Objective
This study was undertaken to determine whether there is familial aggregation of hyperemesis gravidarum (HG), making it a disease amenable to genetic study.
Study Design
Cases with severe nausea and vomiting in a singleton pregnancy treated with intravenous hydration and unaffected friend controls completed a survey regarding family history.
Results
Sisters of women with HG have a significantly increased risk of having HG themselves (odds ratio, 17.3; P = .005). Cases have a significantly increased risk of having a mother with severe nausea and vomiting; 33% of cases reported an affected mother compared to 7.7% of controls ( P < .0001). Cases reported a similar frequency of affected second-degree maternal and paternal relatives (18% maternal lineage, 23% paternal lineage).
Conclusion
There is familial aggregation of HG. This study provides strong evidence for a genetic component to HG. Identification of the predisposing gene(s) may determine the cause of this poorly understood disease of pregnancy.
Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy (NVP), hospitalizes >59,000 pregnant women in the United States annually, with most authors reporting an incidence of 0.5%. Estimates of severe NVP vary greatly and range from 0.3% in a Swedish registry to as high as 10.8% in a Chinese registry of pregnant women. Recent large population studies support ethnic variation in the incidence of HG. A Norwegian study of the medical birth registry of Norway from 1967 through 2005 defined HG as persistent NVP associated with ketosis and weight loss >5% of prepregnancy weight, and revealed an overall prevalence of 0.9%, but when broken down by ethnicity, found HG in 2.2% of 3927 Pakistani women and 1.9% of 1997 Turkish women, both more than twice the incidence of 0.9% in 798,311 Norwegian women. A study of California birth and death certificates >20 weeks’ gestation linked to neonatal hospital discharge data in 1999 with the primary diagnosis of hyperemesis found an incidence of 0.5% (2466 cases of 520,739 births), and women with HG were reportedly significantly less likely to be white or Hispanic compared to nonwhites or non-Hispanics. A Canadian study found HG in 1270 (0.8%) of 156,091 of women with singleton deliveries from 1988 through 2002. This rate was confirmed in a second Canadian study during the same time frame of the population-based Nova Scotia Atlee Perinatal Database of deliveries at 20 weeks’ gestation, which found HG in 1301 (0.8%) of 157,922 pregnancies. Asian populations tend to have higher incidence rates. For example, a Malaysian study identified 192 recorded cases (3.9%) of 4937 maternities. Additionally, a study of 3350 singleton deliveries in an Eastern Asian population observed HG in 119 (3.6%) of the population. As mentioned, a study of 1867 singleton live births revealed the highest rate of severe NVP in Shanghai, China, from 1986 through 1987, with an incidence of 10.8%. However, unlike the other studies mentioned, this study was based on a clinical record of severe vomiting on prenatal care cards, rather than hospitalization for HG; did not limit itself to a primary diagnosis of HG; and included, for example, women with chronic liver disease, chronic hypertension, chronic renal illness, and preeclampsia. HG is the most common cause of hospitalization in the first half of pregnancy and is second only to preterm labor for pregnancy overall. HG can be associated with serious maternal and fetal morbidity such as Wernicke encephalopathy, fetal growth restriction, and even maternal and fetal death.
A biologic component to the condition has been suggested from animal studies. Anorexia of early pregnancy has been observed in various mammals including monkeys. In dogs, anorexia can be accompanied by vomiting and can be severe enough to require pregnancy termination. Several lines of evidence support a genetic predisposition to NVP. Firstly, in the only study of NVP in twins, concordance rates were more than twice as high for monozygotic compared to dizygotic twins. Secondly, several investigators have noted that siblings and mothers of patients affected with NVP and HG are more likely to be affected than siblings and mothers of unaffected individuals. Thirdly, the higher frequency of severe NVP in patients with certain genetically determined conditions such as defects in taste sensation, glycoprotein hormone receptor defects, or latent disorders in fatty acid transport or mitochondrial oxidation, suggests that some portion of HG cases may be related to discrete, genetically transmitted disease states that are unmasked or exacerbated in pregnancy. Finally, in a previous survey administered by the Hyperemesis Education and Research Foundation, approximately 28% of cases reported their mother had severe NVP or HG while pregnant with them. Of the 721 sisters with a pregnancy history, 137 (19%) had HG. Among the most severe cases, those requiring total parenteral nutrition (TPN) or nasogastric (NG) feeding tube, the proportion of affected sisters was even higher, 49 of 198 (25%). Nine percent of cases reported having at least 2 affected relatives including sister(s), mother, grandmother(s), daughter(s), aunt(s), and cousin(s). There is a high prevalence of severe NVP/HG among relatives of HG cases in this study population. Overall, these data suggest that genetic predisposition may play a role in the development of NVP. However, to our knowledge, a case-control study of familial aggregation of severe NVP and HG has never been done. The goal herein is to determine whether there is familial aggregation of severe NVP and HG in a case-control setting.
Materials and Methods
Recruitment
The University of Southern California–Los Angeles and the University of California–Los Angeles are currently conducting a study of the genetics and epidemiology of HG, and >650 participants have been recruited, primarily through advertising on the Hyperemesis Education and Research Foundation World Wide Web site at www.HelpHer.org . The inclusion criteria for cases are a diagnosis of HG and treatment with intravenous (IV) fluids and/or TPN/NG feeding tube. Participants are asked to: (1) submit their medical records; (2) provide a saliva sample; and (3) complete an online survey regarding family history, treatment, and outcomes. Each case is asked to recruit a friend with at least 2 pregnancies that went >27 weeks to participate as a control. Controls are eligible if they experience normal (did not interfere with their daily routine) or no NVP, no weight loss due to NVP, and no medical attention in their pregnancy due to nausea. Eligibility questions for cases and controls are attached in the Appendix .
Survey
Participants were asked to report on the severity of NVP of their family members according to the following definitions:
- 1
No nausea and vomiting : never felt nauseated and never vomited in this pregnancy.
- 2
Very little nausea and vomiting : felt nauseated and/or vomited for a total of 1-7 days during this pregnancy.
- 3
Typical nausea and vomiting : may have nausea and/or vomiting in this pregnancy but (all of the following must be true): (1) did not lose weight from nausea/vomiting; and (2) was able to sustain normal daily routine most days with little change in productivity due to nausea/vomiting most of the time; and (3) no need to consult health professional for medical treatment due to nausea and vomiting.
- 4
More severe morning sickness : (1) persistent nausea and vomiting that interfered with normal daily routine in this pregnancy but did not require IV hydration or TPN due to persistent nausea/vomiting; (2) may have consulted a medical professional to treat nausea and vomiting; and (3) may have lost a few pounds or 1 kg.
- 5
HG : persistent nausea and vomiting with weight loss that interfered significantly with daily routine, and led to need for: (1) IV hydration or nutritional therapy (feeding IV [TPN] or by tube [NG] through the nose); and/or (2) prescription medications to prevent weight loss and/or nausea/vomiting.
- 6
Other or unsure: please describe in text box at end of section.
The survey used for this study can be found at: http://www.helpher.org/HER-Research/2007-Genetics/ .
Statistical methods
Characteristics were summarized for both the case group and the control group, and compared between the 2 groups. For the characteristics race and current pregnancy, the χ 2 test was used to compare the difference between the 2 groups. For the characteristics age, pregnancy losses, number of living children, and voluntary termination, Wilcoxon rank sum test was used to compare the 2 groups.
The familial aggregation of HG was examined by modeling the probability of having ≥1 sister with HG using the logistic regression method. The status whether a participant was a case or a control was assumed to affect the probability of having ≥1 affected sister through a logit fashion, in this way the effect of being a case on having at least 1 affected sister can be expressed in odds ratio (OR). If we use Y to denote the status whether a participant had ≥1 sister with HG, ie, Y = 1 if a participant has ≥1 affected sister, and Y = 0 otherwise, then the probability that a participant had ≥1 affected sister <SPAN role=presentation tabIndex=0 id=MathJax-Element-1-Frame class=MathJax style="POSITION: relative" data-mathml='Pr(Y=1)’>Pr(Y=1)Pr(Y=1)
Pr ( Y = 1 )
was modeled as follows:
Pr ( Y = 1 ) = exp ( β 0 + β 1 X ) exp ( β 0 + β 1 X ) + 1
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