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By John C. Hobbins, MD
Professor, Department of Obstetrics and Gynecology,
University of Colorado School of Medicine, Aurora
Dr. Hobbins reports no financial relationships relevant to this field of study.
Synopsis: A variety of methods and medications are available to treat nausea and vomiting in pregnancy — one of the most common and often vexing problems for pregnant women. Although most of these have had anecdotal suggestion of benefit and documented suggestions of efficacy through randomized trials, some have had limited exposure to investigations involving safety.
Since about three-quarters of pregnant patients will experience some episodes of nausea and vomiting in the first trimester and sometimes further, this Special Feature has been fashioned to help the clinician deal with something that can be difficult for many patients to endure, but also challenging for providers to treat. Fortunately, only about 1-2% of patients will have the very severe form, hyperemesis gravidarum (HG), where there is accompanying weight loss (> 5% of body weight), dehydration, electrolyte imbalance, and ketosis — any of which could require hospitalization.
Some have attempted to categorize the severity of nausea and vomiting in pregnancy (NVP) according to the number of episodes of vomiting per day. For example, mild is described as 1-2 episodes per day lasting < 1 hour; severe is more than 5 episodes of vomiting per day with symptoms lasting for > 5 hours. In some studies, a severity scoring system — the Pregnancy-Unique Quantification of Emesis and Nausea — has been employed, but clinically it is hard to put a number on the degree of discomfort.
Although the timing of nausea and vomiting episodes has resulted in the term "morning sickness," in some patients it also could be easily described as "afternoon" or "evening sickness," leaving some patients completely incapacitated for most of the day. In fact, because of this, it has been estimated that the economic loss of this condition is between $3000 and $17,000 for patients suffering from the severe variety.1
NVP symptoms are temporally related to the rise in hCG and estrogen. Patients with twins, molar pregnancies, and those assisted reproductive technology patients with ovarian hyperstimulation (all having sky-high hCG levels) are particularly susceptible to severe NVP.
Psychological factors can play a role either on the front end or, certainly, as a result of the NVP. Hyperthyroidism has been blamed on occasion (falsely) because pregnancy, in general, causes a hypermetabolic state with a rise in T4 and decrease in thyroid-stimulating hormone. Also, hCG may have an independent thyroid-like effect in pregnancy.
Since NVP is so common, most clinicians will not pursue other reasons for the symptoms until the condition becomes problematic. Another cause may be suspected if the symptoms start before the fifth week or persist well past 14 weeks — and the gastrointestinal (GI) tract is the logical place to start. However, by the time this diagnostic pathway is explored, one cannot tell whether the upper GI symptoms/signs of gastric reflux or esophogitis are primary or secondary factors.
There has been an attempt to link Helicobacter pylori with NVP and HG, since a majority of these patients have H. pylori antibodies. However, there is no correlation with this antibody level and the duration of symptoms.2
Since NVP has been occurring through the ages, there have been more home remedies and concoctions for this than attempted cures for hiccups. I apologize that some of the following information is not new to providers. Below is an up-to-date assortment of therapeutic measures, a few of which have undergone some scientific scrutiny, but many others based predominantly on anecdotal experience alone.
Food and Fluid Intake. An empty stomach should be avoided. Small, frequent meals every 1-2 hours helps. If fluids are not tolerated with feedings, then fluid intake should be given between feedings to eventually attain a recommended threshold of eight glasses per day. With fluid intake, the colder the better, and many affected women have effectively used popsicles to counter dehydration. Sport drinks are often well tolerated and will replace lost electrolytes.
Although some have advocated ingestion of food with high carbohydrate content, there is a suggestion that protein triggers less gastric reflux. There is evidence that avoiding spicy or acid-generating foods, noxious odors, cigarette smoke, or some perfumes is helpful. Chewable antacid tablets can have definite benefit while also replacing calcium and magnesium.
Vitamins. Vitamins, in general, are needed for many pregnant patients and may lessen the chances of having NVP, especially if taken before 6 weeks.3 However, vitamins spiked with iron may have the opposite effect, since iron is a common trigger of nausea and vomiting. There is no doubt that some women require supplemental iron, but in most cases it is not essential in the first trimester. Therefore, it is worth switching to an iron-less option such as a children's chewable vitamins. At least one randomized trial has shown significant improvement in NVP in women taking non-iron containing prenatal vitamins.4
Folic acid is necessary for the reduction of neural tube defects (NTD) and can be taken separately in women who find the typical prenatal vitamin contributory to their NVP. Most prenatal vitamins have 800 ug of folic acid, which is more than the minimal daily dietary requirement of 400 ug (CDC recommendation). However, individuals at risk for NTDs (diabetes, obesity, or previous child with NTD) have been advised to take 4000 ug (4 mg) of additional folic acid per day.5
Most importantly, pyridoxine (vitamin B6) alone has been shown to be of benefit in diminishing nausea and vomiting as a first step remedy6 and has not been associated with adverse fetal effect.
Medications. Often prescribed for motion sickness, the most frequent first-line medications for NVP are the antihistamine H1 blockers: doxylamine (Unisom®), meclizine (Antivert®), dimenhydrinate (Dramamine®), and promethazine (Phenergan). They stabilize the vestibular system while modifying stimuli to the vomiting center. Doxylamine is unlisted according to FDA classifications and, with the exception of promethazine, which has a class C listing, the others are in a class B category.
None of the H1 blockers has been shown to have teratogenic effect, and with pooled data from studies evaluating different antihistamines, there was an improvement in symptoms of NVP by about 70%.7 Maternal side effects include drowsiness, dry mouth, and rare extra-pyramidal effects. Since H1 blockers have weak anticholinergic properties, they should be used with caution in those with asthma, glaucoma, or pre-glaucoma.
The doxylamine story is worth telling. It was a component of a formula specifically designed for NVP when combined with dicyclomine (an antispasmodic) and vitamin B6. For many years, up to 25% of pregnant patients were using this medication, which bore the brand name Bendectin®. There was good documentation of its efficacy8 and there never was any scientific evidence of teratogenicity.9 However, in the 1980s, some lawsuits surfaced with claims that Bendectin® caused various birth defects. Of those going forward, none ended in favor of the plaintiff, but, despite the drug’s vindication in every case, the company chose to take it off the market rather than to engage in, seemingly, never-ending, expensive litigation. Undaunted, many clinicians reverted to the use of doxylamine alone, marketed as a sleeping aid (Unisom) with or without vitamin B6. A company has been making this combination (doxylamine and B6) in Canada under the name Diclectin, and very recently the FDA has approved its use in the United States (class A) under the label Diclegis.
Serotonin Antagonists. Often used in chemotherapy, a medication that has recently gained momentum in treating refractory NVP is a serotonin antagonist, ondansetron (Zofran®). This drug works by blocking the chemoreceptor trigger zone in the medullary vomiting center. Although anecdotal evidence abounds regarding its efficacy in cases of HG, there is a paucity of available randomized data. It carries a class C designation. An initial suspicion of it being linked with cleft lip and palate has not been subsequently validated.10 Also, the FDA has warned about the rare possibility of an association with lengthening of the QT interval, especially in patients with pre-existing cardiovascular problems.11
Dopamine Antagonists. In this category are the phenothiazines, which have antipsychotic as well as antiemetic properties. More commonly used are the phenothiazines, prochlorperazine (Compazine) and chlorpromazine (Thorazine), both carrying Class C labels. Another in this category is the class C benzamide, metoclopramide (Reglan). Combined data from three older randomized, placebo-controlled studies7 showed significant benefit of the phenothiazines in NVP. Safety data, however, have been inconsistent and prolonged use can be associated with withdrawal in newborns and extra-pyramidal affects.
Also working on the vomiting trigger center through dopamine receptors, trimethobenzamide (Tigan) and metoclopramide have been used as second-line drugs in refractory NVP and have class C and B listings, respectively. Yet few data exist regarding their efficacy.
Steroids. Methylprednisolone (prednisone) has been used as a last-ditch treatment for HG, but rarely for milder NVP. Interestingly, although one study12 showed this drug to be superior to promethazine in treating HG, especially regarding rates of re-hospitalization, another later randomized, controlled trial13 found no difference in the rate of re-hospitalization with this steroid vs placebo. Initially, there was a question of a linkage with cleft lip and palate, but this risk is low (1-2 per 1000 treated).14 However, its potential adverse neonatal and maternal effects (on the adrenal) should make this mostly a last-resort, short-term strategy for hospitalized patients.
Alternative Therapies. Lifestyle changes. Avoidance of a stressful environment is easy to prescribe but often difficult to accomplish. The catalyst to NVP is often the home environment, which could be a major reason hospitalization is effective. Unfortunately, providing an alternate living setting often is not practical.
Ginger Root. Thought to have a direct effect on the GI system, the lay literature is replete with testimonials of the efficacy of ginger root in curbing NVP. Many RCTs have suggested its benefit in NVP compared with placebo controls, but others have shown no added benefit over pyridoxine alone. In the treatment of HG, a more recent RCT showed improvement in nausea (85% vs 56%) and vomiting (50% vs 9%) with ginger root compared with placebo.15 There has been no evidence of adverse fetal effects but since there is some suspicion that ginger root can interfere with maternal platelet aggregation, it may not be the first choice in patients on low-dose aspirin or anticoagulants.
Acupuncture. For NVP, the Neguian acupoint on the inner wrist (P6) has been the locus of attention for either pressure via a wristband (either with pressure alone or with acoustic stimulation) or an acupuncturist’s needle. Efficacy studies have had conflicting results, and randomized trials have been hindered by the lack of adequate controls. However, a recent randomized trial from Australia16 did show benefit of acupuncture delivered in two ways. Smith et al assigned 593 patients with NVP to having traditional acupuncture, P6 acupuncture, sham procedures, or no treatment (controls). Both types of acupuncture caused a lessening of nausea, vomiting, and dry retching vs controls. Interestingly, the sham approach reduced nausea and dry retching, but not vomiting.
Marijuana (cannabis). Living in Colorado where marijuana has recently been legalized, how can I not mention this as an alternative to reduce unresponsive NVP? It has been used on occasion to reduce nausea and vomiting from chemotherapy. However, although one can find glowing anecdotal accounts online regarding its use in severe NVP, evidence-based information is difficult to come by — mostly because investigators are reluctant to stray into this highly charged social and political arena.
As an example of the only type of information available on efficacy, in a published survey17 from British Columbia (the Vancouver Island Compassion Society), 84 pregnant women responded anonymously to a questionnaire and 36 admitted to using marijuana to curb nausea and vomiting. Ninety-two percent claimed they found it to be either "extremely effective" or "effective."
A few studies have explored possible adverse effects of marijuana. One often-quoted follow-up investigation18 involved infants of Jamaican mothers who had prenatal exposure to marijuana (ganja), where, despite being illegal, it is commonly used to combat NVP. There were no differences in birth weight or in neurological testing (by the Brazelton scale analysis) at 3 days of age in exposed compared with control neonates. Ill-conceived bumper sticker material could spring from the puzzling finding that the marijuana-exposed infants tested better neurologically after 30 days than controls — which may well have been due to socioeconomic factors. Surveys of 12,060 British women in 2002,19 12,885 Dutch women in 1999,20 as well as 32,483 mothers in Australia in 199721 found no differences in birth weights in marijuana users vs controls after accounting for confounding variables.
Obviously, birth weight is one endpoint to evaluate because of the association between cigarette smoking and intrauterine growth restriction, but more extensive testing would be needed to clear marijuana of a possible effect on the fetal CNS, a possibility suggested by some cognitive studies in children exposed in utero22,23,24 during sustained use, but not others.25 Nevertheless, in special cases the potential benefit of this short-term approach cannot be easily pushed aside.
1. Dietary manipulation
2. Vitamin adjustment
3. Pyridoxine (B6), 25 mg TID
4. Doxylamine (Unisom), 10-20 mg HS
5. Diclegis (instead of 3 and 4), 1-2 tabs HS or up to 5 per day
6. Ginger root, 250 mg QID
7. Acupressure band
8. Avoidance of work or home stressors
Second-line approach (if NVP not improved after 5-7 days)
1. Another H1 blocker such as dimenhydrinate (Dramamine), 25-50 mg q 4-6 hrs; promethazine (Phenergan), 12.5-25 mg TID; or meclizine (Antivert), 25 mg q 4-6 hr
2. A phenothiazine such as prochlorperazine (Compazine), 5-10 mg QID, or another dopamine antagonist such as metoclopramide (Reglan), 5-10 mg TID
3. A serotonin antagonist such as ondansetron (Zofran), 4-8 mg TID
Third-line treatment (if all else fails)
1. Hospitalize if weight loss of > 5% of original body weight, significant dehydration, or electrolyte inbalance.
2. IV hydration and correction of electrolyte inbalance
3. Explore H. pylori (with GI consultation) as a cause and treat if there is a suspicion of causation
4. Consider steroids: methylprednisolone 16 mg TID x 3 days, then taper
5. Short-term parenteral nutrition may be necessary
Severe NVP can occasionally develop into some very serious complications, such as vitamin deficiency (especially thiamin) resulting in conditions such as Wernicke syndrome, as well as hypokalemia, acid-base imbalance, and impressive maternal weight loss. One study has shown that women with HG who gained < 15 pounds have a higher rate of low birth weight infants and lower 5-minute Apgar scores.26 While not having an obvious effect on neurological outcome at 1 year of age, there is a higher rate of low birth weight, preterm birth, and SGA infants.27
Based on the known possible complications of intractable NVP, and its significant disruptive effect on patients and their families, one cannot ignore the known benefits of some second- and third-line therapies when compared with their unknown or unlikely risks. Table 1 represents a simplified approach to the treatment of NVP.