Etiology and Pathophysiology

The exact etiology and pathogenesis of NVP are poorly understood and are most likely multifactorial. A number of leading hypotheses have been proposed and continue to be investigated. A few of these commonly acknowledged theories are psychological predisposition, evolutionary adaptation, hormonal stimuli, and Helicobacter pylori infection. Because NVP has a spectrum of symptoms, an assortment of factors probably play different roles in various degrees in each pregnant woman.

Psychological Predisposition
In the past, NVP was thought to be a psychosomatic illness or conversion disorder, whereby women who experienced it could not cope with the various stresses of being pregnant and converted this stress into physical symptoms.[28] Psychoanalytic theorists described pregnancy as a time when a woman is vulnerable to conversion disorders and previous trauma may be manifested as physical symptoms. This theory of NVP as a conversion disorder has been difficult to confirm because earlier studies were confounded by bias and often were not blinded or lacked control subjects. In some case reports, the authors concluded that women experienced NVP due to problematic relationships with their mothers or husbands or due to a lack of femininity. However, in a recent case-control study, women who experienced hyperemesis gravidarum were compared with women with normal pregnancies.[29] Using a scale for conversion disorder, the authors found no significant difference between women with hyperemesis gravidarum and matched controls. An association may exist between NVP and underlying psychological disorders such as depression, anxiety, and hysteria.[16,30] In addition, personality problems such as immaturity and dependency may lead to the use of nausea and vomiting as a maladaptive coping mechanism during pregnancy. Secondary gain has also been suggested to contribute to symptoms as a means to obtain attention and sympathy from family or friends.[31] The significance of psychological factors in the etiology of NVP has been indicated in some women with hyperemesis gravidarum by the disappearance of symptoms on separation from family and frequent relapses on return to the family environment.[32] Psychosocial factors may play an important role in influencing whether a woman experiences only mild NVP or NVP that progresses to more severe symptoms or to hyperemesis gravidarum.[31] Although supportive literature is limited, the psychological influence of NVP has some merit. For example, patients with cancer exposed to one or more chemotherapy cycles may experience nausea or vomiting after simply passing the location where they received treatment, scheduling appointments, or going to the doctor's office. This illustrates that although nausea and vomiting may have a biologic basis, psychological factors may also play a role. To completely exclude the concept that psychological factors play a role in NVP would be unwise; rather, further evaluation is needed to define the intricate relationship between psychological and biologic factors.

Evolutionary Adaptation
The evolutionary adaptation theory proposes that mild degrees of NVP generally do not harm the mother or embryo and therefore may be a beneficial adaptation rather than a disease or disorder. This theory may explain why some women experience a short-term distaste for certain foods during pregnancy. It may also explain why the occurrence of NVP varies among different cultures based on the safety of foods consumed. The authors of one paper proposed that "nausea and vomiting of pregnancy is an intricate mechanism that probably evolved to serve a useful function: protecting the pregnant woman and embryo from food-borne infections and toxins."[33] Another author proposed that pregnant women learn to avoid food-borne teratogens and abortifacients secondary to nausea and vomiting.[34] For example, NVP symptoms peak during the first trimester, when the fetus is most susceptible to potential teratogenic effects of foreign substances. Moreover, foods often avoided are the potentially harmful, toxic foods such as meat, fish, poultry, and eggs, which are more likely than other foods to contain bacteria or fungi.[35] Evidence indicating that women with NVP have more positive pregnancy outcomes provides additional support for evolutionary adaptation.[8-10] However, clinicians should be careful in applying this theory to their patients; believing that NVP is beneficial and natural could lead to under-treatment of symptoms. Whether or not the condition is meant to be adaptive for the mother and fetus, NVP can be distressful for women both personally and professionally.

Hormonal Stimuli
Another theory regarding the etiology of NVP suggests that changing hormone levels, specifically b-human chorionic gonadotropin (b-HCG), estradiol, and progesterone, may cause NVP.[36] The mechanism of hormones in the etiology of NVP remains unknown. Timing is an important factor in support of this theory because the onset and peak of symptoms seem to mirror closely the increase and peak in the levels of these hormones. b-Human Chorionic Gonadotropin. Two observations support the involvement of b-HCG in the etiology of NVP. One is the temporal relationship between the peak in maternal b-HCG levels and the peak of nausea and vomiting. The other is the more severe nausea and vomiting seen in women with conditions such as multiple gestations or molar pregnancy, which tend to involve elevated levels of b-HCG. A review of 17 studies investigating b-HCG and NVP found a relationship in 13 of the studies.[37] The author noted that the failure of some studies to find an association might be secondary to varying biologic activity of different b-HCG isoforms. bHuman chorionic gonadotropin is structurally similar to thyroid-stimulating hormone except for the major difference in its carboxyterminal portion. Isoforms of b-HCG vary; some are more similar to thyroid-stimulating hormone and therefore are thought to be more thyrotrophic.[38] Of 10 studies investigating thyroid hormones and NVP, eight demonstrated an association between transient biochemical hyperthyroidism and NVP.[37] Hyperthyroidism itself does not usually cause nausea and vomiting, and b-HCG is the

thyroid stimulator of pregnancy; thus, b-HCG rather than thyroid-stimulating hormone is thought to be responsible for this noted association between transient hyperthyroidism and NVP.[39] The exact role of b-HCG in the etiology of NVP remains controversial. Elevated levels of b-HCG probably are involved in the development of NVP but solely do not predict which women will be affected or the severity of their symptoms. Estradiol. Estrogens, specifically estradiol, have also been implicated in influencing NVP. One group of authors demonstrated that women with hyperemesis gravidarum had statistically significant elevated levels of estradiol in the first trimester compared with controls.[14] Lower estradiol levels are associated with cigarette smoking and, of interest, smokers are less likely to experience hyperemesis gravidarum.[40] Exogenous estrogens also have induced nausea and vomiting when given to some nonpregnant patients. For example, some women who take oral contraceptives and experience nausea and vomiting are at increased risk for developing nausea and vomiting when pregnant.[3] Elevated estradiol levels during pregnancy probably play a role in the development of NVP but are not responsible for, or predictive of, the severity of nausea and vomiting symptoms or the development of hyperemesis gravidarum. Progesterone. The hormonal changes of pregnancy may disrupt gastrointestinal neuromuscular function, resulting in nausea and vomiting. Progesterone decreases smooth muscle contractility and may also cause gastric dysrhythmias or delayed emptying.[14] In one study, electrogastrograms of 32 pregnant women with nausea and vomiting indicated that 26 of the women had gastric dysrhythmias, including bradygastrias or tachygastrias.[41] These findings were confirmed by a placebo-controlled trial in which non-pregnant women received estrogen and progesterone in levels equal to those of women during the first trimester of pregnancy.[42]The authors found that the nonpregnant women experienced slow-wave dysrhythmias seen in pregnant women with nausea and vomiting. Both of these preliminary studies support the hypothesis that progesterone and/or estrogen at elevated levels during pregnancy might disrupt normal gastric myoelectric rhythms and contribute to the etiology of NVP.

Helicobacter pylori Infection

Helicobacter pylori infection has been associated with episodes of NVP and hyperemesis gravidarum. A prospective study published in 1998 compared 105 women who had hyperemesis gravidarum with 129 asymptomatic controls.[43] Results indicated a 2-fold increase in serum antibodies to H. pylori in women with hyperemesis gravidarum. A prospective, casecontrol study published in 2002 evaluated 47 women with hyperemesis gravidarum and 39 pregnant, asymptomatic controls at similar gestation.[44] In contrast to the 1998 study, the authors found that although most women with hyperemesis were serologically positive for H. pylori, no correlation was noted between positive serology and duration of symptoms. In a case report describing two women with hyperemesis gravidarum treated with erythromycin for unrelated conditions, both patients demonstrated marked improvement of hyperemesis

symptoms after treatment.[45]Although erythromycin is administered to treat H. pylori infection, it is also a prokinetic agent that has independently improved nausea and vomiting due to delayed gastric emptying.[46] More data are needed to understand the possible role of H. pylori in the etiology of NVP. Given the diversity of proposed hypotheses and lack of definitive evidence for each, one can understand why the pathophysiology of NVP is generally described as complex or unknown. Because the symptoms of pregnant women vary widely, from no nausea or vomiting to frequent episodes, to hyperemesis gravidarum requiring hospitalization, a single etiology for these symptoms is not likely. Hormones, psychological predisposition, psychological changes, evolutionary adaptation, and possible H. pylori infection may all contribute to some degree to the development of NVP.