This study demonstrates a remarkably high risk of more severe morning sickness and HG among relatives of HG cases as approximately one-third of cases reported an affected mother and/or sister. The odds ratio is highest (OR=17) when comparing the proportion of affected sisters of cases to the proportion of affected sisters of controls using the most stringent definition of HG, rather than grouping HG and more severe morning sickness.
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 grandmothers, 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. Other reports 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 [26
The pedigree presented in this study, the fact that mothers and sisters are commonly affected, and the similar frequency of maternal and paternal grandmothers affected, suggest that, HG may be inherited in an autosomal dominant manner with incomplete penetrance, although other modes of inheritance in some families cannot be ruled out. Regardless of the mode of inheritance, this is the first case:control study of familial aggregation for hyperemesis gravidarum and in addition to previous studies showing higher concordance for nausea and vomiting in monozygotic vs. dizygotic twins [16
] and a high prevalence of HG among family members of affected individuals [26
] provides strong 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 and 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 gain [7
], 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 [28
]. 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
]. While smoking during pregnancy was recently reported to decrease the risk of hyperemesis, smoking by the partner was reported to increase the risk [4
]. 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 [30
]. Finally, evidence for a paternal and fetal contribution was 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 [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 case-control 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 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 to misclassify disease status of affected family members as they are given definitions to classify disease in family members and are required themselves to have been treated with iv therapy for severe nausea and vomiting.
Finally, the control group (friends of cases) was not perfectly matched for several characteristics. The controls were significantly older and had more living children than the cases which is likely due to the fact that while cases were eligible with only one pregnancy affected with HG, controls had to have completed at least one pregnancy and 2 trimesters of a second pregnancy without experiencing HG. The fact that controls on the whole were slightly older should not have any affect on the affected status of family members and sisters, in particular, because the number of pregnant and therefore informative sisters was similar for cases and controls. Cases were also more likely to be currently pregnant which is likely due to the fact that some cases searched the internet when they were diagnosed with HG and found the study information at that time. Again, we cannot think of a reason that this would bias the results. However, the cases were not well matched for race and this was of particular concern as genetic factors can be linked to race. We addressed this issue by repeating the analysis with the race that represented the majority for cases and controls (whites) and the results were very similar, suggesting that the differences in race do not affect the results of this study.
Because the incidence of hyperemesis gravidarum is most commonly reported to be 0.5% in the population and the sisters of cases have as much as an 18-fold increased familial risk for HG compared to controls, this study provides strong evidence for a genetic component to extreme nausea and vomiting of pregnancy. In summary, this study demonstrates that maternal genetic susceptibility plays a role in the development of severe nausea and vomiting 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.