. NM and CN wrote the paper. KN, KK, MS, ES, MT, MS, TK, SO, and KK contributed critical revisions to the manuscript. All authors read and approved the final manuscript.

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Correspondence to Seiichi Morokuma.

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We used data collected from the Japan Environment and Children’s Study (JECS), a nationwide prospective cohort study of pregnant women, their spouses, and their children in Japan. The Review Board on Epidemiological Studies of the Ministry of the Environment and the ethics committees of all participating institutions approved the JECS protocol. Written informed consent was obtained from all participants. The study was conducted in accordance with the relevant national and institutional guidelines as well as the Declaration of Helsinki.

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Not applicable.

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The authors declare there are no competing interests.

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Morisaki, N., Nagata, C., Morokuma, S. et al. Lack of catch-up in weight gain may intermediate between pregnancies with hyperemesis gravidarum and reduced fetal growth: the Japan Environment and Children’s Study. BMC Pregnancy Childbirth 22, 199 (2022). https://doi.org/10.1186/s12884-022-04542-0

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