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Protective Effect of Hyperemesis Gravidarum for Nonsyndromic Oral Clefts

From the Foundation for the Community Control of Hereditary Diseases, Budapest, Hungary; and the Department of Medicine, School of Medicine, and Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts.

Address reprint requests to: Diego F. Wyszynski, MD, PhD, Boston University School of Medicine, 715 Albany Street, L-320, Boston, MA 02118; E-mail: dfw{at}bu.edu.

	ABSTRACT

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OBJECTIVE: To evaluate whether hyperemesis gravidarum is associated with a decreased risk for nonsyndromic oral clefts and to examine the relationship between hyperemesis gravidarum, birth weight, and gestational age.

METHODS: This was a population-based, matched case–control study of 1950 subjects with oral clefts (1368 with cleft lip with or without cleft palate; 582 with cleft palate) collected from the Hungarian Congenital Abnormality Registry and 1955 controls identified from the National Birth Registry.

RESULTS: Fewer mothers of newborns with oral clefts had early-onset hyperemesis gravidarum than did mothers of controls (cleft lip with or without cleft palate: 83 cases and 121 controls, odds ratio [OR] = 0.67, 95% confidence interval [CI] 0.50, 0.89; cleft palate: 42 cases and 64 controls, OR = 0.63, 95% CI 0.42, 0.94). The use of dimenhydrinate was more common among mothers of subjects with cleft palate (OR = 2.47, 95% CI 1.11, 5.49), whereas iron seemed to have a protective effect against this condition (OR = 0.26, 95% CI 0.09, 0.80). Gestational age and birth weight were not significantly associated with hyperemesis gravidarum.

CONCLUSION: This study suggests that hyperemesis gravidarum provides a protective effect against risk to oral clefts in newborns.

Nausea and vomiting in pregnancy occurs in 60% to 80% of pregnancies. Hyperemesis gravidarum, however, is relatively infrequent, with a prevalence of approximately 5 per 1000 live births.^1,2 Hyperemesis gravidarum has been defined by Fairweather as "nausea and vomiting occurring before 20 weeks’ gestation and sufficiently severe to require the patient’s admission to the hospital. The vomiting should not be associated with coincidental conditions, such as appendicitis or pyelitis."³

Several studies have reported a protective effect of nausea and vomiting in pregnancy in general, and of hyperemesis gravidarum in particular, from selected congenital anomalies. Their results, however, are inconclusive. One theory to support this hypothesis is that women with nausea and vomiting in pregnancy are less likely to have spontaneous abortions.^4–6 Because studies on spontaneous abortions show that many of the fetuses have congenital anomalies, and very frequently oral clefts,^7,8 this "protective effect" might be a consequence of reduced risk for abortion in women with hyperemesis gravidarum. The purpose of the current study is to evaluate whether hyperemesis gravidarum is associated with a decreased risk for nonsyndromic oral clefts, using a large, population-based, case–control study conducted in Hungary between 1980 and 1996. Additionally, the relationship between hyperemesis gravidarum, birth weight, and gestational age were studied, because we have shown that fetuses with oral clefts have growth retardation.⁹

	MATERIALS AND METHODS

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Eligible subjects were newborns with nonsyndromic cleft lip with or without cleft palate or with isolated cleft palate, identified from the records of the nation-based Hungarian Congenital Abnormality Registry data set and who were born between 1980 and 1996.¹⁰ Notification by physicians of subjects with structural birth defects (ie, congenital abnormalities) to the Hungarian Congenital Abnormality Registry was mandatory during that period. Most cases were notified by obstetricians, because in Hungary virtually all deliveries occur in inpatient obstetric clinics, or from pediatricians who were working in the neonatal units of inpatient obstetric clinics and various inpatient and outpatient pediatric clinics. During the study period, autopsy was required for all infant deaths and was often practiced for stillborn fetuses. Pathologists sent a copy of each autopsy report to the Hungarian Congenital Abnormality Registry if any birth defects were identified. The recorded total (birth + fetal) prevalence of subjects with cleft lip with or without cleft palate and isolated cleft palate was 1.01 and 0.35 per 1000 informative offspring (live-born infants and stillborn and malformed fetuses from electively terminated pregnancies), respectively. About 98% of subjects with cleft lip with or without cleft palate and nearly 86% of cases with isolated cleft palate were reported to the Hungarian Congenital Abnormality Registry during the 17 years of the study period.¹⁰ To exclude syndromic forms of oral clefts, the charts of all eligible cases were examined by a clinical geneticist, according to the recommendations of the International Consortium for Oral Clefts Genetics.¹¹

Controls were infants without congenital abnormalities, matched to each case for sex, week of birth, and district of parent’s residence. The source of control ascertainment was the National Birth Registry of the Central Statistical Office. One control per case was selected. If more than one control was available for a case, only one was selected by a random procedure. About 3% of the matched controls had some congenital abnormality, and these infants were excluded from the study (they were eligible for the "patient control" group in the original protocol of the Hungarian Congenital Abnormality Registry.¹⁰ Patient controls were not used in this study).

Data from mothers of subjects and controls were obtained from three sources.¹⁰ First, mothers of subjects and controls were requested to send us their prenatal care logbook, discharge summary of their delivery, and all other medical records concerning their diseases or child’s congenital anomaly. During the study period, antenatal care was mandatory for all women in Hungary, and women had, on average, seven prenatal visits with a licensed obstetrician.¹⁰ In each visit, the obstetricians was required to record all complications and diseases during the pregnancy, as well as related drug prescriptions, in the logbook. Nearly 90% of mothers of subjects and controls sent their logbook and infant discharge summary to the Hungarian Congenital Abnormality Registry. Second, a postage-paid, structured questionnaire with an explanatory letter was sent to the parents of both subjects and controls immediately after their selection. The questionnaire included questions regarding pregnancy complications (including nausea and/or vomiting), acute and chronic maternal disorders, and drug intakes, among others. Completed questionnaires were returned by 74% of mothers of subjects and 69% of mothers of controls, at an average of 1.6 and 3.5 postnatal months, respectively. If a disagreement was found between the information on illnesses in the logbook and that from the mother’s questionnaire, we used the information reported by the obstetrician in the logbook. Third, regional district nurses visited and interviewed nonresponding families of subjects (although the local ethics committee precluded them from visiting families of controls, 200 nonresponding families of controls were visited and interviewed as part of a validation study). In total, information was available for 88% of cases and for 75% of controls. Of 1950 subjects with oral clefts in the study, 176 (9.0%) had no matched controls; thus, a matched control was selected from the 38,151 available controls and on the basis of the matching criteria.

For this study, women who presented with hyperemesis gravidarum were considered exposed. Hyperemesis gravidarum is defined by the International Classification of Disease, 9th Revision as hyperemesis arising during pregnancy, persistent, and vicious, codes 643.0–643.2. This classification distinguishes three types of hyperemesis gravidarum: early hyperemesis gravidarum onset with symptoms resolving by the 20th week of gestation; hyperemesis gravidarum with metabolic disturbance (early onset and metabolic disturbance, such as carbohydrate depletion, dehydration, or electrolyte imbalance); and late hyperemesis gravidarum, with onset after 22 completed weeks’ gestation. These types of exposures were always recorded in the antenatal logbook or in other medical records for both cases and controls. Thus, exposure misclassification was minimal, if any. The occurrence of hyperemesis gravidarum was evaluated according to gestational months. In Hungary, four anti-emetic drugs were used for the treatment of nausea and vomiting in pregnancy in general and of hyperemesis gravidarum in particular: pyridoxine (vitamin B₆), dimenhydrinate (Dramamine, Gravol), thiethylperazine (Torecan), and magnesium. The effects of these drugs and those of pregnancy supplements, such as folic acid, iron, and particularly multivitamins including vitamin B₆, were analyzed separately.

Statistical analyses were carried out with Stata 7.0 software (Stata Corp., College Station, TX).¹² For continuous data, mean values and standard deviations were calculated. For categorical data, odds ratios (OR) and their 95% confidence intervals (CIs) were estimated. For the crude analysis, we used the Mantel-Haenszel test (or Fisher exact test if the number in any cell was less than five). Conditional logistic regression analysis was used to adjust for potential confounders for oral clefts, such as maternal age, birth order, employment status (as indicator of socioeconomic status), pregnancy complications, and acute and maternal disorders.

	RESULTS

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The data set included 1368 live-born infants with cleft lip with or without cleft palate born between 1980 and 1996 and 1374 matched controls. Table 1 shows the distribution of cases by mean maternal and paternal age, birth order, child’s sex, parity, and maternal employment status. As expected, cleft lip with or without cleft palate was more frequent among male babies. There was no statistically significant difference between subjects with cleft lip with or without cleft palate and controls regarding mean maternal and paternal age, multiple birth occurrence, or birth order. Mothers of controls were of higher socioeconomic status, as determined by their employment status (ie, higher proportion of professionals and managers and lower proportion of unskilled workers and homemakers; ²₁ 32.5, P < .001).

The month of hyperemesis gravidarum onset is shown in Table 2. Nearly 70% of the case mothers and 82% of the control mothers who had hyperemesis gravidarum manifested this condition sometime during the first trimester of gestation. The distribution of hyperemesis gravidarum by month indicates that mothers of subjects with cleft lip with or without cleft palate had first symptoms of this condition during the second to fourth month of gestation, whereas mothers of controls had their highest number of new hyperemesis gravidarum episodes between the first and third month of gestation. Onset of hyperemesis gravidarum after the 16th gestational (14th postconceptional) week was sporadic in both groups. The average duration of hyperemesis gravidarum, approximately a month and a half, did not differ between mothers of subjects with cleft lip with or without cleft palate and controls.

A total of 108 women had reported hyperemesis gravidarum: 7.2% of case group mothers (n = 42) and 11.4% of control mothers (n = 66) experienced this condition (unadjusted conditional OR = 0.61, 95% CI 0.41, 0.91). Stratification by level of severity indicated that 106 mothers had early-onset hyperemesis gravidarum (42 cases and 64 controls, OR = 0.63, 95% CI 0.42, 0.94), two had hyperemesis gravidarum with metabolic disturbance (one case and one control), and two had late hyperemesis gravidarum (one case and one control).

Nearly 81% of the case mothers and 79% of the control mothers who had hyperemesis gravidarum manifested this condition sometime during the first trimester of gestation. Onset of hyperemesis gravidarum after the 16th gestational (14th postconceptional) week was sporadic in both groups. The average duration of hyperemesis gravidarum, approximately a month and a half, did not differ between mothers of subjects with isolated cleft palate and controls.

As for cleft lip with or without cleft palate, vitamin B₆ and thiethylperazine were used more than ten times more frequently by women with hyperemesis gravidarum than by those without hyperemesis gravidarum. No difference in frequency of use was found between case and control mothers (Table 3). Use of dimenhydrinate was more common among mothers of subjects (OR = 2.47, 95% CI 1.11, 5.49), whereas iron seemed to have a protective effect against isolated cleft palate (OR = 0.26, 95% CI 0.09, 0.80). Attributable fraction is a measure that reflects the amount of outcome among those exposed that could be reduced if the exposure were eliminated. The attributable fraction for those exposed to dimenhydrinate was 60% (95% CI 2%, 83%) and 31% for the entire population of subjects whose mothers had hyperemesis gravidarum. The attributable fraction for those exposed to iron was 74% (95% CI 6%, 93%) and 49% for the entire population of subjects whose mothers had hyperemesis gravidarum.

Mean birth weight was slightly higher among newborns of mothers with hyperemesis gravidarum, despite similar duration of gestation compared with mothers without hyperemesis gravidarum. As expected, mean birth weight of subjects with isolated cleft palate was lower than controls, although this difference was not statistically significant.

	DISCUSSION

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In this study, we found that hyperemesis gravidarum of early onset during pregnancy is associated with a reduced risk of giving birth to a child with an oral cleft. Because of the limited sample size of women with early hyperemesis gravidarum onset with metabolic disturbance, the effect of this type of hyperemesis gravidarum could not be assessed. An effect for the use of antiemetic medication on risk of cleft lip with or without cleft palate was not observed. Dimenhydrinate was more common among mothers of subjects with isolated cleft palate, and iron had a protective effect against this condition.

In interpreting the study results and discussing the possible reasons for the reported associations, we should consider the study’s potential strengths and limitations. The major strengths of the data set are these: 1) it is population based, 2) it is prospective (maternal diseases and exposures were recorded throughout pregnancy—before mothers and doctors knew the status of the newborns); 3) it is large, including 1368 subjects with isolated cleft lip with or without cleft palate and 582 with isolated cleft palate, 4) response rate was high: 80% in cases and 75% in controls, 5) controls without a congenital abnormality were individually matched to each case, 6) it is from a homogenous ethnic population in Hungary, 7) cases were carefully studied by a medical geneticist to distinguish nonsyndromic from syndromic oral cleft cases (the latter were excluded from the study), 8) nausea and vomiting during pregnancy were recorded by medical professionals, and 9) potential confounding factors were available for analysis.¹³

Limitations of the data set need to be mentioned as well. The prevalence of women with hyperemesis gravidarum was unusually high, approximately ten times higher than published estimates. This could reflect an over-diagnosis of women with "routine" nausea and vomiting in pregnancy. Given that the notification of hyperemesis gravidarum happens before the baby is born, we would expect a potential misclassification to be nondifferential. Unfortunately, information was not available on maternal smoking. A pilot study carried out on a small percentage of cases and controls indicated that the validity of responses regarding cigarette and alcohol use during pregnancy was very low.¹⁴ Additionally, Singer and Brandt¹⁵ showed that hyperemesis gravidarum is rare among smoking women. If this finding applies to our population, the effect of smoking on the relationship between hyperemesis gravidarum and oral clefts would be negligible. Other unmeasured factors, such as differential pregnancy loss, resulting in changes in the prevalence of oral clefts at birth, may have contributed to the association.

The association between hyperemesis gravidarum and oral clefts has not been studied in detail previously. Saxén¹⁶ and Golding et al¹⁷ found no association between maternal nausea and vomiting in pregnancy and risk of cleft lip with or without cleft palate in the newborn. Similarly, Petitti,⁵ Klebanoff and Mills,¹⁸ and Weigel and Weigel⁶ did not find an association between nausea and vomiting in pregnancy and congenital abnormalities. In concordance with the present study, Yerushalmy and Milkovich⁴ reported that women with nausea and vomiting in pregnancy were less likely to bear children with severe congenital abnormalities than were women who did not experience nausea and vomiting in pregnancy, and Ferencz et al¹⁹ and Boneva et al⁷ found that nausea and vomiting in pregnancy was associated with a reduced risk of congenital heart defects. On the other hand, Kullander and Källen²⁰ showed that women who experienced nausea and vomiting in pregnancy were significantly more likely to bear children with severe congenital abnormalities than were women who did not experience nausea and vomiting in pregnancy.

Although the precise cause and pathophysiology of nausea and vomiting in pregnancy and of hyperemesis gravidarum are not well understood, both are known to be associated with higher blood levels of human chorionic gonadotropin (hCG)^21–23 and to the steroid hormones progesterone and estradiol.²⁴ The peak levels of hCG occur at approximately 4–5 gestational weeks (the embryologic period of cleft formation), and they decrease at approximately 12 gestational weeks. Recently, James²⁵ suggested that the racial distribution of newborns with oral clefts is consistent with low levels of gonadotropins and estrogens (because gonadotropins and estrogens are high in black women,^26,27 who have the lowest prevalence at birth of cleft lip with or without cleft palate and isolated cleft palate,²⁸ and low in Asian women,^29,30 who have the highest prevalence at birth of cleft lip with or without cleft palate and isolated cleft palate³¹). Furthermore, Wyszynski et al³² and Wyszynski and Wu³³ found that maternal cigarette smoking is weakly but positively and significantly linked to both types of oral clefting. Cigarette smoking is antiestrogenic³⁴ and is associated with low gonadotropin levels in women.³⁵

Another potential explanation for this association is that nausea and vomiting in pregnancy (and hyperemesis gravidarum) may cause women to avoid foods that pose potential danger to themselves or the embryos.^36–38 These aversions usually develop because of physiologic responses to exposure to specific food items (ie, coffee, alcoholic beverages, meats) and nonfood items (ie, cigarette smoke). In our study, we were unable to test whether women with hyperemesis gravidarum had a lower prevalence of exposure to putative teratogens than did women who did not experience hyperemesis gravidarum.

The finding that a commonly used drug such as dimenhydrinate increases risk to isolated cleft palate is intriguing. Readers should be very cautious in interpreting this finding, because the sample size of exposed women in our data set was small (21 exposed cases and 19 exposed controls). However, because there are no previous studies on the relationship between dimenhydrinate and craniofacial malformations, we believe that further investigation on this serendipitous association is warranted.

We observed that women with hyperemesis gravidarum had longer pregnancies, and their babies were somewhat heavier than those of women who did not experience hyperemesis gravidarum. These differences, however, were not statistically significant. Gestational age and birth weight were measured fairly reliably, so that unlikely errors of measurement are not expected to obfuscate group differences. The concurrence of our results with those of previous studies^6,39–41 gives increased confidence.

Although the current study cannot answer whether hormones are directly and causally involved in oral clefts formation, an association between hyperemesis gravidarum and reduced risk for oral clefting has now been established and will need to be confirmed by an independent source. A better understanding of the underlying mechanisms involved in cleft formation might reveal opportunities for primary prevention of these common birth defects.

	Footnotes

 
DFW was funded by a contract from the Massachusetts Center for Birth Defects Research and Prevention of the Massachusetts Department of Public Health.

The authors thank the participants of the Hungarian Case–Control Surveillance of Congenital Abnormalities for their collaboration and Burton Cusner for his expert assistance in database management.

doi:10.1016/S0029-7844(02)03125-3

Received July 25, 2002. Received in revised form September 17, 2002. Accepted November 7, 2002.

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