Treatment of nausea and vomiting in pregnancy

Treatment of nausea and vomiting in pregnancy – includes patient information on relieving morning sickness

Morton Kousen

Physicians constantly wrestle with the risks and benefits of treating patients with drugs. Nowhere is this problem better illustrated than in the treatment of nausea and vomiting in pregnancy. Patients are advised to avoid medications as much as possible in pregnancy, especially during the first trimester. Yet nausea and vomiting, which occur in about half of all pregnancies, are predominant in the first trimester.(1)(2) The etiology is unknown but is believed to be multifactorial and to include hormonal, neurologic, metabolic, toxic and psychosomatic factors.

If treatment is unsuccessful, progression to hyperemesis gravidarum (intractable vomiting) may occur, resulting in starvation, ketosis, electrolyte imbalance and dehydration.

Experiencing nausea and vomiting in pregnancy is more than just an annoyance. In addition to potential metabolic complications, nausea and vomiting in pregnancy are responsible for a significant health care expense. For example, at York Hospital, 64 patients were hospitalized with a diagnosis of hyperemesis gravidarum during 1991, at a total cost of $186,000. Seven of these patients had multiple admissions. York Hospital has approximately 3,500 deliveries per year. Thus, the admission rate for patients with hyperemesis gravidarum was 1.8 percent, with an average cost of $2,900 per hospitalized patient.

When nausea and vomiting occur during pregnancy, conditions unrelated to pregnancy (such as gastroenteritis, appendicitis and cholecystitis) and other complications of pregnancy must first be excluded. Once pregnancy is identified as the cause of the nausea and vomiting, various interventions may be tried.

Adequate evaluation of the effectiveness of various therapies is hampered by the often self-limiting nature of this condition and the difficulty of isolating the effects of dietary changes and medication. Empiric trials that are not well controlled have limited value.

Diet

Conservative measures for treating the nausea and vomiting of pregnancy should be attempted initially. Reassurance that the symptoms are generally transient may benefit patients with mild nausea and vomiting. Frequent small meals to avoid being either too hungry or too full may be effective.

General recommendations include choosing a bland diet, increasing carbohydrate intake, decreasing fat intake and avoiding offensive food odors. It may be helpful to omit prenatal vitamins containing iron until the nausea resolves. If reassurance and diet changes fail to improve the condition, medication may be required.

Bendectin

Bendectin, the only drug ever approved by the U.S. Food and Drug Administration for use in the treatment of nausea and vomiting in pregnancy, was withdrawn from the market by the manufacturer, Merrell Dow, in 1983. From the time of its introduction in 1956 to its withdrawal in 1983, 30 million women had used this drug.(3) If the background rate of fetal malformations is 2 to 3 percent, random chance alone would account for 600,000 to 900,000 cases of birth defects in offspring of women who had taken Bendectin in early pregnancy. In view of the millions of women who used the drug, it is unlikely that Bendectin would have escaped detection as a cause of congenital malformations.(4) It was not shown to be either carcinogenic or teratogenic,(3)(5)(6)(7)(8) but reports of possible congenital malformations, as well as the financial cost of defending against numerous lawsuits, convinced the company to cease production of the drug. An editor of Teratology said that Bendectin was the “most famous tortogen/litogen and the best studied human non-teratogen.”(9)

The original formulation of Bendectin included 10 mg of dicyclomine, 10 mg of doxylamine and 10 mg of pyridoxine (vitamin [B.sub.6]). Dicyclomine, an antispasmodic, was removed from the formulation in 1976, when clinical trials failed to show evidence of its benefit as a synergistic antiemetic.

Some physicians informally mention to their patients that doxylamine, an antihistamine, is still available in an over-the-counter medication called Unisom Nighttime Sleep Aid. However, the current tablet strength of 25 mg is greater than the amount in the Bendectin tablet, and the medicolegal implications of prescribing this tablet strength are unfavorable, since pregnancy is listed as a contraindication in the package insert.

In 1979, the American Medical Association Council on Drugs stated that there was no evidence that pyridoxine is effective against nausea, and that earlier studies of its efficacy were uncontrolled.(10) Recently, a randomized, double-blind, placebo-controlled study reported a significant improvement in patients with severe nausea who were treated with 25 mg of pyridoxine every eight hours for three days.(11) Pyridoxine does not appear to be teratogenic in pregnancy.(8)

Other Medications

Piperazine antihistamines frequently have been used for nausea and vomiting in pregnancy. Meclizine (Antivert, Antrizine, Bonine) was widely used in the 1960s, until reports of cleft lip and cleft palate surfaced. Although prospective trials failed to support any causal relationship, the FDA in 1965 ordered that products containing meclizine and cyclizine have a cautionary label warning against their use in pregnancy because of the potential for injury to the fetus.(12) When further studies continued to show no evidence of teratogenicity in humans,(13)(14) the FDA in 1979 authorized the removal of restrictions for the use of meclizine and cyclizine in pregnancy.

In the Collaborative Perinatal Project,(15) 595 women used diphenhydramine (Benadryl) and 319 women used dimenhydrinate (Dramamine), the chlorotheophylline salt of diphenhydramine, in the first trimester of pregnancy. Both of these drugs are ethanolamine antihistamines, as is doxylamine, the antihistamine component of Bendectin. No evidence suggested a reationship to congenital malformations with either diphenhydramine or dimenhydrinate. While a 1974 study(16) reported an association between cleft palate and diphenhydramine use in the first trimester, a 1985 study(17) failed to show any associated congenital malformations.

A 1989 study(18) of 64 women in the first trimester who were using diphenhydramine, followed by various other antiemetics, found three cases of integumental abnormality at birth. The authors did not believe the defects were related to the drug therapy.

In another study,(13) trimethobenzamide (Tigan, Trimazide) was used by 193 patients in the first trimester. No increase in the incidence of severe congenital anomalies was noted when the infants were examined at one month and one year of age, but an increased incidence was observed at five years of age. Complicating factors included some patients who were using other antiemetics. Among 340 patients in the Collaborative Perinatal Project who were taking trimethobenzamide,(15) no increase in congenital malformations was seen.

In 1,309 children born to women exposed to phenothiazines during the first 16 weeks of pregnancy, no increase in congenital malformations was found.(19) However, analysis of specific phenothiazines showed an increased relative risk of ventricular septal defects with the use of prochlorperazine (Compazine).

In another study(20) of 315 women taking phenothizaines in the first trimester, the incidence of congenital anomalies was 3.49 percent, a slightly higher rate than expected.

Chlorpromazine (Thorazine) was associated with a significant increase in malformations, but no significant increase was seen with either promethazine (Phenergan) or prochlorperazine. A 1976 study(21) revealed a positive correlation between promethazine and congenital hip dislocation, although this type of defect is not one that would be expected to result from medication in the first trimester. In the Kaiser Health Plan study,(13) no evidence of malformations was found with either promethazine or prochlorperazine use.

Metoclopramide (Reglan) increases lower esophageal sphincter pressure, decreasing gastroesophageal reflux. It accelerates gastric emptying and acts directly on the central chemoreceptor trigger zone. In one study of patients with hyperemesis gravidarum, metoclopramide was found to be more effective than either prochlorperazine or placebo.(22)

To date, no congenital malformations have been reported in association with metoclopramide, but use in pregnancy has been limited, and more data are needed. In one patient who started taking the drug at 10 weeks of gestation, acute porphyria was diagnosed after eight weeks of therapy.(23) Symptoms resolved after the drug was discontinued and the patient was placed on a high-carbohydrate diet. Slight residual weakness remained in the patient’s lower extremities. This drug has also been associated with extrapyramidal side effects.

Phosphorated carbohydrate solution (Emetrol, Naus-A-Way) is an over-the-counter oral solution containing glucose, fructose and phosphoric acid. The solution relieves nausea through its local action on the wall of the hyperactive gastrointestinal tract. It reduces smooth muscle contractions, in proportion to the amount used. The usual dose is one or two tablespoons every 15 minutes for a maximum of five doses. Diluting the medication by drinking fluids before or after taking a dose should be avoided.

In the Collaborative Perinatal Project,(15) the anticholinergic agent scopolamine was used by 309 patients in the first trimester and by 881 patients sometime during pregnancy. No association with congenital malformations was found. However, since the anticholinergic drug dicyclomine was removed from the Bendectin formulation for lack of proven efficacy, it is difficult to justify the use of scopolamine without further trials. Similar precautions exist for other parasympatholytic drugs used as antiemetics in the first trimester, such as belladonna, atropine and hyoscyamine.

Recommendations

A guideline for treating nausea and vomiting in pregnancy is presented in Figure 1. The goal in treating nausea and vomiting during pregnancy is to prevent progression to hyperemesis gravidarum without using medication, if possible, during the organogenesis phase–the first 10 weeks (Table 1).(24) This goal is best accomplished through reassurance and multiple small meals. The patient should ingest both fluids and calories to prevent dehydration and ketonuria. Foods that may be helpful in controlling symptoms include saltine crackers, unbuttered toast, gelatin desserts, flavored frozen desserts, broth, pretzels, sugared decaffeinated or herbal teas, and nondiet ginger ale.

[CHART OMITTED]

TABLE 1 Critical Stages of Organogenesis

Days (from conception)(*)

Organ Started Completed

Central nervous 18 38

system

Heart 18 49

Ears 22 59

Limbs 24 49

Eyes 24 40

Gonads 37 46

Palate 41 58

External genitalia 44 62

(*)–For days since last menstrual period (i.e., for gestational age), add 14.

Derived from Moore.(24)

A recent study showed a 60 percent positive response with the use of acupressure, versus 30 percent with placebo.(25) No significant side effects were observed. This method of therapy may be tried by wearing acupressure wrist bands available from boating stores or travel agencies such as the AAA Auto Club.

If drug therapy becomes necessary, safety concerns must outweigh efficacy considerations. Thus, the oldest and best-studied drugs should be used, rather than newer, less well-studied medications. A drug can probably never be proved 100 percent safe during pregnancy by epidemiologic studies. A minor teratogenic effect may not be identified until large numbers of patients have been studied. Medicolegal considerations will probably prevent adequate trials from being performed on pregnant women. Thus, a promising drug such as ondansetron (Zofran), which has been successfully used to control nausea and vomiting in chemotherapy patients, should not be used in pregnant patients.

Since pyridoxine, 25 mg three times daily, has been shown to be effective in treating severe nausea and is believed to be nonteratogenic, this drug can be judiciously recommended. Emetrol is also thought to be safe, although data are lacking supporting its effectiveness in nausea and vomiting in pregnancy.

The physician must decide whether to add doxylamine to the treatment. This decision is difficult because of the legal implications. If doxylamine is recommended, 25 mg at bedtime is prescribed, along with 25 mg of pyridoxine. The pros and cons must be discussed with the patient, and informed consent should be obtained.

Other medications have been less well studied. Trimethobenzamide and promethazine appear to have minimal risk. Metoclopramide should be reserved for otherwise uncontrolled hyperemesis gravidarum, until further studies of its use in the first trimester have been completed.

Physicians should always be cautious of anecdotal reports of new drug use, since fetal safety is of prime concern. Teratogenicity can never be ruled out with small numbers of patients.

A patient information handout on nausea and vomiting in pregnancy is provided on page 1284.

Relieving Morning Sickness

What is morning sickness?

Morning sickness is the nausea and vomiting that some women have when they become pregnant. It is caused by the sudden increase in hormones during pregnancy. Although morning sickness is more common in the morning, it can go on all day.

How long will morning sickness last?

Morning sickness is very common in early pregnancy. It tends to go away later in pregnancy, and it’s almost always gone by the second trimester (the fourth month).

Will morning sickness hurt my baby?

It shouldn’t. Many doctors think morning sickness is a good sign because it means the afterbirth is developing well.

Morning sickness can become more of a problem if you can’t keep any foods or fluids down and begin to lose a lot of weight. The tips below may help reduce morning sickness.

Tips to relieve morning sickness:

* Eat small meals throughout the day so that you’re never too full or too hungry.

* Avoid rich, fatty foods.

* Avoid food smells that bother you.

* Eat more carbohydrates (plain baked potato, white rice, dry toast).

* Eat saltine crackers and other bland foods when the nausea bothers you.

* Try gelatin desserts (Jell-O), flavored frozen desserts (Popsicles), broth, nondiet ginger ale, sugared decaffeinated or herbal teas, and pretzels.

* Changing the type of vitamins you’re taking may help. The iron in prenatal vitamins can bother some women. If you think your morning sickness is related to your vitamins, talk with your doctor.

* Wearing “acupressure” wrist bands, which are sometimes used by passengers on boats to prevent sea sickness, may be helpful in some women who have morning sickness. You can buy the bands at boating stores or travel agencies such as the AAA Auto Club.

If these steps don’t give you relief from morning sickness, your doctor may have other ideas. Keep in mind that your symptoms should go away soon and that morning sickness doesn’t mean your baby is sick.

This information provides a general overview on morning sickness and may not apply in each individual case. Consult your physician to determine whether this information can be applied to your personal situation and to obtain additional information.

This handout is provided to you by your family physician and the American Academy of Family Physicians.

REFERENCES

(1.)Koh KS, Walters WA, Wood C. A survey of symptoms occurring in pregnancy. Br J Sex Med 1974; 1: 24-6, 28-35.

(2.)Jarnfelt-Samsioe A, Samsioe G, Velinder GM. Nausea and vomiting in pregnancy–a contribution to its epidemiology. Gynecol Obstet Invest 1983; 16:221-9.

(3.)Brent RR. The Bendectin saga: another American tragedy. Teratology 1983; 27:283-6.

(4.)Hill LM, Kleinberg F. Effects of drugs and chemicals on the fetus and newborn. Mayo Clin Proc 1984; 59:707-16.

(5.)Mitchell AA, Schwingl PJ, Rosenberg L, Louik C, Shapiro S. Birth defects in relation to Bendectin use in pregnancy. II. Pyloric stenosis. Am J Obstet Gynecol 1983; 147:737-42.

(6.)Holmes LB. Teratogen update; bendectin. Teratology 1983; 27:277-81.

(7.)Shiono PH, Klebanoff MA. Bendectin and human congenital malformations. Teratology 1989; 40:151-5 [published erratum appears in Teratology 1990; 41:250-1].

(8.)Niebyl JR, Maxwell KD. Treatment of the nausea and vomiting of pregnancy. In: Niebyl JR, ed. Drug use in pregnancy. 2d ed. Philadelphia: Lea & Febiger, 1988:11-9.

(9.)Skolnick A. Key witness against morning sickness faces scientific fraud charges [News]. JAMA 1990; 263:1468-9, 1473.

(10.)AMA Department of Drugs. AMA drug evaluations. 4th ed. Littleton, Mass.: Publishing Sciences Group, 1979:417.

(11.)Sahakian V, Rouse D, Sipes S, Rose N, Niebyl J. Vitamin B6 is effective therapy for nausea and vomiting of pregnancy: a randomized, doubleblind placebo-controlled study. Obstet Gynecol 1991; 78:33-6.

(12.)Sadusk JF, Palmisano PA. Teratogenic effect of meclizine, cyclizine and chlorcyclizine. JAMA 1965; 194:139-41.

(13.)Miklovich L, van den Berg BJ. An evaluation of the teratogenicity of certain antinauseant drugs. Am J Obstet Gynecol 1976; 125:244-8.

(14.)Shapiro S, Kaufman DW, Rosenberg L, Slone D, Monson RR, Siskind V, et al. Meclizine in pregnancy in relation to congenital malformations. Br Med J 1978; 1(6111):483.

(15.)Heinonen OP, Slone D, Shapiro S, Gaetano LF. Birth defects and drugs in pregnancy. Littleton, Mass.: Publishing Sciences Group, 1977.

(16.)Saxen I. Cleft palate and maternal diphenhydramine intake [Letter]. Lancet 1974; 1(854):407-8.

(17.)Aselton P, Jick H, Milunsky A, Hunter JR, Stergachis A. First-trimester drug use and congenital disorders. Obstet Gynecol 1985; 65:451-5.

(18.)Gross S, Librach C, Cecutti A. Maternal weight loss associated with hyperemesis gravidarum: a predictor of fetal outcome. Am J Obstet Gynecol 1989; 160:906-9.

(19.)Slone D, Siskind V, Heinonen OP, Monson RR, Kaufman DW, Shapiro S. Antenatal exposure to the phenothiazines in relation to congenital malformations, perinatal mortality rate, birth weight, and intelligence quotient score. Am J Obstet Gynecol 1977; 128:486-8.

(20.)Rumeau-Rouquette C, Goujard J, Huel G. Possible teratogenic effect of phenothiazines in human beings. Teratology 1977; 15:57-64.

(21.)Kullander S, Kallen B. A prospective study of drugs and pregnancy. II. Anti-emetic drugs. Acta Obstet Gynecol Scand 1976; 55:105-11.

(22.)Harrington RA, Hamilton CW, Brogden RN, Linkewich JA, Romankiewicz JA, Heel RC. Metoclopramide. An updated review of its pharmacological properties and clinical use. Drugs 1983; 25:451-94.

(23.)Milo R, Neuman M, Klein C, Caspi E, Arlazoroff A. Acute intermittent porphyria in pregnancy. Obstet Gynecol 1989; 73(3 Pt 2):450-2.

(24.)Moore KL. The developing human. 3d ed. Philadelphia: Saunders, 1982.

(25.)de Aloysio D, Penacchioni P. Morning sickness control in early pregnancy by Neiguan point acupressure. Obstet Gynecol 1992; 80:852-4.

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