This observational cohort study showed that symptoms of nausea, vomiting or poor appetite during pregnancy were associated with adverse birth outcomes. Overall, symptoms experienced any time during pregnancy was significantly associated with a 20% increased risk of LBW and a 16% increased risk of SGA. Symptoms during the second trimester were significantly associated with all the outcomes and showed a 17% increased risk of LBW, a 16% increased risk of SGA and a 25% reduced risk of preterm birth. In the third trimester, symptoms were significantly associated with a 20% increased risk for LBW and a 14% increased risk for SGA. Symptoms during the first trimester were not significantly associated with any of the outcomes.
Previous literature lacks consensus about whether nausea or vomiting in pregnancy increases the risk of LBW. Studies in low-income countries have generally been in agreement with our results. (8) Some studies from middle-to-high-income settings have not reported positive associations. (4, 7, 9, 27) This suggests that it might be the combination of symptoms and setting (e.g. maternal malnutrition) that leads to adverse birth outcomes, rather than the symptoms themselves. The conflicting results may also be due to differences in classification of exposure.
The finding that symptoms in the first trimester are not associated with adverse birth outcomes suggests that symptoms during later trimesters in pregnancy may be more severe in terms of its adverse effects on the fetus. This has not been shown in the previous literature. A previous study showed an association between nausea and vomiting in late pregnancy and lower birth weights in the infant and lower weight gain in the mother, and that the effect on birth weight was even more significant when the weight gain was poor in the mother. (35) Additionally, women with hyperemesis gravidarum more often have persisting symptoms throughout pregnancy, and hyperemesis gravidarum has in turn been associated with adverse birth outcomes. (16, 21) This agrees with our study findings that nausea, vomiting or poor appetite experienced in mid to late pregnancy have higher relative risks of adverse birth outcomes than earlier in pregnancy. It also raises the question of whether our findings could reflect an additive effect of symptoms across all trimesters since women with symptoms in the second and third trimester might be more likely to have experienced symptoms in the earlier trimesters as well. One study showed that severe early pregnancy vomiting was associated with vomiting in the third trimester, and that this had a greater impact on maternal nutritional intake and infant birthweight. (31) Another study showed an increased risk of SGA in women who had hyperemesis gravidarum during pregnancy, but studies on the effects of milder symptoms have shown either a protective effect of nausea and vomiting of pregnancy or no difference. (4, 29, 30) Of note, these studies all took place in high-income countries. On the other hand, studies in high-income settings have showed a significantly increased risk of LBW and SGA in women with hyperemesis gravidarum. (16, 29)
There was a lower adjusted relative risk of preterm birth among women with nausea, vomiting or poor appetite in the second trimester compared to symptom free women when one of the covariates adjusted for was number of visits per woman. We included number of visits as a covariate given that some women may have had fewer visits because they had a preterm birth. With fewer visits, the chance of capturing the experience of symptoms during pregnancy would also have decreased. Equivocal results around preterm birth have been observed in previous studies. However, no studies to date have examined the effect of nausea, vomiting or poor appetite during pregnancy on preterm birth in a low-income, rural setting as in this study. (4, 23, 25, 28, 29)
The present study showed a cumulative incidence of nausea, vomiting or poor appetite of 60.6% during the first trimester, which is on the lower end of what has been previously reported. (1, 5) Previous literature has shown that nausea and vomiting during pregnancy is less likely to be reported among Asian and African populations as compared to Caucasian populations and the cumulative incidence in the current study agrees with previously reported numbers from Bangladesh and Tanzania. (2, 8, 13) On the other hand, hyperemesis gravidarum has been shown to be more commonly diagnosed among women of Asian ethnicities as compared with Caucasians, which may contribute to why the present study showed positive associations between nausea, vomiting or poor appetite and adverse birth outcomes in the light of other studies having failed to do so. (21, 22)
Strengths of the study include detailed population-based data on obstetric history, pregnancy morbidity and infant birth characteristics in a large number of mother-infant pairs. The prospective nature of the data ensured that temporality was not an issue and minimized the risk of recall bias. Since the women were interviewed monthly, we ensured that the recall time was relatively short for both the date of last menstrual period and reported symptoms.
Limitations include that while nausea and vomiting is most common during the first trimester, relatively few women were enrolled in the first trimester (22.6%) due to the enrollment protocol. Therefore, for most women we only had information from the second and third trimesters. Nausea and vomiting of pregnancy peaks during the first trimester and is uncommon after 22 weeks gestation. (7, 9, 10) However, given that we were able to analyze the data by trimester, we do not perceive this as a major problem unless there were some confounders that might have been associated with both first trimester enrollment and the exposure. Also, because few women enrolled in the first trimester we were unable to calculate weight gain during pregnancy or pre-pregnancy body mass index (BMI). Weight gain and BMI can affect both the development of nausea, vomiting and poor appetite as well as birth outcomes. Obesity has been shown to increase the risk of nausea and vomiting during pregnancy and has also been associated with the risk of adverse birth outcomes. (36-38) Additionally, inadequate weight gain during pregnancy has been linked to adverse birth outcomes including LBW, SGA and preterm birth. (12, 24) Nausea and vomiting, in particular severe vomiting such as in hyperemesis gravidarum, has been linked to inadequate weight gain and potentially even weight loss. (12, 13, 16, 17, 25) If we had information on weight at the start of pregnancy, we might also have been able to detect weight loss and, with that, potentially detect hyperemesis gravidarum in the enrolled women. Future studies should attempt to design data collection so that it allows for pre-pregnancy or early first trimester BMI and weight to be collected. We also did not collect data on severity of symptoms during pregnancy. Other studies have shown a difference in the effect of mild symptoms of nausea vs. more severe symptoms of repeated vomiting in the form of hyperemesis gravidarum. (4, 29, 31) For example, severe nausea and vomiting (defined as not being able to retain meals) has been associated with reduced food intake to a higher degree than milder symptoms. (39) In addition, another study showed that vomiting associated with lower birthweight as opposed to nausea alone if symptoms were experienced in the first trimester. (15) While we had number of days in the past 30 days where each symptom was present, the time at risk for exposure by trimester or total pregnancy was variable, depending on when they enrolled and length of pregnancy. In addition, the number of days of symptoms was not differentiated by when in the past 30 days these had occurred and whether the symptoms overlapped in time or were experienced at distinct time periods. Therefore we were unable to isolate symptoms and examine duration of exposure more precisely. We attempted to examine the severity of symptoms by using seeking medical attention for symptoms as a proxy for severity, but given that only 5.3% (N=95) of exposed women sought medical attention for the symptoms, we determined that numbers were too low to include in the analysis. Another limitation was the inability to distinguish between nausea, vomiting or poor appetite due to pregnancy vs. other causes. Nausea, vomiting and poor appetite during pregnancy may have variable etiologies that may need to be considered and grouping the symptoms together may have further complicated this issue. (7, 10) It may have been useful to collect symptom patterns in terms of onset (few women start having symptoms after 9 weeks) and temporal patterns (nausea and vomiting of pregnancy may be more persistent and continuous across weeks and persistent throughout the day) or, as other studies have done, separate women who reported nausea and vomiting in association with fever or diarrhea. (14, 18) Sample size might also have been an issue when estimating the effect size of nausea, vomiting or poor appetite during pregnancy by trimester as fewer women reported symptoms in the second and third trimester.
Despite these limitations, the results suggest nausea, vomiting or poor appetite during pregnancy in this limited resource setting have a significant impact on birth outcomes, particularly in the second and third trimesters. These symptoms are often considered to be normal in pregnancy given that they are so common and generally self-limiting, but the effects of such symptoms in settings where resources and access to health care are limited need to be examined. (28, 39-41) Several studies have shown that women with nausea and vomiting of pregnancy tend to change their diet during pregnancy and steer away from certain foods. (14, 17) Limited resources may affect the woman’s ability to adjust her diet accordingly. These results challenge the notion that nausea and vomiting are harmless symptoms of pregnancy, which can be used to raise awareness among pregnant women and health care workers in these settings. Of note, limited resource settings are not confined to rural areas of developing countries, which is where this study took place. Attention should be given as well to these issues in urban parts of developing countries and potentially in certain areas of higher income countries, which may be highly affected by poverty and health disparities as well.
While the evidence for efficacy is currently limited, there are several accepted treatments for nausea and vomiting that are considered safe in pregnancy. These include pre-conception vitamin supplementation, dietary changes, pharmacologic treatment with antiemetics or vitamin B6, and intravenous fluid replacement. (42) In addition, studies have shown that treatment of early symptoms may prevent later complications. (14, 17, 42) In terms of pharmacologic treatment, several medications are considered safe and effective. These include vitamin B6 supplementation with or without doxylamine, which is considered first line pharmacologic treatment in the United States, and dopamine antagonists such as metoclopramide. (43, 44) While some of these interventions may not be suitable for low resource settings, nutritional support, pre-conception vitamin supplementation, and oral rehydration therapy could be considered relatively inexpensive interventions in terms of reducing the impact of nausea and vomiting in these settings. Micronutrient deficiencies and limited access to adequate nutrition is a significant concern in developing countries. Given this, targeted interventions in low resource settings may have an even greater benefit on reducing the impact of nausea, vomiting and poor appetite in pregnancy, including reducing the impact of milder symptoms that would not have been medically treated in a high income setting.