Abstract
Nausea and vomiting of pregnancy (NVP) affects approximately 80% of pregnant women; however, this condition is not always addressed, let alone treated appropriately. NVP can be physically debilitating and can also interfere with the socioeconomic aspects of a woman's life. Some women and healthcare providers are unaware of the various NVP treatments and means of management. Lack of treatment may result from misinformation or misperception regarding NVP treatments and its safety during pregnancy. However, several studies have shown that there are effective pharmacological options that do not cause adverse effects in the mother or her unborn baby. The potential consequences of untreated NVP include substantial maternal weight loss, dehydration, hospitalization, low birthweight and depression. The following review provides a detailed description of NVP and how it can adversely affect a woman's life, as well as evidence-based information on treatment strategies.
Approximately 75–80% of pregnant women experience some degree of nausea and vomiting of pregnancy (NVP), yet there is still much that is unknown about this condition, its causes, and its treatment. The abruptness, persistence and severity of these symptoms can be the first indication of pregnancy, in addition to missing the menstrual period. Hyperemesis gravidarum (HG), the most severe form of NVP, which can put a pregnant woman at risk of dehydration, substantial maternal weight loss, electrolyte imbalance and often requires hospitalization, affects approximately 1% of pregnant women [1]. Therefore, it is important to emphasize and encourage the treatment of NVP, whatever the degree of severity, to promote a healthy pregnancy for mother and child. This article describes the clinical presentation of NVP, including a review of the etiology and aggravating factors of NVP, and outlines in detail the pharmacological and nonpharmacological treatments.
Clinical presentation & assessment
NVP usually starts between 4–7 weeks of pregnancy, and the symptoms peak in severity at approximately 8–12 weeks. Although it is anticipated that symptoms gradually improve after 12 weeks (first trimester), they may not improve until the woman reaches 20 weeks (halfway point of pregnancy), or in a minority of cases, NVP may persist throughout pregnancy. In a study of 160 pregnant women, 50% had relief by 14 weeks, 90% by 22 weeks, and 10% had some degree of nausea persisting beyond that point [2]. It was observed in another study that women who experienced NVP late in pregnancy (>20 weeks) had a much higher parity, were older, gained less weight in pregnancy, and slept fewer hours per night compared with women who did not experience late NVP [3]. On a daily basis, NVP is not only ‘morning sickness’, but may actually be most prevalent for some women in the afternoon, evening or all waking hours. In the same study of 160 pregnant women, 80% experienced NVP all day (morning, afternoon, evening and bedtime), while a small proportion (<10%) reported experiencing symptoms at only specific times of the day (i.e., morning only or evening only) [4]. Some pregnant women can tolerate the frequency or persistence of NVP (i.e., mild nausea all day long), but it may become unbearable if the intensity of NVP is severe.
The Motherisk pregnancy-unique quantification of emesis and nausea (PUQUE) scoring system (Table 1) is a validated tool to measure the severity of NVP based on frequency [5]; however, it is often difficult to account for the effect of intensity on NVP severity.
Motherisk-PUQUE scoring system.
Total score: mild, <6; moderate, 7–12; severe, 13. PUQUE: Pregnancy-unique quantification of emesis and nausea.
Currently, the most applicable tools to measure the intensity of NVP are those used in measuring the severity of nausea and vomiting produced by chemotherapy treatment such as the McGill Nausea Questionnaire (Figure 1) [4]. The selection of adjectives within the McGill Nausea Questionnaire provides a fairly accurate depiction of NVP intensity.
McGill Nausea Questionnaire.
In addition to the three main symptoms of NVP – nausea (the most common), retching and/or dry heaving, and vomiting – pregnant women may also describe dizziness, fatigue, and/or lack of energy, all of which may result from the symptoms or sleep interrupted by NVP. Furthermore, women may also report that NVP is triggered or aggravated by swallowing difficulties, an increased sense of smell, food aversions, excessive salivation or teeth brushing [2].
HG is often described as a condition of uncontrollable vomiting during pregnancy that can lead to dehydration, nutrition deficiency, electrolyte and acid–base imbalance and severe maternal weight loss [1]. Women suffering from HG are frequently hospitalized to receive intravenous fluid therapy, vitamin supplementation, electrolyte imbalance correction and antiemetic therapy [1]. When left untreated, HG can deteriorate or even threaten the mother's health, and can lead to adverse pregnancy outcomes such as low birthweight or preterm delivery. In addition, the unbearable effects can lead to a woman deciding to have an elective termination, which has been documented to occur in approximately 2% of pregnancies [1].
The socioeconomic effect of NVP
NVP can substantially affect the economic, personal and emotional wellbeing of women's lives. Many employed pregnant women who suffer with untreated NVP must take time off work, which results in loss of income. A British study determined that 35% of pregnant women lost an average of 62 h from paid work due to NVP; which is similar to the findings of an American study, showing that women lost an average of 8.4 days (approximately 64 h) from paid work [6,7]. The societal cost/patient was approximated to be US $2947, which includes lost wages, hospitalization, and visits to various healthcare resources (i.e., physicians, clinics and dieticians) [7]. The debilitating effects of NVP can also interfere with domestic work and social functioning. It is not unusual for NVP to adversely affect a woman's relationship with her partner or employer, resulting in feelings of helplessness, frustration or resentment among all parties involved. The isolating and stressful experience of NVP, particularly severe NVP, has also been associated with frequent feelings of depression, an increased consideration of terminating the pregnancy, and a misperception that NVP would harm the unborn child [8]. Therefore, the psychosocial morbidity caused by NVP is as relevant as the physical effects.
Etiology & aggravating factors
Hormonal changes
The etiology of NVP remains unknown and requires ongoing research; however, different investigators have proposed several causes. Pregnancy results in a dramatic change in hormone levels, which is often hypothesized as the primary cause of NVP. The pattern of NVP mimics that of human chorionic gonadotropic (hCG) hormone levels during pregnancy: both peak at approximately 10–14 weeks of pregnancy, decline at approximately week 20, and stabilize beyond that point [2]. Molar and multiple pregnancies (i.e., twins, triplets) are associated with elevated hCG levels, as well as quite persistent and severe NVP [2]. However, a causal relationship between hCG levels and NVP remains inconclusive because there are some pregnant women with elevated hCG levels who do not experience any or suffer very mild NVP, and there are some pregnant women who experience moderate to severe NVP throughout the entire pregnancy even when hCG levels have lowered. Changes in levels of estrogen, progesterone and other hormones (i.e., thyroid-stimulating hormone [TSH]) have also been implicated in causing NVP; however, the evidence has been circumstantial [1,2].
Changes within gastrointestinal tract
It has also been suggested that pregnancy-induced hormonal changes are associated with gastrointestinal (GI) tract dysfunction or abnormalities such as gastric dysrhythmia or gastroparesis, resulting in NVP symptoms [2,9]. Other GI symptoms that can potentially result from this GI tract dysfunction include heartburn, acid reflux, abdominal pain or discomfort, indigestion (i.e., bloating), constipation and diarrhea, all of which are commonly reported by pregnant women and, if left untreated, can trigger or worsen NVP. In addition, some pregnant women have GI medical conditions such as irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, or peptic ulcers, which require proper management through diet and/or medications. Untreated GI medical conditions can result in symptoms (i.e., constipation, heartburn and abdominal pain) that trigger or worsen NVP.
Some investigators have suggested that infection by the Helicobacter pylori bacteria factors into the etiology and aggravation of NVP; however, the evidence has been limited and contradictory. H. pylori, a gram-negative bacterium that can cause chronic gastric infection, affects approximately 30% of the population in developed countries (and up to 80% in developing countries) [10,11]. H. pylori infection can result in GI upset (i.e., abdominal pain after meals) and malabsorption of some micronutrients (e.g., iron, folic acid and vitamin C), and can potentially lead to chronic gastritis, duodenal and gastric ulceration, or some types of gastric cancer [10,11]. A few studies have suggested that H. pylori infection is associated with HG or severe NVP, while other studies have countered that no relationship exists [10,12].
One study of 185 pregnant women, who were tested for H. pylori with the IgG antibodies test, suggested that only a temporal relationship exists, determining that H. pylori infection may be associated with vomiting in early pregnancy (first trimester), but not with vomiting that occurs later [12]. Some investigators proposed that the hormonal and gastric pH changes during pregnancy can activate a dormant H. pylori infection within the system, causing abnormal gastric emptying and hypersensitivity to gastric or duodenal distention, which can all trigger or worsen NVP [12]. Pregnant women who are diagnosed with HG or struggling with severe NVP in which all treatment options have failed may want to consider testing for H. pylori to obtain appropriate treatment in the case of infection.
Food and fluid options that pregnant women may find tolerable with nausea and vomiting of pregnancy.
Handful of dried fruit/nuts
Handful of cereal
Trail mix
Ginger cookies/candies
Pregnant women are not limited to just these suggestions and should try any type of food that they can tolerate – the key is small portions.
Liquid supplements
Fruit juice slushies
Fruit smoothies
Popsicles/freezies
Tea (up to three cups allowed per day, avoid raspberry leaf tea)
Sports drinks
Ginger tea/ale
Multivitamins
Many pregnant women supplement with prenatal multivitamins to prevent vitamin and mineral deficiency and promote healthy fetal development. However, common (over-the-counter) prenatal multivitamins can contain a high iron dose to compensate for the inhibited iron absorption due to calcium. Although iron supplementation is important during pregnancy to prevent iron deficiency, anemia and low birthweight, it can trigger adverse GI effects such as nausea, vomiting, constipation, diarrhea, heartburn or abdominal discomfort [13]. Most multivitamins are also large in tablet size (‘horse pill’) and swallowing them can trigger gagging and vomiting. Thus, continuing to take multivitamins with a high iron dose or a large tablet size can worsen NVP symptoms.
Treatment strategies for NVP
Treatment and management of NVP initially involves healthcare providers (i.e., physicians, obstetrician and midwives) who should inquire about NVP, as some pregnant women focus only on the health of their baby and neglect to mention their NVP. Second, the severity of the symptoms should be assessed, if possible utilizing the Motherisk-PUQUE score and the McGill Nausea questionnaire. Third, it is important to rule out and treat other causes of nausea and vomiting such as GI medical conditions (i.e., Crohn's disease) or H. pylori infection. Healthcare providers and pregnant women should then proceed to treat and manage NVP with an effective strategy that suits the individual, combining nonpharmacological and pharmacological treatments.
Nonpharmacological treatments
Managing NVP will require utilizing modalities in the area of nutrition, minimizing aggravating factors and promoting physical comfort. Most pregnant women suffering with NVP will notice changes in their appetite and dietary habits as a result of a sensitive digestive system in which certain foods and fluids can trigger NVP. Pregnant women should avoid eating and drinking large amounts since the sensitive digestive system cannot tolerate those quantities (even though they may have been comfortable portions prior to pregnancy). Thus, it is preferable to eat small portions – as small as one or two bites – of food, and sip fluids every 1–2 hours throughout the entire day. Eating and drinking small portions frequently (i.e., hourly rate) helps pregnant women avoid having an empty stomach, which can also trigger NVP. Pregnant women should be encouraged to pursue a variety of foods and fluids which they can tolerate; especially when there is frequent vomiting, it is important to select foods and fluids that do not aggravate vomiting and can nourish the mother and unborn child (Box 1).
GI symptoms are very common during pregnancy and include abdominal discomfort, heartburn, acid reflux, indigestion, diarrhea and constipation, all of which can aggravate NVP, so alleviating GI symptoms is crucial in NVP management. Pregnant women can safely relieve heartburn, acid reflux and indigestion with over-the-counter antacids, most of which act locally in the GI tract, with minimal systemic absorption (although it is recommended to avoid antacids with bismuth, mainly due to its greater systemic absorption). Frequent diarrhea can cause dehydration, and women should maintain their fluid intake. Constipation can cause great discomfort and is often associated with hemorrhoids; therefore, preventing or alleviating constipation requires an adequate amount of dietary and supplementary fiber, adequate fluid intake, and possibly use of a stool softener upon consultation with a healthcare provider.
Alternative remedies that can offer some relief to pregnant women suffering from NVP include vitamin B6 supplementation, incorporating ginger into the diet, and wearing acupressure wristbands. Vitamin B6 is found at low doses in most prenatal multivitamins, as well as in the first-line pharmacological treatment of NVP, doxylamine–pyridoxine (Diclectin®, Duchesnay Inc., Canada). Two studies where vitamin B6 was administered at higher doses (25–30 mg) demonstrated that it can safely and substantially decrease nausea and vomiting episodes [14]. As a general guideline, women who are recieving doxylamine–pyridoxine can supplement with an additional 25 mg of vitamin B6, up to four times/day [14]. Women not medicated on doxylamine–pyridoxine can supplement with 25 mg of vitamin B6, up to seven times/day.
Supplementing with prenatal multivitamins is beneficial to pregnant women who suffer from NVP and lack dietary intake. Multivitamins can prevent vitamin and mineral deficiencies and promote a healthy pregnancy, and periconceptional (before and early in conception) intake has been shown to decrease NVP [14]. Owing to the high iron dose, large tablet and chalky taste of common prenatal multivitamins, many pregnant women find that taking their supplements triggers or worsens NVP. It is therefore recommended that women take multivitamins that are small in tablet size and have a low iron dose (recommended daily allowance: 27 mg). It is also acceptable to discontinue or even delay the start of prenatal multivitamins until the NVP is better managed. Pregnant women may tolerate taking a folic acid supplement alone, a children's chewable multivitamin or liquid vitamin supplements.
In addition, pregnant women may find some relief from NVP by ingesting ginger (i.e., ginger in food, ginger cookies, ginger candies, ginger tea or ginger root powder supplement) based on two studies, which showed that ginger intake reduced nausea and vomiting episodes [14]. Furthermore, a number of studies have suggested that acupressure wristbands can stimulate the Neiguan (P6) point, located on the inside of the wrist, which triggers several biochemical events in the body to control nausea and vomiting [15].
Pharmacological treatments
Many women and even some healthcare providers are hesitant or even opposed to treating NVP with any pharmacological interventions; however, these feelings may have resulted from misinterpreting the data on the safety of medications for nausea and vomiting. First, there is a great deal of misinformation regarding the teratogenic risk of NVP medications, arising from advisories in the media, popular books for pregnancy, and even some physicians, who may rely on outdated references [16]. The warnings may be misleading and inaccurate, and may overly emphasize the risks but rarely discuss the safety of NVP medications or the benefits of treatment [16]. Second, some women and healthcare providers may still perceive the risk of NVP medications to be high based on their own beliefs, opinions, or personal experiences, even after they are informed of the evidence from studies which strongly suggest that the use of the drug does not increase the risk of having a malformed child compared with the general population (baseline risk of 1–3%) [16]. Therefore, it is essential that both healthcare providers and women have access to updated evidence-based information (see information resources).
Figure 2 is an algorithm of NVP treatments based on evidence of fetal safety and effectiveness, as depicted by the hierarchical outline [16,17]. The first-line therapy is a combination of pyridoxine (vitamin B6) and an old antihistamine called doxylamine (or doxyalmine succinate); however, in Canada, the two active ingredients are formulated in a drug called Diclectin. Diclectin is a generic version of an older antiemetic called Bendectin® (Merrell Dow Pharmaceuticals Ltd., Canada), which was the only FDA-approved drug for NVP but was removed from the market due to unsubstantiated claims of teratogenicity [18]. Based on doxylamine–pyridoxine studies, Diclectin is safe to use during pregnancy and can be quite effective in reducing and controlling NVP, especially with a dosing regimen that is appropriate for the woman's weight and NVP severity [19].
Pharmacological treatment algorithm for nausea and vomiting of pregnancy.
Optimizing the use of doxylamine-pyridoxine
Healthcare providers should emphasize the following instructions to patients to optimize the effectiveness of doxylamine–pyridoxine:
A single dose or tablet of doxylamine–pyridoxine contains 10 mg doxylamine and 10 mg pyridoxine. The standard dose is four tablets each day, two at bedtime, one in the morning, and one in the afternoon.
Women must take the medication as prescribed every day (even on days when they do not feel ill).
After the first week of consistently taking doxylamine–pyridoxine, and depending on the severity of NVP, women can consult with their healthcare providers regarding increasing the dose and adjusting the schedule to ensure effectiveness.
It is safe to take up to eight tablets per day, each tablet may take up to 4 h to absorb into the bloodstream, and the slow release of each tablet can last up to 8 h.
If vomiting is frequent, then to avoid vomiting up the doxylamine–pyridoxine tablets, it is recommended that a 50 mg dimenhydrinate suppository (maximum of 200 mg/day) be taken 30 min before the scheduled doxylamine–pyridoxine. Dimenhydrinate, which is safe in pregnancy, provides short-term relief from the vomiting, long enough to allow the doxylamine–pyridoxine to be absorbed into the system.
Women can gradually wean off doxylamine–pyridoxine once they begin to feel almost 100% rid of symptoms. It is recommended that they eliminate one tablet at a time, testing out the new lower dose for 2–3 days to make sure they still feel comfortable before eliminating the next tablet.
It is important to understand that the medication is one part of the strategy and women must also make an effort with the nonpharmacological treatments.
Other NVP medications in the algorithm
When NVP is severe with frequent vomiting (it may be diagnosed as hyperemesis) and doxylamine–pyridoxine (even combined with dimenhydrinate) is ineffective, some pregnant women may require medications that are further along in the algorithm. The majority of evidence on the use of dopamine antagonists (i.e., chlorpromazine, prochlorperazine, promethazin, and metaclopramide) to treat NVP has been reassuring, especially to suggest no increased risk of malformations; however, the evidence is limited (i.e., small sample size, few studies) and these medications should only be considered when first-line therapies have failed [17]. Only one published study is available on the safety of ondansetron use during pregnancy. It is not indicated for NVP, but rather for nausea and vomiting due to cancer chemotherapy; however, some healthcare providers may resort to this treatment for their pregnant patients. Although the study is limited due to its sample size of 176 pregnant women who took the drug during pregnancy, the results are reassuring, suggesting no increased risk of malformations [20].
Furthermore, it should be noted that if pharmacological and nonpharmacological treatments discussed thus far lack effectiveness in minimizing and managing NVP, then severely ill patients may need to be hospitalized in order for them to be monitored by healthcare providers and properly treated (i.e., intravenous infusions).
Conclusion
Since NVP affects such a substantial number of pregnant women and can render serious consequences, it cannot be ignored, especially when there are safe and effective treatments available. When interviewing a pregnant woman during her first prenatal visit, it should be mandatory for healthcare providers to inquire about NVP, as many women do not volunteer this information. This is often because their symptoms have been minimized by others and they have been told that it is something they just have to tolerate when pregnant. Many are not even aware that there are safe and effective treatments. Healthcare providers should be made aware of the updated evidence-based information regarding various treatment modalities and offer them to their patients when appropriate. NVP manifests itself differently in each woman, so management should be tailor-made for each individual. This may include using treatments that are pharmacologically-based or more holistic, or most often, an effective combination of both. Timing of NVP treatment is also important since early treatment may prevent NVP from worsening, thus preventing socioeconomic problems such as hospitalization and time lost from paid employment, as well as preventing emotional and psychological problems. It is important that women and their healthcare providers understand that the benefits of safe and effective NVP treatments predominantly outweigh the potential or theoretical risks, thus all treatment options should be considered.
Future perspective
We are hopeful that within the next 10 years, it will be standard to address and treat NVP in prenatal care. It is important to rectify the misinformation and misperceptions of NVP treatments so that the ongoing suffering of many pregnant women and the potential consequences of untreated NVP are minimized, if not prevented. Hopefully, the use of reliable and updated evidence-based resources such as the Motherisk Program NVP Helpline will enable healthcare providers and women to feel more comfortable utilizing medications and other treatment options to manage NVP.
Information resource
The Motherisk Program NVP Helpline: