Nausea and vomiting are common experiences in pregnancy, affecting 70% to 80% of all pregnant women. Various metabolic and neuromuscular factors have been implicated in the pathogenesis of nausea and vomiting of pregnancy (NVP) and hyperemesis gravidarum (HG), an entity distinct from NVP. However, their exact cause is unknown. Consequently, treatment of NVP and HG can be difficult, as neither the optimal targets for treatment nor the full effects of potential treatments on the developing fetus are known. This article reviews the epidemiology, pathology, diagnosis, outcomes, and treatment of NVP and HG.
Nausea and vomiting are common experiences in pregnancy, affecting 70% to 80% of all pregnant women. Although most women with nausea and vomiting of pregnancy (NVP) have symptoms limited to the first trimester, a small percentage have a prolonged course with symptoms extending until delivery. Women with severe nausea and vomiting during pregnancy may have hyperemesis gravidarum (HG), an entity distinct from NVP, which if left untreated may lead to significant maternal and fetal morbidity.
Various metabolic and neuromuscular factors have been implicated in the pathogenesis of NVP and HG; however, their exact cause is unknown. Consequently, treatment of NVP and HG can be difficult, as neither the optimal targets for treatment nor the full effects of potential treatments on the developing fetus are known. This article reviews the epidemiology, pathology, diagnosis, outcomes, and treatment of NVP and HG.
It is estimated that 70% to 80% of pregnant women experience NVP. In the United States and Canada this translates to approximately 4 million and 350,000 women who are affected each year, respectively.
NVP is found more often in Western countries and urban populations, and is rare among Africans, Native Americans, Eskimos, and most Asian populations. Only a few studies have examined the racial distribution of NVP in a given population with conflicting results. One such study from Canada of 367 women found that Asians and blacks were less likely to report symptoms of NVP than Caucasians. Sociodemographic factors did not account for the racial/ethnic variation in disease prevalence, suggesting that genetic and/or cultural factors may be at play. However, in a study from the United States, 89% of 2407 pregnant women reported symptoms of NVP. Prevalence of NVP was highest in non-Hispanic black and Hispanic women.
HG is rare in comparison with NVP, occurring in 0.3% to 2% of all pregnancies. The incidence appears to vary with ethnicity and ranges between 3 and 20 per 1000 pregnancies.
Data from the Collaborative Perinatal Project, one of the largest studies to date of pregnant women, found NVP to be more common in younger women, primigravidas, women with less than 12 years of education, nonsmokers, and obese women. Increased risk of NVP in the first trimester has also been reported in women with multiple gestation as compared with women with singleton pregnancies (87% vs 73%, P <.01).
NVP has been associated with low income levels and part-time employment status. Housewives have also been found to be at increased risk, whereas women with white collar occupations appear to be protected. Whether employment status is a true risk factor for NVP or a confounder, however, remains unclear, as affected women may cease employment because of their symptoms. Similarly, their decision to not work outside the home may be attributable to multiparity and the need to care for other children.
Maternal genetics also appear to serve as risk factors for NVP. Data from a large Norwegian twin population show higher use of nausea medication in pregnancy among female monozygotic twins compared with female dizygotic twins. In addition, higher levels of nausea have been found in women who had mothers who experienced trouble with nausea in their pregnancy. A personal history of NVP has also been shown to be a risk factor for NVP in subsequent pregnancies ; however, this finding has not been consistent across studies.
Other risk factors for NVP include a personal history of motion sickness, due possibly to a common vestibular mechanism, and history of migraine headaches. Women who have a history of nausea when taking estrogen-containing oral contraceptives also appear to be at an increased risk for NVP.
Location of the corpus luteum may also serve as risk factor for NVP. Ultrasound studies have shown that pregnant women experience more nausea and vomiting when the corpus luteum is present in the right ovary. This condition may be caused by differences in venous drainage between the left and right ovary and a higher concentration of sex steroids when the corpus luteum is on the right side.
A higher daily intake of total fat, especially saturated fat, prior to pregnancy increases the risk of hospitalization for NVP. Smoking before pregnancy and vitamin use before and/or in early pregnancy are associated with a decreased risk for NVP. Maternal alcohol consumption prior to conception has also been found to be protective for NVP.
Risk factors for HG are similar to those of NVP and include nulliparity, multiple gestations, trophoblastic disease, HG in prior pregnancy, fetal abnormalities such as triploidy, trisomy 21, and hydrops fetalis. Family history of HG is also a risk factor, with approximately 28% of women reporting a history of HG in their mothers and 19% reporting that their sisters had similar symptoms. Additional risk factors include married or partnered status and age older than 30 years. Cigarette smoking, as in NVP, may be protective.
Maternal body mass index has been evaluated as a risk factor for HG, with inconclusive results. In a study by Depue and colleagues, obesity increased the risk for HG by 50%. Work by Cedergren and colleagues, however, found that a low body mass index (<20 kg/m 2 ) was associated with a 40% higher risk of HG and that obesity decreased the risk of hospitalization for HG. A more recent study of 33,647 women in Norway found that being either underweight or overweight increased the risk for HG, but only in nonsmokers. It is postulated that underweight women with low body mass indices have low prepregnant estrogen levels and thus may have an exaggerated response during the first trimester when estrogen levels surge. By contrast, in obese women fat deposits may neutralize placental factors thought to contribute to the pathogenesis of HG.
With regard to fetal gender, an association between HG and female gender of the fetus has been found in several studies. Using data from the Swedish Medical Birth Registry, Kallen found HG to be overrepresented in 3068 pregnancies when the infant was a girl. Similarly, in a study of pregnant women hospitalized with HG in the first trimester, the odds of having a female infant were 50% higher in cases than in healthy pregnant controls (odds ratio 1.5, 95% confidence interval [CI] 1.4–1.7).
Metabolic and Hormonal Factors
Although the exact pathogenesis of NVP and HG are unknown, it is widely accepted that gestational vomiting results from various metabolic and endocrine factors, many of placental origin. The most implicated factor is human chorionic gonadotropin (hCG). This link between hCG and NVP is based largely on the temporal relationship between the peak of NVP and the peak of hCG production, both of which occur between 12 and 14 weeks’ gestation. In addition, nausea and vomiting are often worse in pregnant women with conditions associated with elevated hCG levels, such as molar pregnancies, multiple gestations, and Down syndrome. Higher urinary hCG and serum hCG levels have also been found in women with NVP compared with those who are asymptomatic. Furthermore, a study by Goodwin and colleagues found that concentrations of hCG correlated positively with the severity of nausea and vomiting in women with HG.
Despite the multitude of studies linking hCG to NVP and HG, others have found no relationship between serum hCG in pregnant women during the first trimester and the frequency or intensity of nausea and vomiting. In a study by Soules and colleagues, even in a subset of women with molar pregnancies in whom levels of hCG in women were 5 to 10 times higher than in controls, no correlation was found. Furthermore, studies have found high levels of hCG to be associated with fetal growth retardation and preterm delivery whereas NVP appears to be protective for preterm delivery, making it unlikely for hCG to be the sole contributor to the pathogenesis of NVP.
It is postulated that varying biologic forms (ie, isoforms) of hCG may explain the variability between hCG levels and nausea and vomiting in normal and sick populations. Each hCG isoform has a unique half-life and potency at the luteinizing hormone (LH) and thyroid-stimulating hormone (TSH) receptor. Isoforms without the carboxy-terminal portion have shorter half-lives but more are more powerful stimulants of both the LH and TSH receptors. Different isoforms of hCG are likely the result of genetic factors or long-term environmental changes and may explain the differences in HG prevalence found among populations. In addition to isoform variation, hCG receptor mutations may also explain some of the variability in the relationship between NVP and hCG.
The ovarian hormones, estrogen and progesterone have also been implicated in the pathogenesis of NVP and HG. It is known that some women experience nausea when taking oral contraceptives. Furthermore, states of high estrogen concentration such as low parity and high maternal body mass index have been associated with a higher incidence of HG. Estrogen is thought to contribute to HG by stimulating the production of nitric oxide via nitric oxide synthetase, which in turn relaxes smooth muscle, slowing gastrointestinal transit time and gastric emptying.
Jordan and colleagues reported a significant association between hyperemesis gravidarum and a history of intolerance to oral contraceptives. Using a more quantitative approach, Depue and colleagues found mean levels of total estradiol to be 26% higher and mean levels of sex hormone binding–globulin binding capacity to be 37% higher in patients with HG than in control subjects after adjusting for gestational age. It is important to bear in mind, however, that like the relationship between hCG and NVP, the relationship between estrogen levels and NVP has been inconsistent across studies. A review of 17 studies showed a positive association between NVP and estrogen in only 5 studies. Furthermore, estrogen levels peak in the third trimester of pregnancy, whereas HG tends to improve during late pregnancy.
Progesterone in combination with estrogen may also have a role in NVP. Progesterone decreases smooth muscle contractility, and may alter gastric emptying and lead to increased nausea and vomiting. Using elastogastrography after a standard meal, Walsh and colleagues showed that the same slow-wave gastric rhythm disruption found in women with NVP could be evoked in nonpregnant women by progesterone alone or in combination with estradiol in doses that reproduce levels in pregnancy. Other studies, however, have not found any significant difference between progesterone levels in women with or without NVP.
The role of placental prostaglandin E 2 (PGE 2 ) has also been evaluated in the pathogenesis of NVP, due to its effect on gastric smooth muscle. hCG stimulates placental PGE 2 , and like hCG peaks between 9 and 12 weeks of gestation. North and colleagues quantified maternal serum PGE 2 , and found levels to be higher during periods of nausea and vomiting in 18 women in early pregnancy than during asymptomatic periods. These investigators also evaluated maternal levels of interleukin-1β and tumor necrosis factor α (TNF-α) levels, and found both to be similar during symptomatic and asymptomatic periods.
Because of its role in chemotherapy-induced nausea and vomiting, serotonin has also been hypothesized to contribute to NVP. A study by Borgeat and colleagues, however, did not show any difference in serotonin levels among pregnant women with HG, asymptomatic pregnant women, and nonpregnant women. In addition, a randomized controlled trial comparing the serotonin 5-HT 3 receptor antagonist, ondansteron, with promethazine found no significant difference in symptom control.
Due to the cross-reactivity between hCG and the TSH receptor, thyroid dysfunction has also been studied as a possible mechanism for NVP and HG development. In fact, abnormal results of thyroid function are found in two-thirds of women with HG. This “biochemical thyrotoxicosis” is characterized by suppressed TSH and slightly elevated free T4. Despite these laboratory abnormalities, women with HG are generally euthyroid with no history of prior thyroid diseases, absent goiter, and negative antithyroid antibodies. Furthermore, studies have not found a relationship between thyroid dysfunction and the severity of symptoms, and almost all women with HG have normal TSH levels by 20 weeks’ gestation without any intervention.
Recently, a relationship between the hormone leptin and HG has been proposed. Increased serum leptin levels during pregnancy, possibly the result of increased total fat mass and the placenta production, have been found to be significantly higher in patients with HG when compared with healthy pregnant controls. Leptin may contribute to HG by increasing hCG secretion by the paracrine action of the placenta or by decreasing appetite and promoting more severe nausea and vomiting. It is noteworthy, however, that prospective cohort studies have not found a statistically significant difference in serum leptin levels in HG between cases and controls.
Immune system dysregulation has also been proposed to occur in women with HG. Increased concentrations of fetal cell free DNA have been found in mothers’ serum, causing a hyperactive maternal immune response and trophoblast damage. Furthermore, the normal shift in pregnancy wherein T-helper cell types move into T-helper cell type 1 is more exaggerated in women with HG. This in turn leads to increased release of interleukin-4 as well as TNF-α, both of which have been linked to HG. Adenosine, which attenuates TNF-α, has also been found to be increased in HG. Likewise, Il-6, IgG, IgM, complement levels, and lymphocyte counts have been found to be increased in HG. One cannot precisely define the role of these immunologic factors, however, because in starvation states the immune system is usually suppressed, not activated; thus, perhaps the boost in immune factors seen in HG could be an attempt to limit the progression of HG.
Other hormones including TSH, growth hormone, prolactin, adrenocortical-stimulating hormone, cortisol, LH, and follicle-stimulating hormone have also been evaluated, and are not considered to contribute to the pathogenesis of NVP.
An increased incidence of infection with Helicobacter pylori has been observed in women with HG and is now considered to play a role in its pathogenesis. Frigo and colleagues found that 90.5% of women with HG were H pylori IgG positive, compared with 46.5% of controls. Bagis and colleagues used the gold standard test, histologic examination of the mucosal biopsy, and found that 95% of HG patients tested positive for H pylori compared with 50% of controls. These investigators also found higher H pylori densities in the gastric antrum and corpus in HG patients, suggesting a possible relationship between H pylori density and the severity of symptoms.
A systematic review from 2007 evaluating 14 case-control trials from 1966 to 2007 found a significant association between maternal H pylori infection and HG in 10 studies. Odds ratios in the studies varied from 0.55 to 109.33. Similarly, an updated systematic review and meta-analysis from 2009 of 25 studies found a pooled odds ratio of 3.32 (95% CI: 2.25–4.90) for H pylori infection in women with HG. Of note, high heterogeneity among studies was found in both reviews.
Infection with H pylori in pregnancy may occur because of steroid hormone–induced changes in gastric pH and/or increased susceptibility due to changes in humoral and cell-mediated immunity. However, there is no clear evidence that pregnancy predisposes to de novo H pylori infection. On the contrary, it has been suggested that H pylori may exacerbate hormone-induced changes in the nerve and electric functioning of the stomach, and thereby increase the risk for infected women to be at the more severe end of the spectrum of nausea and vomiting.
Although the association between H pylori and HG is intriguing, it is important to note that infection does not necessarily correlate with symptoms. In fact, most infected women are asymptomatic. In a study by Weyermann and colleagues, 23% of 898 postpartum mothers were positive for H pylori by 13 C-urea breath test; however, positivity did not correlate with symptoms of nausea, vomiting, or reflux symptoms during pregnancy. Similarly, Wu and colleagues found 69% of pregnant women to be seropositive for H pylori compared with 50% in the general population; however, they did not find any correlation between antibody status and gastrointestinal symptoms.
Why H pylori cannot be precisely linked to NVP and HG has been attributed to several factors. First, most studies used antibody testing to assess for infection. However, serologic testing for H pylori cannot distinguish between active infection and past infection, and active versus past infection may produce different effects on symptoms. Second, most studies have not assessed and/or accounted for the H pylori strain. Cytotoxin-associated gene A (CagA) protein is a marker for increased peptic ulcers and is linked to a more aggressive strain of H pylori . Only a single study included in the 2009 meta-analysis assessed for CagA pathogenicity. In this study by Xia and colleagues, CagA positivity was more prevalent in patients with HG.
Treatment eradicates H pylori in the majority of patients; however, currently there are no guidelines for the evaluation or treatment of H pylori during pregnancy, as the subsequent alleviation of symptoms of HG has not been widely studied. Case reports and cases series suggest that treatment and eradication of H pylori can decrease nausea and vomiting in pregnancy and should be considered in patients with intractable symptoms. Larger studies, however, are needed to determine if and when treatment should be initiated during pregnancy given the concerns of drug safety. At present, experts recommend that after pregnancy and lactation have been completed, patients should be treated with triple therapy for 2 weeks.
Alterations in lower esophageal sphincter (LES) resting pressure and esophageal peristalsis have been linked to NVP. Although these changes are more typically associated with heartburn in pregnancy, gastroesophageal reflux disease (GERD) may produce atypical symptoms such as nausea, and contribute to NVP. Estrogen and progesterone are the likely mediators of esophageal dysmotility in pregnancy, wherein estrogen serves as a primer and progesterone causes LES relaxation.
Changes in gastric rhythmic activity may also contribute to NVP. Normal gastric myoelectric activity results in slow-wave propagation from the proximal body to the distal antrum at a rate of 3 cycles per minute (cpm). Rhythm disturbance, either increased or decreased slow-wave propagation, is associated with nausea. Using elastogastrography (EGG), Koch and colleagues demonstrated that individuals with normal slow-wave activity were less likely to complain of nausea during pregnancy. By contrast, individuals with higher or lower rates were more likely to complain of nausea. Similarly, Riezzo and colleagues found that pregnant women without symptoms of nausea and vomiting at the time of EGG recordings have normal 3-cpm myoelectrical activity. They also found that pregnant women with NVP had more unstable EGG activity compared with women after voluntary abortions and nonpregnant controls. Riezzo and colleagues speculated that this may be due to restoration of the normal gastric slow-wave pattern after abortion following normalization of estradiol and progesterone levels.
However, it is noteworthy that many studies have found no difference in gastric motility between pregnant and nonpregnant women. Using gastric scintigraphy, no significant differences in the liquid emptying rate were found in pregnant women before voluntary abortion, 6 weeks after abortion, and in nonpregnant control women. Using dye dilution methods with phenol red, Davison and colleagues found gastric emptying to be delayed in women during labor but not in the third trimester, as compared with nonpregnant controls. Similarly, studies using paracetamol showed no gastric emptying delay in the first, second, or third trimester.
Alterations in gastric motility in pregnancy have been attributed to high levels of progesterone. Moreover, in late pregnancy, compression from an enlarged uterus may contribute to symptoms.
Meal composition may also serve a pathogenic role in NVP. Jednak and colleagues demonstrated that protein-dominant meals were associated with decreased symptoms and corrected slow-wave dysrhythmias. Carbohydrate or fat-dominant meals had no effect on symptoms or slow-wave dysrhythmias.
Finally, small bowel transit time has been evaluated with regard to NVP pathogenesis. Using the lactulose hydrogen breath test, an indirect measure of small bowel transit time, Lawson and colleagues found transit times to be prolonged in the second and third trimester compared with the first trimester, with the longest times found when progesterone levels were highest. Wald and colleagues used similar techniques, and found transit time to be prolonged in the third trimester when progesterone and estrogen levels were high in comparison to the postpartum period. However, in both of these studies, delayed intestinal transit times did not correlate with NVP.
Early studies proposed that NVP may be a psychosomatic illness in which vomiting represents intrapsychic conflicts. Some have speculated that NVP is a manifestation of a pregnant woman’s subconscious attempt to reject an unwanted pregnancy, as studies have found that women with NVP in the first trimester are more likely to have unplanned or undesired pregnancies.
HG has also been associated with psychological disturbances, namely neurotic tendencies, hysteria, rejection of femininity, and rejection of pregnancy, as well as depression and psychological stress related to poverty and marital conflicts. Recent studies, however, have not found definite psychogenic causes of HG. Some investigators, therefore, argue that sociocultural factors rather than scientific evidence have led to the labeling of HG as a psychologically based condition and that it is more likely that psychological disturbances such as depression are the result rather than the cause of HG.
Thus although NVP and HG are likely not the result of a conversion disorder or other psychological disorder, it is well recognized that affected women have psychological responses that become intertwined with, and possibly exacerbate, their physical symptoms.