Summary of Data on Hyperemesis Gravidarum

by Frederic Paik Schoenberg

The Birthkit, Spring, 2000, p4,8.

Hyperemesis gravidarum (HG), or severe nausea and vomiting during pregnancy, is a serious disorder occurring in roughly 1 percent of pregnancies. An important question to the patient with HG is: how likely is it for HG to recur in subsequent pregnancies? I recently set out to read every medical journal I could get my hands on, in an effort to try to find data to address this question. What follows is a summary of interesting things I found out about HG along the way. The most striking thing is how little data there is on HG. After extensive searching I could find only one longitudinal study on women with HG, and it was a small study with few subjects based in Scotland in 1956.⁷ There are scores of articles on the efficacy of drug treatments, however.

1. Definition of Hyperemesis Gravidarum (HG)

There is some variation here. A typical example is "severe vomiting in early pregnancy that causes 5% weight loss and ketonuria . . . usually associated with increased hCG concentration."¹⁰ Another example is "vomiting that appears before the 20th week of pregnancy, is severe enough to require admission to the hospital and is unassociated with coincidental conditions. The vomiting is typically intractable and leads to evidence of disturbed nutrition, altered electrolyte balance or dehydration."⁹

2. Occurrence

NVP (Nausea and vomiting during pregnancy) affects about 70-80 percent of pregnant women. Some reports range from 50-90 percent, but most are in the 70-80 percent range.^{2, 3,8,13,15,19,21,22} In 20 percent of NVP cases, these symptoms persist throughout pregnancy.³ Incidence of HG seems to be about 0.8 percent or 0.9 percent, though estimates vary from 0.3 percent to 2 percent.^{1,3,4,6,7,11,14,19}

3. Recurrence

From results of surveys of women with HG, one can find a variety of statistics that appear at first glance to shed light on the question of the recurrence rate. For example, about 40 percent of patients with HG are in their first pregnancy, and about 45 percent of women with HG who have been pregnant once before were treated in the hospital for HG in their prior pregnancy.^{6, 7}

A moment's reflection reveals that the above statistics are of little value to the sufferer of HG who may be wondering what her chances are of getting HG again in a later pregnancy. The only data that is directly relevant to the recurrence rate of HG is longitudinal (i.e. data obtained by following up on patients over many years).

Unfortunately, it appears that only one such longitudinal study has been done on HG, and the study was very small and is now potentially out-of-date. The study, done by J. Fitzgerald from 1938 to 1953, examined just a few dozen women based in Aberdeen, Scotland.⁷ Nevertheless the Fitzgerald study is still cited by many authors. It is important to realize that, while numerous articles state that HG in a prior pregnancy is a risk factor for HG in a subsequent pregnancy (e.g. ^{3, 6, 11}), by and large the only evidence upon which this claim is based comes from the Fitzgerald study.

Here is a summary of Fitzgerald's recurrence data. Fitzgerald followed 159 women who had HG in their first pregnancy. Fifty-six of these women then had another pregnancy that was recorded by Fitzgerald, and nineteen women had two subsequent pregnancies recorded by Fitzgerald.

• 27 of the 56 women had HG in their second pregnancy.

• 7 of 19 women had HG in their third pregnancy.

4. Impact

Surprisingly, NVP and HG do not seem to have an adverse effect on the fetus. There is no significant difference in infants’ gestational weight or birth weight.^{6, 13, 15, 16} There is no increase in proportion of stillbirth, miscarriage or spontaneous abortion.^{2, 3, 13, 15, 16, 18, 23} In fact there is a significant decreased risk in fetal loss among women with NVP or HG versus women who do not vomit during pregnancy (4.9 percent instead of 8.6 percent).^{2, 3} However, the results are a little mixed; some studies have found that when women with very severe HG are considered separately, they have a slightly lower birth weight and gestational weight.^{9, 11}

There are a host of studies to see if certain complications are related to HG. Many report no significantly increased risk.³ Some report a "statistically significant" increased risk of this or that, but in practical terms the risk does not seem to go up much. For instance, the risk of congenital malformation increases among HG pregnancies from 5 percent to 5.8 percent.^{3, 14} Further, many of the complications that do arise may be the result of poor treatment for HG, especially in cases where fluid and electrolyte imbalances are not readily corrected.^{3, 9}

5. Symptoms

HG has been linked to a variety of symptoms including dehydration, ketosis, ptyalism (excessive salivation), high thyroxine, low pyridoxine, high serum transaminase, hyperthyroidism, hyperparathyroidism, altered lipid metabolism, liver dysfunction, rising pulse rate, falling blood pressure, dry and furry tongue, loss of skin elasticity, chronic hypovolemia, and jaundice.^{1, 3, 11} Symptoms typically occur during the first trimester of pregnancy, usually beginning between the fourth and tenth weeks of gestation, peaking between the eighth and twelfth week, and resolving by the twentieth week.^{1, 3, 6, 11}

6. Psychology

The links between psychological characteristics and HG appear to be wildly exaggerated in medical research. The evidence to substantiate any claims of psychological "risk factors" for HG is extremely weak at best, and in the case of many traits virtually nonexistent. Nevertheless, some authors claim that "unquestionably" there is a link to psychological factors such as "infantile and immature personality," "hysteria," "strong maternal dependence," "protest reaction against pregnancy," "poor communication with husband," and "stress and doubts about pregnancy." ^{6, 11} Often studies that purport such relationships admit there is a severe lack of data to support these findings.^{3, 11, 19} Studies on psychological components of HG "have been scarce, uncontrolled, or, when controlled, have covered series that are too small to provide valid tests." ¹¹

It is thus inexplicable why so many researchers have appeared to embrace the existence of these psychological components. Such speculation may encourage doctors and others to view HG as essentially a psychosomatic condition, which is a disturbing prospect. One recent HG patient told me she received little sympathy from either her employer or her doctor, who said that her condition was "mainly from the neck up."

Certain studies have rejected outright any major psychological component to HG and have convincingly backed up their reasoning with data.^{5, 16} For example, "It has been suggested that pregnancy vomiting is psychosomatic in origin and represents subconscious oral rejection of the fetus. If this were so it would seem likely that the condition should be commoner in single than in married women, since single women will generally have greater reasons for rejecting pregnancy.... symptoms were actually somewhat less common in single than in married women, and although the difference is not statistically significant ... there is certainly no evidence to support the psychosomatic hypothesis." ⁵

By all accounts it is important for a doctor to provide reassurance. "The obstetrician should offer the patient emotional support and reassure her about the generally excellent prognosis." ¹¹

While the relation between most psychological factors and HG appears to be unfounded, there is some case-study evidence suggesting that dietary behavior may play a role. A risk factor for HG seems to be an "unsuitable diet, with large and infrequent meals." ¹²

7. Treatments

In the 18th century, HG was thought to be caused by a "fullness of the vessels of the uterus" and was treated by "bleeding."¹¹ Today the standard and vastly successful treatment is immediate correction of fluid and electrolyte deficits and of acidosis and alkalosis. ^{3, 11, 21,25} Associated conditions of multiple gestations and hydatidiform mole should be ruled out. ³ Before dehydration is corrected and vomiting subsides, nothing should be given by mouth.^{3, 11} Then small, frequent feedings, gradually advancing from liquids to solids, can be attempted as tolerated.³ "Time-honored, conservative treatment with small carbohydrate meals and avoidance of greasy foods is useful." ¹¹ If the patient has had prolonged hyperemesis, parenteral vitamins should be administered, especially vitamins B6, C and K.^{3, 11, 17, 20, 26}

The safety of anti-emetic drugs is questionable, especially during the first ten weeks of pregnancy.³ Usually these are given only when necessary, and then at small doses one at a time, until one is found which is effective enough that liquid feedings may resume. ³ "Drug therapy, as such, is unimportant and the main therapeutic concern should be the correction of fluid, electrolyte and acid base imbalances."⁶ "Drugs should be used during pregnancy only when absolutely necessary." ³ The overall incidence of major malformations in the general population is between 1 percent and 3 percent, and drug exposure accounts for a similar percentage of birth defects.³ Vitamin B6 seems to be the safest anti-emetic, but its efficacy is rather limited. ^{3, 24}

The Food and Drug Administration (FDA) classifies certain drugs for use during pregnancy with safety ratings of A, B, C, D, or X. A means well-controlled studies show no fetal risk. B means animal studies show no risk but human studies are inadequate, or animal studies show some risk but the risk is not supported by human studies. C means animal studies show risk but human studies are lacking, or there are no studies in humans or animals. D means definite fetal abnormalities in human studies, but potential benefits may outweigh risks. X means risks outweigh potential benefits. Here are the FDA ratings for some drugs. ^{3, 11, 19}

Pyridoxine (Vitamin B6) A

Doxylamine (Unisom) B

Cyclizine (Merezine) B

Meclizine (Antivert) B

Dimenhydrinate (Dramamine) B

Diphenhydramine (Benadryl) B

Metoclopramide (Reglan) B

Scopolamine C

Promethazine (Phenergan) C

Prochlorperazine (Compazine) C

Chlorpromazine (Thorazine) C

Trimethobenzamide (Tigan) C

Cisapride (Propulsid) C

Droperidol (Inapsine) C

Ondansetron (Zofran) C

Corticosteroids C

Hydroxyzine (Atarax) C

8. Summary

It is clear that Hyperemesis Gravidarum (HG) is a condition requiring much further study. The best estimate of the recurrence rate of HG (around 40-50 percent) is based solely on Fitzgerald's study of a few dozen Scottish women in the 1950s. Further longitudinal data is required in order to obtain a more accurate estimate. Psychological risk factors are unsubstantiated and occasionally contra-indicated yet are often discussed. While drug treatments have received much attention, none have been found which are safe and effective. On the other hand, there is some good news: treatments involving correction of fluid and electrolyte deficiencies appear to be safe and highly effective; patients receiving such treatment have an excellent prognosis with no significant increased risk of fetal loss or major complications.

References:

1. Abell, T. and Riely, C. (1992). Hyperemesis gravidarum. Gastroenerol. Clin. North Am. 21:835.

2. Brandes, J. (1967). First trimester nausea and vomiting as related to outcome of pregnancy. Obstet. Gynecol. 30:427.

3. Broussard, C. and Richter, J. (1998). Pregnancy and Gastrointestinal Disorders. Gastroenterology Clinics 27(1):1.

4. Depue, R., Bernstein, L., Ross, R., Judd, H. and Henderson, B. (1987). Hyperemesis gravidarum in relation to estradiol levels, pregnancy outcome and other maternal factors: a seroepidemiologic study. Am. J. Obstet. Gynecol. 156:1137.

5. Diggory, P. and Tomkinson, J. (1962). Nausea and vomiting in pregnancy: a trial of meclozine dihydrochloride with and without pyridoxine. Lancet, August 25:370.

6. Fairweather, D., and Loraine, J. (1968). Nausea and vomiting in pregnancy. Am. J. Obstet. Gynecol. 102:135.

7. Fitzgerald, J. (1956). Epidemiology of hyperemesis gravidarum. Lancet 1:660.

8. Gadsby, R., Barnie-Adhead, A., and Jagget, C. (1993). A prospective study of nausea and vomiting during pregnancy. Br. J. Gen. Pract. 43:245.

9. Godsey, R. and Newman, R. (1991). Hyperemesis gravidarum: A comparison of single and multiple admissions. J. Reprod. Med. 36(4):287.

10. Hershman, J. (1999). Human chorionic gonadotropin and the thyroid: hyperemesis gravidarum and trophoblastic tumors. Thyroid 9(7):653.

11. Hod, M., Orvieto, R., Kaplan, B., Friedman, S., and Ovadia, J. (1994). Hyperemesis gravidarum: A review. J. Reprod. Med. 39:605.

12. Iatrakis, G., Sakellaropoulos, G., Kourkoubas, A., et al. (1988). Vomiting and nausea in the first 12 weeks of pregnancy. Psychother. Psychosom. 49:22.

13. Jarnfelt-Samisoe, A., Samsioe, G., and Velinder, G. (1983). Nausea and vomiting in pregnancy: a contribution to its epidemiology. Gynecol. Obstet. Invest. 16:221.

14. Kallen, B. (1987). Hyperemesis during pregnancy and delivery outcome: A registry study. Eur. J. Obstet. Gynecol. Reprod. Biol. 26:291.

15. Klebanoff, M., Koslowe, P.,Kaslow, R., and Rhoads, G. (1985). Epidemiology of vomiting in early pregnancy. Obstet. Gynecol. 66:612.

16. Medalie, J. (1957). Relationships between nausea and/or vomiting in early pregnancy and abortion. Lancet 2:117.

17. Merkel, R. (1952). The use of menadione bisulfite and ascorbic acid in the treatment of nausea and vomiting of pregnancy. Am. J. Obstet. Gynecol. 139:189.

18. Milkovich, L., and van den Berg, B. (1976). An evaluation of the teratogenicity of certain antinauseant drugs. Lancet 2:117.

19. Nageotte, M., Briggs, G., Towers, C., and Asrat, T. (1996). Dropiderol and diphenhydramine in the management of hyperemesis gravidarum. Am. J. Obstet. Gynecol. 174:1801.

20. Reinken, L., and Gant, H. (1974). Vitamin B6 nutrition in women with hyperemesis gravidarum during the first trimester of pregnancy. Clin. Chim. Acta 55:101.

21. Safari, H., Alsulyman, O., Gherman, R., and Goodwin, T. (1998). Experience with oral methylprednisolone in the treatment of refractory hyperemesis gravidarum. Am. J. Obstet. Gynecol. 178:1054.

22. Snell, L. (1998). Metabolic crisis: hyperemesis gravidarum. J. Perinat. Neonatal Nurs. 12(2):26.

23. Tierson, F. Olsen, C. and Hook, E. (1986). Nausea and vomiting of pregnancy and association with pregnancy outcome. Am. J. Obstet. Gynecol. 155:1017.

24. Vutyavanich, T., Wongtra-ngan, S., and Ruangsri, R. (1995). Pyridoxine for nausea and vomiting of pregnancy: A randomized, double-blind, placebo-controlled trial. Am. J. Obstet. Gynecol. 173:881.

25. Williams, J. (1989). Obstetrics, 18th ed. Eastman, NY.

26. Wright, J. (1984). Therapy of nausea and vomiting of pregnancy. Am. J. Obstet. Gynecol. 149:107.