INTRODUCTION

Nausea and vomiting occur in about 80% of pregnancies.^1,2 Hyperemesis gravidarum is a more severe form affecting up to 1% of pregnancies.³ As nausea and vomiting during pregnancy are difficult to treat, many therapies have been utilized.⁴ Prochlorperazine, promethazine, metoclopramide, and pyridoxine (vitamin B₆ or B₆) are often used as first-line therapy.⁵ Newer regimens using ondansetron or steroids are also utilized, either as first-line therapy or more likely after initial therapy failure. The majority of studies tend to focus on the management of hyperemesis gravidarum with little investigation of nausea and vomiting in pregnancy.⁶ Since nausea and vomiting can adversely affect the quality of the pregnant woman's life,⁷ we investigated therapies that may abate these symptoms.

The purpose of this study was to evaluate the effectiveness of three commonly prescribed pharmaceutical regimens in the outpatient management of nausea and vomiting in pregnancy: a B₆–metoclopramide combination, prochlorperazine, and promethazine. We assessed therapeutic successes subjectively and objectively by the degree of symptom resolution, the occurrence of side effects, and the rate of hospitalization.

MATERIALS AND METHODS

We prospectively evaluated 174 patients with singleton gestations presenting in the first trimester to their obstetrical provider with nausea and/or vomiting between January 1994 and December 1996. With ethical board approval, informed consent was obtained from the patients enrolled in the study. The patients were recruited from both private and clinic general obstetric population. All participants underwent general physical and obstetrical evaluations. An ultrasound examination confirmed gestational age, viability, and plurality of the pregnancy. Laboratory studies obtained included complete blood count, urinalysis with culture, free T₄ and thyroid-stimulating hormone, and hepatitis B surface antigen testing. All patients were advised to discontinue their iron or vitamin supplementation until their symptoms improved.

Patients excluded from the study prior to randomization included women with a medical condition manifesting as nausea or vomiting, women necessitating hospital admission upon initial assessment, women hospitalized or treated for hyperemesis gravidarum during their current pregnancy, and patients lost to follow-up. Clinical thyroid disease was an exclusion factor. However, subclinical patients with only mild dysfunction (low TSH, normal free T₄) and no prior thyroid disease were included. Women with both abnormal TSH and abnormal free T₄ were excluded.

Patients were divided into three groups based on a computer-generated randomization. The patients in Group A received one 50 mg intramuscular injection of pyridoxine, with metoclopramide 10 mg orally every 6 hours as needed. The patients in Group B received prochlorperazine, as needed, 25 mg rectal suppositories every 12 hours, or 10 mg tablets orally every 6 hours as needed. The patients in Group C received promethazine 25 mg orally every 6 hours as needed.

Symptoms were subjectively assessed and recorded by the patients on the third day of treatment. Subjective scores of 1–5 were noted by the patient as follows: much worse (1), worse (2), same (3), better (4), and much better (5). The responses were then divided into two subgroups: those that answered 1–3 (same-worse) and those that answered 4–5 (better). In addition, patients also reported their medication compliance.

To obtain quantitative data on treatment effectiveness, all patients recorded the number of emesis episodes the day before and on the third day of treatment. Dry heaves were counted as nausea, but not vomiting episodes. Worsening of symptoms was evaluated and patient admission for hydration or inpatient management was considered on an individual basis. Hospitalization for the specific management of nausea or vomiting was noted.

Statistical analysis employed ², analysis of variance, and the Kruskal–Wallis tests. Statistical significance was defined as p<0.05. Based on our preliminary data, a power analysis calculation indicated that we needed at least 46 patients in each group to reach statistical significance when comparing groups A and B, or A and C (=0.05; =0.20).

RESULTS

Of 174 pregnant women screened for eligibility, 169 were enrolled. Five were excluded before randomization for medical reasons. In all, 12 patients were lost to follow-up, similarly distributed among the groups (three, five, and four from groups A, B, and C, respectively). One patient withdrew from the study due to acute dystonic reactions, thought to be secondary to metoclopramide on day 3 of treatment. The symptoms resolved spontaneously 6 to 8 hours after the last dose. This patient declined further antiemetic treatment and proceeded to have an uneventful pregnancy. We completed data analysis for 54 patients in group A, 50 patients in group B, and 52 patients in group C. There were no statistically significant differences among the groups when compared for maternal age, gestational age at enrollment, parity, and subsequent hospitalization for nausea or vomiting (Table 1). Drug usage and compliance was comparable between all the three groups. Patients in group A did not express difficulty or concern regarding the use of pyridoxine as an intramuscular injection rather than as an oral form.

Table 1 - Group Characteristics.

Full table

While there were no statistically significant differences between the groups in the number of emesis episodes before treatment, group A had significantly lower number of emesis after treatment than either group B or C (Table 2). B₆–metoclopramide combination was better than prochlorperazine (relative risk (RR)=0.59; 95% confidence interval (CI)=0.39 to 0.88) or promethazine (RR=0.62; 95% CI=0.42 to 0.91) in improving the subjective symptoms of these patients. Figure 1 depicts the subjective responses of the patients following the different regimens.

Figure 1.

Subjective patient responses to the three antiemetic regimens. ^*p<0.05 when group A compared to either group B or group C.

Full figure and legend (62K)

Table 2 - Patient Response to the Different Antiemetic Regimens.

Full table

The Kruskal–Wallis test demonstrated that the mean number of emesis after treatment for the patients in the pyridoxine–metoclopramide group was significantly lower, that is, better than the other two groups (Table 2). The Kruskal–Wallis test was also used to evaluate the three groups with respect to their subjective responses to the different antiemetic regimens used. The groups did differ (p=0.012), with an apparent advantage to the pyridoxine–metoclopramide regimen compared to the other two agents.

At enrollment, 14 patients had borderline elevation in free T₄, but normal thyroid-stimulating hormone levels. Thyroid function testing was repeated in the second trimester and was normal in all. Subsequent pregnancy courses were similar among the three groups. No neonatal anomalies were seen, except for one ventricular septal defect in the prochlorperazine group. None of the patients had any relevant allergic reaction history.

SIGNIFICANCE

Nausea and vomiting are common complaints during the first trimester of pregnancy. Symptoms are usually worse in the morning, but may continue throughout the day. The genesis of pregnancy-induced nausea and pregnancy is not clear. Chorionic gonadotropin has been implicated on the basis that levels are high at the same time when nausea and vomiting are more common.^8,9 Moreover, nausea and vomiting are prominent features in conditions where chorionic gonadotropin is significantly elevated, such as in women with hydatidiform mole. Others found no relationship between chorionic gonadotropin and nausea of pregnancy.^3,10 A progesterone effect has been implicated by some, especially in relation to relaxation of the esophageal-gastric sphincter. Agents that enhance sphincter tone and promote gastrointestinal motility, such as metoclopramide, may help prevent reflux, which may be manifested as nausea or vomiting. Having small meals at more frequent intervals may help as well. Estrogens in the combined birth control pill have been shown to induce nausea or vomiting in a dose-related fashion.¹¹ Nausea or vomiting of pregnancy is also more common in the morning hours of the day,⁹ hence "morning sickness". Social and psychological factors can also contribute to the severity of the nausea.¹² Some have even described an evolutionary advantage to nausea and vomiting, protecting the fetus from certain harmful substances in food.¹³

Pyridoxine was first used to manage nausea and vomiting in pregnancy by Willis et al.¹⁴ in 1942. Pyridoxine requirements are increased in pregnancy, but low serum concentrations are not usually seen in normal pregnancies before the second and third trimesters of pregnancy. Pyridoxine deficiency without clinical symptoms is common in pregnancy.¹⁵ Pyridoxine and doxylamine were included in the formulation of Bendectin^®, which was approved by the Food and Drug Administration for the use of nausea in pregnancy, before subsequently being pulled from the market. When pyridoxine alone is not successful, a combination regimen have been suggested.¹⁶

We have been using 50 mg single pyridoxine injection with apparent success in the treatment of nausea of pregnancy. The effect noted was often an all-or-none effect. Although we could not duplicate their results, others have described oral pyridoxine as effective therapy when given orally.⁵ Our past experience as well as others did not mirror that result.¹⁷ Therefore, oral pyridoxine was not used. Patient satisfaction may be increased when a combination of parenteral and oral medications is given. This has prompted us in the past to combine intramuscular pyridoxine injection and oral metoclopramide. The reason for combining two agents and comparing that treatment with two other single agents was to specifically mirror local common practices. We acknowledge that these regimens may not necessarily be the first choice regimens in other communities. We also understand that such grouping may raise questions of fairness in combining two agents that may also work independently, and compare that with monotherapy. A placebo effect in the route of administration may also play a role in the patient's response, which is not shared by the groups taking prochlorperazine or promethazine. We did not intend to compare route of administration (intramuscular vs oral vs rectal) or placebo effect, which may have led to a more attractive but different study. We intended to mirror established local practices, hence the corresponding grouping of the patients in this study.

Metoclopramide counteracts some of the physiologic changes of the gastrointestinal tract in pregnancy that may lead to nausea or vomiting. It helps strengthen the basal sphincter tone of the lower esophageal sphincter, which is usually decreased in pregnancy.¹⁸ In the small intestines, propulsive motility is decreased, and transit time is increased. This may lead to bloating and bowel distention, which may be manifested as nausea or malaise. Some have attributed these changes to effects of progesterone or chorionic gonadotropin.¹⁹ From a pharmacological basis, metoclopramide appears to address these specific issues by promoting upper gastrointestinal tract motility, relaxing the pyloric sphincter and duodenal bulb, and increasing the lower esophageal sphincter tone.

The subjective response of the patients to the different regimens is a very important measure of the treatment success, since a major indication of the treatment is to alleviate the subjective symptoms. The pyridoxine–metoclopramide group appeared to have an advantage when the subjective responses of the patients are evaluated. As shown on Table 2, the number of emesis after the treatments appeared to differ as well.

Prochlorperazine is a neuroleptic phenothiazine that is believed to work centrally in relieving nausea or pregnancy. Promethazine is a phenothiazine antihistamine derivative, with H₁ receptor blocking properties. They both have sedative effects. Metoclopramide and prochlorperazine increase the risk of tardive dyskinesia, although this is more common in the elderly, and thought to be dose-dependent.

Metoclopramide and promethazine have been evaluated for the treatment of emesis during labor. They were equally effective, and both better than placebo, in reducing the incidence of nausea and vomiting after the administration of pethidine.²⁰ However, promethazine was found to be associated with a more persistent sedative effect (66%), compared to metoclopramide (41%). Sedation may be considered a serious side effect, especially in active women, and the availability of a less-sedating medication with similar or better effectiveness and safety profile should be encouraged.

A thorough comparison of the serious side effects of the different agents was not practically possible because of the small sample population and the low risk of serious side effects. Among our recruited patients, only one who received metoclopramide had acute dystonic reactions that resolved spontaneously. In its product information (A.H. Robbins, July 2002), metoclopramide may be associated with this complication in one in 500 patients treated. However, evidence-based view regarding the utilized medications in the therapy of nausea and vomiting of pregnancy concluded that they are safe and effective.²¹

Nausea remains a difficult symptom to quantify, and we admit that assigning a score to the different responses was arbitrary but logical. It would have been ideal to randomize the patients in a double-blind fashion, and possibly to establish a placebo group. The intramuscular injection of pyridoxine may have been evaluated on its own, or may have been given to all the three groups. However, the groups were established as such to mirror outpatient treatment regimens already in practice in our local community. This study shows favorable results in the use of a pyridoxine–metoclopramide regimen in the treatment of nausea and vomiting of pregnancy, possibly because it addresses the physiologic changes of pregnancy that may have led to these symptoms.

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