Hyperemesis gravidarum occurs in approximately 0.3–2.0% of pregnancies1–6 and can be responsible for increased health care use,7,8 hospitalization,2,7,8 time lost from work,1,7,9 and reduced quality of life7 during pregnancy. Because hyperemesis is often associated with nutritional deficiencies,10 maternal weight loss,5 and fluid and electrolyte imbalances,10 concerns about possible adverse perinatal outcomes are raised.3
Results of studies to date that have investigated the relationship between hyperemesis and perinatal outcomes are somewhat conflicting. The majority of studies have not found hyperemesis to be a risk factor for preterm delivery,3,4,11–14 and some have even reported a reduced risk of preterm delivery in pregnancies complicated by hyperemesis.15,16 Lower birth weight has been reported by some,12,13,17 but not all,1,3,4,11,14–16 studies of hyperemesis. It does not appear that hyperemesis is associated with low 5-minute Apgar scores.3,11 Pregnancies complicated by hyperemesis may be characterized by reduced pregnancy weight gain,11,12,14 possibly indicating more severe manifestation of the condition.13 Although usually purported to have a protective effect on fetal death,14,16 there are also studies that did not find any association between hyperemesis and fetal death.3,4 This study explores the relationship between hyperemesis and pregnancy outcomes in a large, population-based cohort over a 15-year period.
MATERIALS AND METHODS
This was a population-based retrospective cohort study of all singleton deliveries at 20 weeks or more of gestation and weighing 500 g or more in Nova Scotia, Canada, between 1988 and 2002. Clinical and other information for this study was obtained from the Nova Scotia Atlee Perinatal Database. The database collects information on medical conditions, lifestyle factors, labor and delivery events, and neonatal outcomes. Trained health records personnel abstract data, after delivery, from standardized clinical forms and hospital records. Ongoing data quality assurance programs and validation studies show that the information in the database is reliable.18,19 We defined hyperemetic pregnancies as those with one or more antepartum admissions for hyperemesis, the first of which had to have occurred before 24 completed weeks of gestation.
We studied the relationship between hyperemesis and the following outcomes: maternal delivery weight less than 80 kg (176.4 lb), pregnancy weight gain less than 7 kg (15.4 lb), gestational diabetes, pregnancy-induced hypertension, perinatal death, Apgar score less than 7 at 5 minutes, low birth weight (defined as less than 2,500 g), small for gestational age (SGA, defined as the bottom 10th percentile for weight according to week of gestation and gender), preterm delivery (defined as birth before 37 weeks of gestation), cesarean delivery, and labor induction. Additionally, we attempted to assess the impact of the severity of hyperemesis on each outcome using 2 approaches: stratifying hyperemetic pregnancies into those with 1 or 2 admissions compared to those with 3 or more admissions and stratifying by maternal pregnancy weight gain (< 7 kg [15.4 lb] versus ≥ 7 kg). Low weight gain in this study was defined as a gain of less than 7 kg (15.4 lb), which corresponds to the lowest recommended weight gain for pregnant women, based on a guideline from the National Academy of Sciences for optimal pregnancy weight gain according to prepregnancy body mass index.20 Perinatal death was not analyzed by the severity indicators because of small number of cases.
Logistic regression analysis was used to generate odds ratios for all outcomes. Observations for women who had more than one delivery during the study period are potentially not independent (eg, an outcome in a woman may be more or less likely to occur because of her outcome from a previous delivery). To adjust for this nonindependence, the variance estimates were calculated using general estimating equations. When observations are not independent, general estimating equations have the effect of increasing the variance estimates, and therefore, widening the confidence intervals. Because the prevalence of most outcomes in the study population exceeded 10%, we applied the method described by Zhang and Yu21 to convert odds ratios to relative risks. Unadjusted relative risks (RR) and 95% confidence intervals (CI) were calculated for all outcomes. We then used a backward stepwise approach to identify potential confounders of the relationship between hyperemesis and each outcome. Potential confounding factors for hyperemesis were subsequently entered into a model with each outcome and with hyperemesis as the principal independent variable of interest. Potential confounders included maternal age, time period, maternal prepregnancy weight, maternal smoking, parity, pre-existing diabetes, depression, psychiatric disorder, ulcer or other gastrointestinal disorder, asthma or other respiratory disease, previous molar pregnancy, previous pregnancy with a fetal death, and fetal gender. We began by removing the risk factor with the highest P value and evaluated the degree of change in the point estimate for hyperemesis. If removing the factor did not change the point estimate by 5% or more, the factor was left out and the process repeated. All analyses were conducted with SAS 8.2 software (SAS Institute Inc, Cary, NC). Institutional ethics approval was received before commencing data analysis.
Of the 156,091 antenatal singleton deliveries between 1988 and 2002 in Nova Scotia, there were 1,270 women with an admission for hyperemesis. Figure 1 presents the natural history of hyperemesis in a subgroup of women who were known to be nulliparous at their first recorded delivery in the database. The rate of hyperemesis in the first pregnancy was 0.9%. Among women who went on to have a second pregnancy, the rate of hyperemesis in the second pregnancy was 19% if the first pregnancy was complicated by hyperemesis, compared with 0.7% among women who were not hyperemetic in their first pregnancy.
Table 1 shows the distribution of demographic variables between women with and those without an admission for hyperemesis. Table 2 shows the adjusted relative risks for each of the outcomes overall for women with an antepartum admission for hyperemesis and stratified by number of admissions. After controlling for maternal prepregnancy weight and maternal smoking status, the rate of low pregnancy weight gain (< 7 kg [15.4 lb]) was 2.1 times higher among pregnancies with hyperemesis (95% CI 1.8–2.5). Among women with 3 or more admissions, the adjusted RR for low pregnancy weight gain was 4.2 (95% CI 2.6–6.1). We did not observe a relationship between hyperemesis and gestational diabetes, pregnancy-induced hypertension, low 5-minute Apgar score, or perinatal death. Infants from pregnancies complicated by hyperemesis were more likely to be of low birth weight, although the effect size was modest (adjusted RR 1.3, 95% CI 1.0–1.7). Among women with 3 or more admissions, the adjusted RR associated with low birth weight was 2.5 (95% CI 1.3–4.6). The rate of preterm delivery was slightly higher among pregnancies with hyperemesis (RR 1.2, 95% CI 1.0–1.5). The rate of cesarean delivery was slightly higher among women with hyperemesis, but was not increased among women with 3 or more admissions. A woman was 30% more likely to have labor induction if her pregnancy was complicated by hyperemesis (95% CI 1.2–1.4).
Table 3 shows the results according to weight gain (≥ 7 kg [15.4 lb] and < 7 kg) during pregnancy. Even among women with more severe hyperemesis, there was no significant association with gestational diabetes or gestational hypertension. The risk of having a 5-minute Apgar score less than 7 was increased among women with hyperemesis who had a weight gain during pregnancy of less than 7 kg (RR 5.0, 95% CI 2.6–9.6). The risks of having a low birth weight infant, an infant small for gestational age, or a preterm delivery were higher in women with hyperemesis and who had weight gain less than 7 kg than in women without hyperemesis. Conversely, there was no difference in the rates of low birth weight, SGA, or preterm delivery among women with hyperemesis and weight gain of 7 kg or more compared with women without hyperemesis.
The analyses were also run contrasting women with hyperemesis and low weight gain with women with no hyperemesis and low weight gain (data not shown). Compared with women with no hyperemesis and with low weight gain (the referent group), women with hyperemesis and low weight gain did not have a significantly increased risk of low birth weight (RR 1.3, 95% CI 0.8–2.0), SGA (RR 1.1, 95% CI 0.7–1.5), or preterm birth (RR 1.4, 95% CI 0.9–2.1). Women with hyperemesis and low weight gain did have significantly increased risk of a low Apgar score, compared with women without hyperemesis and low weight gain (RR 3.1, 95% CI 1.5–6.5).
The definition of hyperemesis used in this study was similar to that proposed by Fairweather22 (nausea and vomiting occurring before 20 weeks of gestation sufficiently severe to require hospital admission), except that we used admission before 24 weeks of gestation for our definition. Hyperemesis resulting in hospitalization is relatively uncommon in Nova Scotia and Canada (about 1%). Although having one affected pregnancy increases the likelihood of the next pregnancy requiring hospitalization for hyperemesis, over 80% of these women did not require hospitalization for hyperemesis in the subsequent pregnancy. Because women with severe hyperemesis might avoid subsequent pregnancy, our data on the recurrence of hyperemesis may be an underestimate. Of primary concern among women with hyperemesis are maternal and fetal outcomes.
Hyperemesis can occur in varying degrees of severity, and previous studies have attempted to consider severity of disease in relation to outcomes. Some measures of severity have included the number of hospital admissions,12 low weight gain during pregnancy,13 and biochemical imbalances.4,11 We evaluated pregnancy outcomes in relation to 2 indicators of severity: number of admissions for hyperemesis and low weight gain associated with hyperemesis. Women with hyperemesis had more than a 2-fold higher risk of having pregnancy weight gain of less than 7 kg (15.4 lb) compared with women without hyperemesis. In our study population, hyperemesis during pregnancy appears to be associated with adverse neonatal outcomes when it is associated with maternal weight gain of less than 7 kg. We found increased risks for each of the neonatal outcomes that were examined (eg, 5-minute Apgar score < 7, low birth weight, SGA, and preterm birth) among the subgroup with hyperemesis and low weight gain. Additionally, the excess risk (the difference in the absolute rates) was 4.4%, 8.3%, 4.6%, and 9.0% for the factors Apgar score less than 7, low birth weight, SGA, and preterm birth, respectively. There was no evidence of increased risk in any of these outcomes among women with hyperemesis but with weight gain of 7 kg or more. When analyzing the neonatal outcomes with respect to the number of admissions (1–2 versus 3 or more antepartum admissions), the only outcome associated with number of admissions was the risk of low birth weight. Hospital admission for hyperemesis has decreased during the study period, consistent with a move toward more conditions being treated on an outpatient basis. Surprisingly, it does not appear that hospitalization in the later years of the study was restricted to the more severe cases of hyperemesis because the decline in the rate of hospitalization for hyperemesis was similar for women with and those without low pregnancy weight gain.
Thus, it appears from our data, that hyperemesis itself is not a risk factor for most of the adverse neonatal outcomes evaluated in this study but that the outcomes are a consequence of the low weight gain associated with the condition. This finding was confirmed in a subanalysis, in which we compared the outcomes among women with low weight gain and hyperemesis with the outcomes for women without hyperemesis but low weight gain. With the exception of Apgar score, the group with hyperemesis and low weight gain did not have significantly increased risks (compared with women with low weight gain but no hyperemesis). It is unknown why hyperemesis would increase the risk for a low Apgar score above the risk conferred with low weight gain. Among the previous studies reporting on outcomes among women with hyperemesis, the findings have been inconsistent, which may be due to the different definitions of severity that were used. Among the few studies that have looked at outcomes according to a measure of severity that incorporated weight gain, results have found higher rates of low birth weight and higher rates of small for gestational age.13,17 Godsey and Newman12 found increased rates of low birth weight among women with more than one admission for hyperemesis and suggested that this was because these women had reduced pregnancy weight gain. A significant association between hyperemesis, irrespective of severity, and gestational age was noted by Paauw et al23 but was likely due to the fact that gestational age was analyzed as a continuous variable. In their study, the mean gestational age was over 38 weeks of gestation in women with and those without hyperemesis.23 Studies that used biochemical parameters (eg, hematocrit > 43%, ketonuria + 3) as a measure of severity have not observed increased rates of low birth weight or SGA among women with severe hyperemesis.4,11
We were unable to evaluate the outcomes of women who were on total parenteral nutrition (TPN) because the database does not include this information. If low weight gain is the primary reason for the poorer outcomes seen in women with hyperemesis, then there is a potential benefit of TPN in these patients. Although some studies have reported improved outcomes associated with TPN for severe hyperemesis,24 a recent study found a high rate of complications directly attributable to TPN (25% for line-related sepsis and 3% for line-related thrombosis).25 Therefore, the benefits of TPN will need to be weighed against the potential complications related to TPN.
The comparisons made in this study were between women with an admission for hyperemesis and all other pregnant women, including those with complications during pregnancy. If we had restricted the comparison group to women with an uncomplicated pregnancy, we would likely have observed higher risk estimates for some outcomes among the hyperemesis group.
The rate of preterm birth was 3 times higher among women with hyperemesis whose weight gain was less than 7 kg (15.4 lb) than it was for women who did not have hyperemesis, whereas women with hyperemesis but with weight gain of 7 kg or more had similar rates of preterm birth compared with women without hyperemesis. The induction rates were found to be higher among women with hyperemesis, but we were unable to determine the indication for the induction in a large proportion of the cases. Among the subgroup of women with hyperemesis and low weight gain, 55% of the preterm births were spontaneous and 45% were medically indicated. This is in contrast to the proportion of preterm births for women without hyperemesis (65% spontaneous and 35% medically indicated preterm births). Among women with hyperemesis and weight gain of 7 kg or more, the ratio of spontaneous and medically indicated preterm births was similar to that in women with hyperemesis and low weight gain (ie, 49% of the preterm births were medically indicated).
A limitation of this study is that the perinatal database does not include information on medications that were used for hyperemesis, so we were unable to distinguish whether the observed outcomes are a possible effect of low weight gain or an effect of medication. In Nova Scotia, most women with hyperemesis are prescribed Diclectin (Duchesnay Inc, Laval, Quebec, Canada), which is identical to Bendictin (Merrell Dow Pharmaceuticals, Inc, Cincinnati, OH). There have been concerns about teratogenicity related to Bendictin, but for the most part, these studies have not supported an association with birth defects or stillbirths.5,26–28
The perinatal database contains information on infants of 500 g and more. Therefore, we were unable to look at the association between hyperemesis and early pregnancy loss. Hyperemesis gravidarum has been shown to be a protective factor for spontaneous early pregnancy loss, possibly reflective of the elevated level of free β-hCG.4,14,29
The power of this study was limited for rare outcomes such as perinatal death. Compounding this limitation is that fact that weight gain information was missing for approximately 17% of the cohort. As a result, there were very few perinatal deaths among women with hyperemesis who had weight gain information.
The results of this study suggest that the adverse infant outcomes associated with hyperemesis are a consequence of the poor maternal weight gain. Whether or not the neonatal outcomes would be improved if weight gain were not compromised among women with severe hyperemesis remains to be answered.
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