This study demonstrates a remarkably high prevalence of HG among relatives of HG cases. The prevalence is higher among sisters of cases that require more aggressive treatments, suggesting affected familial prevalence increases with the severity of nausea and vomiting of pregnancy. Although we realize that shared environmental risk factors can also contribute to the observed high prevalence of affected family members, to our knowledge no such factors have been identified. In addition, although sisters commonly have a similar in-utero and childhood environment, it is unlikely that they share the same environment during their own pregnancy, when HG occurs. This study also suggests mothers and daughters commonly share severe nausea of pregnancy and it is unlikely that this can be entirely explained by shared cross-generational environmental factors. Reports in this study of half-siblings reared in separate states and identical twins pregnant and diagnosed with HG while residing in different countries, although anecdotal, lend further support to a role for genetics. The pedigrees presented in this study, the fact that mothers and sisters are commonly affected, and the relatively equal numbers of maternal and paternal secondary relatives affected, suggest that, HG may be inherited in an autosomal dominant manner with incomplete penetrance, although other modes of inheritance in some families can not be ruled out. Regardless of the mode of inheritance, this is the first report to show a high prevalence of affected family members for hyperemesis gravidarum, and along with a previous study showing higher concordance for nausea and vomiting in monozygotic vs. dizygotic twins16
provides support for a genetic contribution to severe nausea and vomiting of pregnancy.
HG often leads to extreme weight loss and may result in a state of nutrient deprivation, malnutrition, and starvation for both the mother and the developing fetus. Fetal outcome remains controversial. Some studies suggest infants exposed to HG in utero
are significantly more likely to be born earlier, weigh less, be small for gestational age, and die between 24–30 weeks gestation than infants not so exposed.6
Other studies show that these associated outcomes are only significant in cases with hyperemesis and low pregnancy weight gain7
, and that, if treated early, severe nausea may be associated with a protective effect against major malformations.26
While few long-term studies of HG offspring have been conducted, there is a body of literature on starvation in pregnancy in humans and animals, providing convincing evidence that nutritional deprivation in utero
, can have lasting or lifelong significance.27
These data, along with the evidence of a familial component to HG, suggest that healthcare providers should be vigilant in identifying and treating women with a family history of HG.
While our data implicate a strong maternal genetic component, other observations suggest that additional risk factors may influence severity of NVP. An increased incidence of HG has been reported with multiple gestations, gestational trophoblastic disease, fetal chromosomal abnormalities and central nervous system malformations, and for mothers of female offspring.8,28
While smoking during pregnancy was recently reported to decrease the risk of hyperemesis, smoking by the partner was reported to increase the risk.4,8
Other than second-hand smoke, to our knowledge, no environmental factors have been identified that increase risk. Non-genetic maternal factors such as advanced maternal age have been associated with decreased risk, and adolescent pregnancy with increased risk for HG.29,30
Finally, evidence for a paternal and fetal contribution are controversial. While one study suggested that HG recurrence decreases with a change in partner, suggesting paternal genes expressed in the fetus may play a role, this conclusion was recently refuted by a separate study.31,32
Additionally, a consanguinity study also found no increased risk of HG, suggesting recessive fetal genes may not be involved in HG risk.5
A major strength of this study stems from the collaboration with the HER Foundation, which allowed collection of family history information on a large sample of women affected by HG. To date, most studies of hyperemesis gravidarum have been small case series or population studies relying on hospital databases with no information on family history. Thus this study is the first report of its kind.
Admittedly, this study has some methodological concerns. One potential limitation arises from the use of an internet-based survey. While internet-based research is quickly becoming scientifically recognized as a reliable recruiting tool, the study population consists only of cases with internet-access, and thus may represent women of higher education and income. We feel, however, that the generalizability of our study results should be reasonably good since we have no reason to suspect that education level and income would affect the likelihood of having a family history of HG.
Another limitation is that both proband HG status and family history of HG were based on self-reports, which can lead to misclassification of disease status and/or family history. However, we believe it would be highly unlikely for women in the most severe subgroup that required TPN or NG tube to misclassify their disease status and that of affected family members, and the results in this group were even stronger (25% sisters affected) than the participants as a whole (19% sisters affected).
Finally, the Internet-based survey on the HER Foundation website selected for participation only women self-reporting HG, without recruiting a control group. Thus, this study relies on comparing the reported incidence of family history to previous published reports. Because the incidence of hyperemesis gravidarum is most commonly reported to be 0.5%, this study provides strong but preliminary evidence for a genetic component to extreme nausea and vomiting of pregnancy. Future studies using a control group are warranted to determine the true familial relative risk of HG.
In summary, this study provides strong, but preliminary, evidence that maternal genetic susceptibility plays a role in the development of severe nausea and vomiting of pregnancy. This report is meant to serve as preliminary evidence of a familial component to HG and to focus needed attention on this incapacitating condition of pregnancy. Future work should focus on reproducing these results in other populations and on the identification of genetic variants that may contribute to HG susceptibility. Identification of genetic factors will elucidate the biology of nausea and vomiting in pregnancy and allow novel therapeutics to be developed to treat the cause of the disease rather than the symptoms.