NVP Medications – Detailed
Women should read NVP Medication Introduction for additional background information prior to this page.
When lifestyle and diet modifications are inadequate at controlling symptoms to a tolerable level, women have effective non-pharmaceutical and pharmaceutical options with good (or increasing) safety profiles.
Numerous studies have indicated the earlier a woman asks for help, the more effective these options are in preventing further complications. Additionally, researchers are starting to recognize that even preemptive administration of some of these options may prevent symptoms from becoming too unmanageable in the first place.
However, overall, the actual effectiveness of any option is highly likely dependent on when the medication is started, contributing factors and additional symptoms of a woman's NVP, as well as severity of symptoms.
Most obstetrics organizations follow a "ladder" plan, in which the bottom rung is tried first (ginger capsules), and if ineffective, the next (higher) rung is tried (various prescription medications). However, this plan may not work for some women, as women with severe symptoms may need to start near the top.
Women should call their HCP when they begin experiencing symptoms. HCPs can evaluate certain aspects of a woman's life, overall health, risk factors, contributing factors, responsibilities, employment, stressors, and available support at home which can help women and their HCPs determine a path forward should symptoms become more severe.
Pregnant women should never take any over-the-counter medication, to include vitamins, sleeping aids, or antihistamines without speaking to their HCP first.
Background
When diet and lifestyle modifications cannot control symptoms, women have various non-pharmaceutical (ginger, vitamin B6) and pharmaceutical (prescription) options.
While many HCPs may be reluctant to treat NVP with certain medications, current evidence indicates there are numerous options available with increasing safety profiles.
It is important that women have a risks and benefits conversation with their HCP regarding all medication options currently recommended to treat NVP, based on that individual woman’s medical history, health and stage of pregnancy, risk factors, and severity of symptoms.
Prenatal Vitamins/Supplements
Prenatal vitamins taken at least one month before fertilization may have significant value in the prevention of NVP. It has been shown that women who took prenatal vitamins at least one month prior to pregnancy were less likely to suffer severe symptoms. This exact reason for this is unknown but may be due to an increased level of vitamin B6 (B6) in the body (women should not take supplemental B6 at any time without talking to an HCP first; described in further detail below).
Note: Magnesium is often indicated for nausea, but is not recommended for the treatment of NVP. Evidence regarding the use of supplemental magnesium for the prevention/treatment of NVP is lacking and is not routinely recommended. Further, if a woman is not deficient in magnesium, then supplemental magnesium can make NVP symptoms worse (see Magnesium).
Ginger
Although studies are relatively limited in scope and size, ginger has largely been shown to be an effective strategy for reducing nausea and vomiting during early pregnancy for some women. Studies have assessed ginger’s effectiveness in capsules, powder, syrup, biscuits, and root; most studies used ginger capsules at 1,000 (250 milligrams (mg), four times per day).
However, these forms are rarely compared to each other, as most studies only selected one and compared it to placebo or vitamin B6. Therefore, the most effective method of taking ginger is not known, and women may find swallowing capsules four times a day very difficult.
Regarding safety, although dozens have studies have shown very few adverse effects, bleeding is currently a likely “theoretical” but possible risk. However, almost all studies indicate that more research is needed in larger groups of women to determine any possible risk of bleeding during pregnancy associated with ginger.
Ginger can also cause heartburn, stomach irritation, drowsiness, headache, and dehydration; it can also interact with certain medications. Although most obstetric organizations recommend ginger as a first-line therapy for reducing NVP symptoms, women should talk to their HCP prior to taking any form of ginger, especially in women with acid reflux and frequent vomiting.
Read more detailed information (and references) regarding the safety and effectiveness of ginger on NVP symptoms.
Antacids
Acid reflux can be both a cause and a complication of NVP; acid reflux can cause nausea and vomiting; nausea and vomiting can also cause acid reflux. Additional studies have shown that some women gain significant relief while taking antacids because their NVP appears to be aggravated by or even completely caused by acid reflux.
H2 receptors, which can mediate nausea and reflux, are found in the brain and stomach and can be blocked through the action of acid reflux medications. H2 blockers (famotidine) and proton pump inhibitors (omeprazole) can be used safely to treat acid reflux and/or heartburn in women with NVP.
Read detailed information on the safety of these medications (see Heartburn/Acid Reflux).
Vitamin B6 (Pyridoxine) and/or Doxylamine
Vitamin B6 (pyridoxine/B6) is commonly recommended for the treatment of mild to moderate NVP and is considered a first-line therapy after dietary and lifestyle modifications – with or without doxylamine.
The exact mechanism for how B6 relieves nausea is not known, but most of B6’s primary effects are on the central nervous system. When B6 is broken down by the body, its main metabolite, pyridoxal-5-phosphate (P5P/PLP; its active form) may have a primary role but is still being researched.
Diclegis®, a delayed-release tablet containing a combination of pyridoxine and doxylamine was approved by the FDA in 2013, and is the first and only* FDA-approved drug for NVP.
This formulation was previously available on the market under the name Bendectin. Bendectin was taken off the market in 1983 in the U.S. due to reports of congenital malformations with first trimester use; it remained available in Canada (as Diclectin®).
Almost 30 years later, the FDA concluded “Bendectin was not withdrawn from the market for reasons of safety or effectiveness” and was finally approved as Diclegis® in 2013 (doxylamine succinate 10 mg, pyrodioxine hydrochloride 10 mg).
Numerous studies have been published documenting the effectiveness of B6/doxylamine on NVP.
According to a study presented at the 2013 National Pregnancy Sickness Support Conference in London, pre-emptive Diclectin® therapy may prevent severe NVP from recurring in a subsequent pregnancy.
However, this may not be specific to Diclectin®, as a Canadian study that compared women with NVP who took pre-emptive antiemetics before, or at the immediate start of their symptoms, reported less severity and better management of NVP during a subsequent pregnancy.
However, many other studies have indicated the drug combination is not effective, and that more research is necessary given that a significant number of women are prescribed this medication.
Notably, in their 2016 guidelines reading NVP, the United Kingdom’s Royal College of Obstetricians and Gynaecologists (RCOG) indicated that B6 should be not be used alone for NVP due to a lack of effectiveness; however, B6 with doxylamine had been shown to be slightly more effective.
Despite this, the American College of Obstetricians and Gynecologists (ACOG) indicated “that vitamin B6 (pyridoxine) alone or vitamin B6 (pyridoxine) plus doxylamine in combination is safe and effective and should be considered first-line pharmacotherapy".
Additionally, Health Canada has released numerous statements and guidelines standing by the effectiveness and safety of the drug combination; it remains a first-line therapy and is prescribed to an estimated 50% of pregnant women in Canada.
B6, and B6 in combination with doxylamine, have not been associated with adverse pregnancy outcomes, to include birth defects, miscarriage, low birth weight, preterm delivery, stillbirth, or neonatal death.
However, recommended dosing can vary, and depending on formulation, women are often recommended to take either B6 alone or with doxylamine up to three to four times/day.
The B6 tolerable upper intake limit in adults and in pregnancy is 100 mg/day, which can be reached or exceeded in some women depending on their recommended dose, especially if they are also taking prenatal vitamins. Although it does not appear that adverse effects during pregnancy have been indicated below 200 mg, women should talk to their HCP if they are concerned about reaching this daily limit, especially if they need to take the medication for months (read B6 Overview).
According to the FDA, Diclegis® is contraindicated in women with known hypersensitivity to doxylamine succinate, other ethanolamine derivative antihistamines, pyridoxine hydrochloride or any inactive ingredient in the formulation, as well as in women who are taking monoamine oxidase inhibitors (MAOIs). The most common adverse reaction reported with Diclegis® is drowsiness. Women should talk to their HCP regarding additional contraindications and adverse reactions with other medications.
In general, side effects of B6 can include headaches, fatigue, and paresthesia, or the sensation of “pins and needles".
Antihistamines
Antihistamines are the most widely used antiemetics for general nausea and vomiting. Antihistamines block histamine (H1 receptor) effects which increase stimulation of the vestibular system that can trigger the vomiting center.
Brand names include: Dramamine® (dimenhydrinate), Benadryl® (diphenhydramine), Unisom® (doxylamine)
Antihistamines are commonly prescribed during pregnancy. As of 2014, it was estimated that about 10% to 15% of pregnant women took an antihistamine for NVP, indigestion, allergies, or asthma.
Various antihistamines have been shown to be effective for the treatment of NVP.
Additionally, numerous studies have been published regarding the effectiveness of B6 plus the antihistamine doxylamine, as described above.
Reviews of dozens of studies have demonstrated a lack of association between antihistamine exposure during pregnancy and birth defects or adverse pregnancy outcomes and antihistamines not assessed to be teratogenic. However, antihistamines need to be further assessed individually for more optimal data.
The ACOG, RCOG, and Society of Obstetric Medicine of Australia and New Zealand (SOMANZ) recommend antihistamines after diet and lifestyle modifications, ginger capsules, and Vitamin B6 and doxylamine have failed to control symptoms.
Phenothiazines
Promethazine (Phenergan®), an antihistamine and phenothiazine, is predominantly used as an antiemetic to treat general nausea and vomiting and prevent motion sickness. Tt is also used for anxiety, tension, and as a mild sleeping aid. It is considered safe and effective to use for NVP but can cause considerable drowsiness, dry mouth, and sedation.
Chlorpromazine (Thorazine®) and prochlorperazine (Compazine®) are dopamine antagonists and have been shown to reduce NVP symptoms, to include symptoms of Hyperemesis Gravidarum (HG).
Because these drugs also have antihistamine effects, they are often used in the “same line” as antihistamines for the treatment of NVP.
Studies regarding this class of medications for NVP is much more limited than antihistamines in general.
Phenothiazines have been associated with an increased risk of birth defects and neonatal extrapyramidal side effects (see metoclopramide for more information) in the first trimester, particularly with chlorpromazine. However, as referenced above, many studies have not found these results; therefore, more research is necessary.
Ondansetron (Zofran®)
Ondansetron is a very popular and effective antiemetic for post-operative, chemotherapy-induced, and general nausea and vomiting. It is also often the medication of choice given to women for NVP in the U.S. who visit the emergency department, as well as those diagnosed with HG.
The use of ondansetron during pregnancy is intensely debated due to its significant effectiveness in most women with NVP/HG, but controversial safety profile. Most studies agree that ondansetron, overall, is not associated with major birth defects; however, associations have been made to cardiac septum defects and cleft lip and/or palate. These results are also inconsistent, and not every study has found these associations.
More detail regarding ondansetron can be read here.
Metoclopramide
Metoclopramide (Reglan®), a dopamine and serotonin antagonist, is both a prokinetic (promotes gastrointestinal motility) and antiemetic (anti-nausea/vomiting) medication used in the therapy of gastroesophageal reflux disease, gastroparesis, chemotherapy induced nausea, and NVP.
Metoclopramide specifically influences gastric contractions by promoting motility and accelerating emptying. It is believed (but debated) that gastric motility slows down due to progesterone in early pregnancy; therefore, metoclopramide could reduce NVP symptoms in women whose gastric function is impaired, or is a contributing factor to their symptoms.
Metoclopramide is not studied as well as other medications for the management of NVP, and its effectiveness remains inconsistent, as well as its possible adverse effects on pregnancy outcomes. However, most data are reassuring.
While one recent study found an increased risk of genital organ defects with the use of metoclopramide, another larger study did not find this association, nor did it find an increased risk of low birth weight, preterm delivery, or perinatal death. An additional smaller study also found no increased risk of adverse pregnancy outcomes.
A meta-analysis published in September 2021 of 33,374 metoclopramide-exposed and 373,498 controls found no significant increase in the rate of major congenital malformations (birth defects) following metoclopramide use during the first trimester.
Metoclopramide has been shown to have similar effectiveness to promethazine, but may be less effective than ondansetron. Further, it may have very little effect on motion sickness (vestibular system rather than gastrointestinal). Therefore, in women where susceptibility to motion sickness is a risk factor for NVP, it may not have much effect in these particular women, but more research is needed.
Metoclopramide has a rather large side effect profile due to the blocking of dopamine receptors. This side effects are known as “extrapyramidal symptoms”, or involuntary movement disorders. Metoclopramide may also cause drowsiness, dystonia, and dry mouth more than other antiemetics.
In 2009 the FDA added a black box warning to metoclopramide due to the risk of tardive dyskinesia (involuntary eye/facial movements) with chronic use; risk increases with total dosage and duration of treatment; therefore, FDA recommends it should not be used for longer than 12 weeks.
In July 2013, the European Medicines Agency recommended changing the use of metoclopramide to 10 mg three times a day up to 5 days to reduce the risk of these side effects; however, this was assessed to hinder women’s options as 5 days is rarely long enough to manage NVP.
Metoclopramide has been shown to be effective for NVP but due to its current safety profile, is used further “up the ladder” after antacids, B6 and doxylamine, and antihistamines.
In 2016, RCOG noted women should be made aware of the possible above-mentioned side effects, and indicated metoclopramide should not be used as a “first-option” for managing NVP, but can made available in women who do not respond to other medications.
ACOG currently recommends metoclopramide after lifestyle/dietary medications, ginger, B6 and doxylamine, and antihistamines have failed to control symptoms (same line as ondansetron).
Metoclopramide medication guide and side effect information is located here (FDA).
Corticosteroids
Corticosteroids are believed to exert an antiemetic effect on the CTZ in the brainstem. Oral and intravenous corticosteroids have been used for HG when all other options have failed to control symptoms; however, effectiveness is inconsistent.
There are no established guidelines for the use of corticosteroids for HG. However, it is usually recommended that treatment be stopped if no improvement is seen within three days.
With regards to safety, corticosteroids have low risk of teratogenicity, but have been associated with an increased risk of cleft lip; however, this risk can be minimized if used after 10 weeks of pregnancy.
Intravenous Fluids/Nutrition
Severe cases of NVP/HG or dehydration may require intravenous (IV) fluid therapy, enteral nutrition, or parenteral nutrition to improve the health of mother and prevent fetal growth restriction.
Women requiring multiple emergency department visits or hospitalizations may be considered for in-home IV hydration.
Enteral/Parenteral nutrition
Enteral tube feeding (a tube placed in the nose, the stomach, or the small intestine), and total parenteral nutrition (directly into peripheral or central vein) can be considered if IV therapy is not successful in reducing symptoms and there is still an increased risk of malnutrition.
Enteral: Nasogastric tubes (nose), jejunostomy (small intestine) may not be tolerated well in some women. Percutaneous endoscopic gastrostomy tubes (through the abdomen and into the stomach) have been used successfully in women with HG; however, infection and dislodgement of the tubes due to ongoing vomiting is a common complication.
Parental: Total parenteral nutrition (TPN) is considered in women who cannot tolerate enteral feeding. TPN is a nonprotein calorie source, usually glucose or lipid emulsions, that provides nitrogen, electrolytes, trace elements, water, and fat-soluble vitamins. Infection, bleeding, and tube dislodgment are frequent complications.
Marijuana
Marijuana has antiemetic (anti-nausea/anti-vomiting) properties, and the prevalence of pregnant women using marijuana to relieve NVP is increasing.
However, there is no evidence that marijuana is a current viable management option for NVP or HG, especially based on the potential for fetal harm, and the high amount that may be needed to see any relief. Further, marijuana/THC use can worsen NVP in some cases.
A recent study published in 2020 concluded THC may be effective for HG, but “should be studied in appropriately powered, controlled studies, fully considering potential fetal risks” and to date, marijuana cannot be considered safe during pregnancy. Additionally, the study only assessed its efficacy in four women, and much more research is necessary before THC can be considered a possible option.
Caution should also be considered, as some studies have shown marijuana use to increase the severity of NVP (cannabinoid hyperemesis syndrome), which can cause cyclical nausea and vomiting in long-term marijuana users, and can be mistaken for HG in early pregnancy.
Read more information on marijuana during pregnancy.
Action
Women should call their HCP when they begin experiencing symptoms. HCPs can evaluate certain aspects of a woman's life, overall health, risk factors, contributing factors, responsibilities, employment, stressors, and available support at home which can help women and their HCPs determine a path forward should symptoms become more severe.
Women should also make sure they understand all dosing instructions, how often they need to take any medication (i.e. round the clock or only as needed), how to manage side effects, and what to do if they miss a dose.
Many women suffering with moderate to severe NVP cannot take weeks (or months) away from work, parenting, or their otherwise every day routine. Women should not feel guilty if they need a prescription medication (recommended by their HCP) to help them manage their symptoms.
Pregnant women should never take any over-the-counter medication, to include vitamins, sleeping aids, or antihistamines without speaking to their HCP first.
Women should also consider sharing their NVP experience below, especially if their experience included taking any form of medication for their symptoms. This can help other women talk to their HCP and gain additional perspectives on this condition when diet and lifestyle changes have failed to work.
Partners/Support
It is not uncommon for partners to feel helpless once a woman's NVP symptoms start spiraling. Partners and other family members of pregnant women can help women keep track of their vitamins, supplements, and various medications, as well as doses and time each dose was taken. It may be difficult for some women to accurately keep track of time/dose when they are not feeling well or are falling in and out of sleep. Partners should also attend prenatal appointments and learn the NVP management plan as well.
Resources
Nausea and Vomiting of Pregnancy: Committee Opinion 189; January 2018 (American College of Obstetricians and Gynecologists)
Morning Sickness: Nausea and Vomiting of Pregnancy (American College of Obstetricians and Gynecologists)
Pregnancy sickness (nausea and vomiting of pregnancy and hyperemesis gravidarum) (Royal College of Obstetricians and Gynecologists)