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Clinical Reviews


Nausea and vomiting of pregnancy: Q&A with T. Murphy Goodwin

An expert tells why this common condition is undertreated, and what can help, including how to formulate the effective drug formerly marketed as Bendectin.

August 2004 · Vol. 16, No. 8

KEY POINTS

  • About 35% of gravidas have nausea and vomiting severe enough to disrupt their daily routine. As many as 50% of women with severe NVP are not offered antiemetic therapy, studies show.
  • At any level of severity, nausea and vomiting cause psychosocial morbidity.
  • Multivitamin use at the time of conception reduces the severity of nausea and vomiting.
  • When drug therapy is necessary, start with 10 to 25 mg pyridoxine (vitamin B6) 3 or 4 times daily.
  • If nausea and vomiting continue, add 12.5 mg doxylamine (by halving the over-the-counter sleep aid Unisom) to each dose of pyridoxine. The pyridoxine-doxylamine combination is the same formulation as the highly effective drug Bendectin, which is no longer available in the US.

T. Murphy Goodwin, MD, a contributor to the new American College of Obstetricians and Gynecologists practice bulletin on nausea and vomiting of pregnancy (NVP), 1 tells why it is important to ask every patient about nausea and vomiting, when to intervene, and what the best treatments are—including a substitute compound for the no-longer-available drug Bendectin.

Dr. Goodwin is professor of obstetrics and gynecology at the Keck School of Medicine, University of Southern California, Los Angeles.

Many patients assume they must endure nausea, vomiting

  • Women do not always mention nausea and vomiting, believing they must “live with it.” Prompt intervention can stave off more severe NVP, so it makes sense for Ob/Gyns to raise the subject early.

OBG MANAGEMENT: What new information in the American College of Obstetricians and Gynecologists (ACOG) practice bulletin should the Ob/Gyn be aware of?

GOODWIN: Rather than “new information,” I would call it a change in emphasis. Previously, the focus was almost exclusively on life-threatening hyperemesis gravidarum, while lesser degrees of nausea and vomiting of pregnancy went untreated or undertreated. In reality, approximately 35% of gravidas have NVP severe enough to interfere with their daily routine. Fortunately, effective therapy is available.

OBG MANAGEMENT: Some authorities believe NVP is a continuum between mild upset and hyperemesis gravidarum. How would such a continuum affect patient care?

GOODWIN: Epidemiologic studies suggest that women with mild NVP and those with hyperemesis are significantly similar, strongly supporting the notion of a continuum. 2 This fact underscores the importance of treating NVP in its early stages, before it advances to hyperemesis.

My own sense is that a small group of women with hyperemesis are predisposed to it because of rare genetic disorders such as mitochondrial mutations.

OBG MANAGEMENT: Since so many women experience NVP, should obstetricians routinely ask about it, including its psychosocial effects?

GOODWIN: Yes. This is important because of the continuum we mentioned—and because many women consider NVP “normal” and may not mention it unless they are asked.

OBG MANAGEMENT: Do you think some physicians share this mindset?

GOODWIN: Undoubtedly. Studies have shown that as many as 50% of women with severe NVP are not offered antiemetic therapy.3,4 But the days of letting the condition “run its course” are past. Now the best strategy is asking about it—and intervening early.

What causes NVP?

  • The factors at play in each patient help determine the best treatment. NVP is more likely with high levels of hCG and estrogen.

OBG MANAGEMENT: In a 2002 study,5 you concluded that NVP is actually a syndrome rather than a single condition.

How would this concept affect management of NVP?

GOODWIN: Women who are susceptible to NVP because of a vestibular mechanism might respond to a medical regimen that works at that site. Still other women may have “background” gastrointestinal motility dysfunction that makes them more susceptible to NVP; in that case, therapies to treat motility abnormalities would be appropriate. Others may have a strong behavioral overlay and would be expected to respond to the kinds of treatment used for anticipatory nausea and vomiting associated with chemotherapy.

These are theoretical scenarios at present, but a new paradigm will allow new ways of thinking about therapy.

OBG MANAGEMENT: In the early 1990s, you and your colleagues 6 reported your study on the link between human chorionic gonadotropin (hCG) and NVP. What is the association?

GOODWIN: A temporal association has attracted the attention of obstetricians for years. In addition, biochemical hyperthyroidism and NVP are strongly associated. Fifty percent to 70% of women with hyperemesis gravidarum have transient hyperthyroidism, with no goiter.7 (If a goiter is present, suspect primary thyroid disorder.) Because hCG causes the biochemical hyperthyroidism related to pregnancy, and because hyperthyroidism by itself rarely causes vomiting, hCG is implicated. However, it remains unclear how hCG would cause NVP—perhaps by stimulating the ovary to produce more estrogen, which causes emesis, or through some other, unknown step.

Interestingly, a number of “high-hCG” conditions are associated with increased NVP: molar pregnancy, multiple gestation, and Down’s syndrome. Conversely, trisomy 18 is a “low-hCG” condition anecdotally associated with reduced NVP.

OBG MANAGEMENT: What is estrogen’s role?

GOODWIN: Estradiol and hCG are the only 2 hormones ever found to differ when women with NVP are compared to controls. Women who get sick with estrogen exposure are much more likely to develop NVP. Some studies have found increased estradiol levels in women with NVP, compared with controls.6,8 Conversely, low estradiol levels may reduce the risk of NVP. Take smoking, for example. It is associated with lower hCG and estradiol levels, and smokers are less likely than non-smokers to have NVP.

Studies also have focused on a possible link between cytokines and hyperemesis, and between hyperemesis and tumor necrosis factor alpha.

OBG MANAGEMENT: Do these findings alter clinical management?

GOODWIN: No. The findings about etiology do not affect management at present.

NVP can be protective or perilous

  • Some degree of nausea and vomiting affects the vast majority of pregnancies. Unless it is severe, however, NVP appears to have a protective effect on the fetus.

OBG MANAGEMENT: What is the prevalence of NVP, and what are its characteristics?

GOODWIN: About 70% to 85% of gravidas experience it. 9 In the spectrum of NVP, about 50% of women experience both nausea and vomiting, 25% experience nausea alone, and 25% are unaffected.10

Hyperemesis gravidarum affects roughly 3 to 20 of every 1,000 pregnancies.

It generally is categorized according to the level of intervention required:

  • Mild NVP does not affect daily life.
  • Moderate NVP interferes with daily life.
  • Severe NVP, or hyperemesis, requires fluid and/or nutritional support. Hyperemesis is further defined as persistent vomiting, weight loss exceeding 5% of prepregnancy weight, and significant ketonuria, with or without electrolyte disturbances. Hospitalization usually is required.

OBG MANAGEMENT: What is the clinical course?

GOODWIN: NVP almost always appears before 10 weeks’ gestation. If it begins any later, it is likely the patient has a different condition associated with nausea and vomiting.

One study found that most women develop NVP at about 4 to 7 weeks’ gestation, and that it resolves at less than 10 weeks in about 30% of women, at 10 to 12 weeks in another 30%, and at 12 to 16 weeks in another 30%.10

As for diurnal changes, symptoms tend to occur with greater frequency early in the day.

OBG MANAGEMENT: Is NVP ever harmful for the fetus?

GOODWIN: It is associated with improved fetal outcomes unless hyperemesis supervenes. Then it is associated with mild fetal growth delays and rare cases of fetal death.

We lack studies of the long-term effects of severe NVP on the fetus, but starvation and weight loss in women during famine have been shown to cause many diverse problems in offspring later in adult life.

OBG MANAGEMENT: What do you make of evidence that suggests NVP plays a protective role in pregnancy?

GOODWIN: If true, it likely represents a vestigial response that is no longer beneficial—similar to thrombophilias in pregnancy, which played an important role protecting women against bleeding at childbirth but now are more of a clinical problem because of the associated thrombosis.

NVP at a glance: Pervasive, disabling, and undertreated

Prevalence. 70% to 85%.1

Presentation. About 50% of women have both nausea and vomiting, 25% have nausea only, and 25% are not affected.10

Hyperemesis gravidarum. 3 to 20 of every 1,000 pregnancies. Marked by persistent vomiting, weight loss exceeding 5% of prepregnancy weight, and significant ketonuria.

Clinical course. If NVP is going to occur, it is present before 10 weeks’ gestation. It resolves at less than 10 weeks’ gestation in about 30% of women, at 10 to 12 weeks in another 30%, and at 12 to 16 weeks in another 30%.10

Predisposing factors. History of illness with estrogen exposure, motion sickness, migraine, or hyperemesis; mother or sister with hyperemesis; female fetus; mitochondrial disorders; multiple gestation; gestational trophoblastic disease; and fetal anomalies such as Down’s syndrome and triploidy.

Undertreatment. As many as 50% of women with severe NVP are not offered therapy.3,4

Physical discomfort. Intensity and character similar to nausea and vomiting induced by cancer chemotherapy, even at milder levels of severity.11

Social and psychological impact. Reduced job efficiency, lost work time, negative impact on family relationships and mental health, decision to terminate an otherwise desired pregnancy. Women with hyperemesis are more likely to have anxiety, depression, somatization, psychoticism, and obsessive-compulsive symptoms, but return to normal after delivery.21

Fetal effects. Improved fetal outcomes unless hyperemesis supervenes. Hyperemesis with maternal weight loss is associated with mild fetal growth delays and rare cases of fetal death.

Maternal effects. Not linked to adverse effects except for hyperemesis gravidarum, in which Wernicke’s encephalopathy, Mallory-Weiss tears, splenic avulsion, esophageal rupture, pneumothorax, acute tubular necrosis, or peripheral neuropathy (due to vitamins B6 and B12 deficiencies) can result.

Effects on the mother and predisposing factors

  • Even at milder levels, physical discomfort is considerable. Predisposing factors include a female fetus, history of hyperemesis, migraine headaches, and a tendency to develop motion sickness.

OBG MANAGEMENT: How does NVP affect the mother?

GOODWIN: Serious sequelae are limited to hyperemesis, in which case Mallory-Weiss tears, splenic avulsion, esophageal rupture, pneumothorax, acute tubular necrosis, peripheral neuropathy (due to deficiencies of vitamins B6and B12), or Wernicke’s encephalopathy can result. This last condition is the most serious potential complication, and it can be difficult to recognize. Look for signs of confusion, memory loss, and blunted affect.

Even at milder levels of NVP, however, physical discomfort can be considerable. One prospective study using the McGill Nausea Questionnaire found the nausea experienced by pregnant women to be similar in character and intensity to that experienced by cancer patients on chemotherapy.11

OBG MANAGEMENT: Are there predisposing factors?

GOODWIN: Yes. They include a history of illness upon exposure to estrogen (for example, oral contraceptives), as well as a history of motion sickness and migraine.

Hyperemesis is more likely when the fetus is female. Women who had hyperemesis in a previous pregnancy are likely to experience it again in their next gestation, and their daughters and sisters also are more likely to develop it.

Bendectin: The sad saga of a useful drug

The most widely prescribed drug for nausea and vomiting of pregnancy (NVP), Bendectin, was voluntarily withdrawn from the US market in 1982, after numerous, unsuccessful lawsuits alleged it had caused birth defects.

After its withdrawal, hospitalization rates for NVP doubled while solid evidence of Bendectin’s safety continued to accumulate. In the years since, researchers have found no difference in major malformations between infants in the general population and those born to women who took Bendectin. Nor has there been any decrease in specific malformations. As the New England Journal of Medicine pointed out, a decrease in the number of malformations “would be expected for a truly teratogenic drug estimated to have been used by up to 40% of pregnant women at one time.”18

The drug is still available in Canada, where it is marketed as Diclectin. In the US, its ingredients—pyridoxine (vitamin B6) and doxylamine—can be compounded by a pharmacy, or the patient can be instructed to take 10 to 25 mg of pyridoxine and 12.5 mg of Unisom (half a tablet) 3 or 4 times daily. (Unisom is an over-the-counter sleep aid containing doxylamine succinate.)

We also know that inherited and acquired disorders of mitochondria commonly manifest as migraine and/or gastrointestinal disease, including nausea and vomiting.12

Continued...
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