Hyperemesis gravidarum refers to intractable vomiting during pregnancy that leads to weight loss and volume depletion, resulting in ketonuria and/or ketonemia. There is no consensus on specific diagnostic criteria, but it generally refers to the severe end of the spectrum regarding nausea and vomiting in pregnancy. It occurs in approximately two percent of all pregnancies in the United States. It can cause a significant impact on the quality of life of patients and, unfortunately, may be difficult to treat.
The etiology of hyperemesis gravidarum is largely unknown, but several theories exist (see pathophysiology). There are, however, risk factors associated with the development of hyperemesis during pregnancy. Increased placental mass in the setting of a molar or multiple gestations has been associated with a higher risk of hyperemesis gravidarum. Additionally, women who experience nausea and vomiting outside of pregnancy due to the consumption of estrogen-containing medications, exposure to motion, or have a history of migraines are at higher risk of experiencing nausea and vomiting during pregnancy. Some studies also suggest a higher risk of hyperemesis in women whose immediate family members, such as mothers or sisters, who also experienced hyperemesis gravidarum.
Up to ninety percent of women experience nausea during pregnancy. Studies show that approximately 27% to 30% of women experience only nausea, while vomiting may be seen in 28% to 52% of all pregnancies. The incidence of hyperemesis gravidarum ranges from 0.3% to 3% depending on the literature source. Geographically, hyperemesis appears to be more common in western counties.
The exact cause of hyperemesis gravidarum remains unclear. However, there are several theories for what may contribute to the development of this disease process.
Changes in the Gastrointestinal System
The history of a patient with suspected hyperemesis gravidarum should include their pregnancy status, estimated gestational age, history of complications during prior pregnancies, the frequency of nausea and vomiting, any interventions during which the patient has already tried to treat symptoms, and the outcomes of the attempted interventions. The average onset of symptoms happens approximately 5 to 6 weeks into gestation.
The physical exam should include fetal heart rate (depending on gestational age) and an examination of fluid status, which should include an examination of blood pressure, heart rate, mucous membrane dryness, capillary refill, and skin turgor. A patient weight should be obtained for comparison to previous and future weights. Abdominal examination, as well as pelvic examination, if indicated, should occur to determine the presence or absence of tenderness to palpation.
There is no single accepted definition for hyperemesis gravidarum. However, it generally refers to extreme cases of nausea and vomiting during pregnancy. It is a clinical diagnosis. The criteria for diagnosis include vomiting that causes significant dehydration (as evidenced by ketonuria or electrolyte abnormalities) and weight loss (the most commonly cited marker for this is the loss of at least five percent of the patient’s pre-pregnancy weight) in the setting of pregnancy without any other underlying pathological cause for vomiting. Significant abdominal tenderness, pelvic tenderness, or vaginal bleeding should prompt a workup for alternative diagnoses.
The evaluation should include urinalysis to check for ketonuria and specific gravity, in addition to a complete blood count and electrolyte evaluation. An elevation in hemoglobin or hematocrit may be due to hemoconcentration in the setting of dehydration. Significant dehydration may result in acute kidney injury as evidenced by an elevation in serum creatinine, blood urea nitrogen, and a reduced glomerular filtration. Potassium, calcium, magnesium, sodium, and bicarbonate may be affected by prolonged bouts of vomiting and reduced oral intake of fluids. Thyroid tests, lipase, and liver function testing may also be completed to evaluate for alternate diagnoses.
Radiographic studies may be appropriate to rule out alternate diagnoses. Obstetrical ultrasounds may be considered to rule out multiple gestations, ectopic pregnancy, and gestational trophoblastic disease depending on the patient’s history and prior obstetrical evaluations. Magnetic resonance imaging (MRI) may be used to assess alternative diagnoses, such as appendicitis.
Treatment should be guided by the American College of Obstetrics and Gynecology (ACOG) Nausea and Vomiting in Pregnancy guidelines. Initial treatment should begin with non-pharmacologic interventions such as switching the patient’s prenatal vitamins to folic acid supplementation only, using ginger supplementation (250 mg orally 4 times daily) as needed, and by applying acupressure wristbands. If the patient continues to experience significant symptoms, the first-line pharmacologic therapy should include a combination of vitamin B6 (pyridoxine) and doxylamine. Three dosing regiments are endorsed by ACOG, including pyridoxine 10 to 25 mg orally with 12.5 mg of doxylamine 3 or 4 times per day, 10 mg of pyridoxine and 10 mg of doxylamine up to 4 times per day, or 20 mg of pyridoxine and 20 mg of doxylamine up to 2 times per day. As demonstrated in multi-center randomized controlled trials, these first-line medications demonstrate efficacy in the treatment of nausea and vomiting, preserved good fetal and maternal safety profiles and are listed as one of the few FDA pregnancy category A medications.
Second-line medications include antihistamines and dopamine antagonists such as dimenhydrinate 25 to 50 mg every 4 to 6 hours orally, diphenhydramine 25 to 50 mg every 4 to 6 hours orally, prochlorperazine 25 mg every 12 hours rectally, or promethazine 12.5 to 25 mg every 4 to 6 hours orally or rectally. If the patient continues to experience significant symptoms without exhibiting signs of dehydration, metoclopramide, ondansetron, or promethazine may be given orally. In the case of dehydration, intravenous fluid boluses or continuous infusions of normal saline should be given in addition to intravenous metoclopramide, ondansetron, or promethazine. Electrolytes should be replaced as needed. Severe refractory cases of hyperemesis gravidarum may respond to intravenous or intramuscular chlorpromazine 25 to 50 mg or methylprednisolone 16 mg every 8 hours, orally or intravenously.
The diagnosis of hyperemesis gravidarum is clinical and largely a diagnosis of exclusion. The list of potential differential diagnoses for patients with similar symptoms is quite extensive. It can include:
It is important to evaluate patients for gestational trophoblastic disease and multiple gestations as they may also include severe nausea and vomiting in the first trimester of pregnancy. The workup may begin with an obstetrical ultrasound, which will confirm the diagnosis in most cases. Other first-trimester obstetrical concerns include ectopic pregnancy, which is more likely to include abdominal pain, syncope, or vaginal bleeding and can again be evaluated by obstetrical ultrasound and B-hCG levels.
The onset of nausea and vomiting after nine weeks should spark concern for alternative diagnoses. Preeclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelets), and acute fatty liver of pregnancy typically present themselves during the late second or third trimester of pregnancy.
Non-obstetrical causes for nausea and vomiting can also occur during pregnancy and should always remain on the differential, keeping in mind that pregnant patients are considered to be at higher risk of blood clotting; therefore diagnoses that result in ischemia or thrombus formation may be more common during pregnancy. Gastrointestinal causes such as gastroenteritis, small bowel obstruction, gastroparesis, peptic ulcer disease, cholecystitis, pancreatitis, hepatitis, and appendicitis should be considered. Pyelonephritis, urinary tract infections, renal stones, and ovarian torsion may also include vomiting. Metabolic derangements such as diabetic ketoacidosis, hyperthyroidism, and hyperparathyroidism may also have similar symptoms. Neurologic disorders such as migraine, intracranial hemorrhage, pseudotumor cerebri, and venous sinus thrombosis can also cause vomiting but are likely to have associated headaches or neurologic deficits. Psychiatric disorders such as anxiety and depression may also result in vomiting, as can toxic ingestions and myocardial ischemia.
Nausea and vomiting in pregnancy are common. Symptoms usually begin prior to 9 weeks gestation and the majority of cases are resolved by week 20 of gestation. A minority of patients, approximately 3%, will continue to experience vomiting during the third trimester. Approximately 10% of patients with hyperemesis gravidarum will be affected throughout the pregnancy.
As hyperemesis gravidarum involves 2 patients, both must be considered when discussing complications.
In severe cases of hyperemesis, complications include vitamin deficiency, dehydration, and malnutrition, if not treated appropriately. Wernicke’s encephalopathy, caused by vitamin-B1 deficiency, can lead to death and permanent disability if it goes untreated. Additionally, there have been case reports of injuries secondary to forceful and frequent vomiting, including esophageal rupture and pneumothorax. Electrolyte abnormalities such as hypokalemia can also cause significant morbidity and mortality. Additionally, patients with hyperemesis may have higher rates of depression and anxiety during pregnancy.
Studies report conflicting information regarding the incidence of low birth weight and premature infants in the setting of nausea and vomiting in pregnancy. However, studies have not shown an association between hyperemesis and perinatal or neonatal mortality. The frequency of congenital anomalies does not appear to increase in patients with hyperemesis.
Obstetrics consultation is indicated in the setting of hyperemesis gravidarum as it is the most severe form of nausea and vomiting in pregnancy. Admission is indicated for intravenous antiemetics and fluids in the setting of refractory symptoms, failed outpatient treatment, severe dehydration, or electrolyte disturbance.
Daily intake of a multivitamin with folic acid at least one month prior to conception not only reduces the risk of congenital anomalies such as neural tube defects but has also been associated with reduced frequency and severity of nausea and vomiting in pregnancy.
An interprofessional team that provides comprehensive care and an integrated approach to the treatment of nausea and vomiting in pregnancy can lead to the best patient-centered outcomes. [Level V]
|||Erick M,Cox JT,Mogensen KM, ACOG Practice Bulletin 189: Nausea and Vomiting of Pregnancy. Obstetrics and gynecology. 2018 May [PubMed PMID: 29683896]|
|||Goodwin TM, Hyperemesis gravidarum. Clinical obstetrics and gynecology. 1998 Sep [PubMed PMID: 9742356]|
|||Matthews A,Haas DM,O'Mathúna DP,Dowswell T, Interventions for nausea and vomiting in early pregnancy. The Cochrane database of systematic reviews. 2015 Sep 8 [PubMed PMID: 26348534]|
|||Lacasse A,Rey E,Ferreira E,Morin C,Bérard A, Nausea and vomiting of pregnancy: what about quality of life? BJOG : an international journal of obstetrics and gynaecology. 2008 Nov [PubMed PMID: 18752585]|
|||Fejzo MS,Ingles SA,Wilson M,Wang W,MacGibbon K,Romero R,Goodwin TM, High prevalence of severe nausea and vomiting of pregnancy and hyperemesis gravidarum among relatives of affected individuals. European journal of obstetrics, gynecology, and reproductive biology. 2008 Nov [PubMed PMID: 18752885]|
|||Czeizel AE,Dudas I,Fritz G,Técsöi A,Hanck A,Kunovits G, The effect of periconceptional multivitamin-mineral supplementation on vertigo, nausea and vomiting in the first trimester of pregnancy. Archives of gynecology and obstetrics. 1992 [PubMed PMID: 1503509]|
|||Emelianova S,Mazzotta P,Einarson A,Koren G, Prevalence and severity of nausea and vomiting of pregnancy and effect of vitamin supplementation. Clinical and investigative medicine. Medecine clinique et experimentale. 1999 Jun [PubMed PMID: 10410832]|
|||Goodwin TM, Nausea and vomiting of pregnancy: an obstetric syndrome. American journal of obstetrics and gynecology. 2002 May [PubMed PMID: 12011884]|
|||Bernstein L,Pike MC,Lobo RA,Depue RH,Ross RK,Henderson BE, Cigarette smoking in pregnancy results in marked decrease in maternal hCG and oestradiol levels. British journal of obstetrics and gynaecology. 1989 Jan [PubMed PMID: 2923845]|
|||Weigel MM,Weigel RM, The association of reproductive history, demographic factors, and alcohol and tobacco consumption with the risk of developing nausea and vomiting in early pregnancy. American journal of epidemiology. 1988 Mar [PubMed PMID: 3341360]|
|||Hinkle SN,Mumford SL,Grantz KL,Silver RM,Mitchell EM,Sjaarda LA,Radin RG,Perkins NJ,Galai N,Schisterman EF, Association of Nausea and Vomiting During Pregnancy With Pregnancy Loss: A Secondary Analysis of a Randomized Clinical Trial. JAMA internal medicine. 2016 Nov 1 [PubMed PMID: 27669539]|
|||Gadsby R,Barnie-Adshead AM,Jagger C, A prospective study of nausea and vomiting during pregnancy. The British journal of general practice : the journal of the Royal College of General Practitioners. 1993 Jun [PubMed PMID: 8373648]|
|||Lacasse A,Rey E,Ferreira E,Morin C,Bérard A, Epidemiology of nausea and vomiting of pregnancy: prevalence, severity, determinants, and the importance of race/ethnicity. BMC pregnancy and childbirth. 2009 Jul 2 [PubMed PMID: 19573237]|
|||Kimura M,Amino N,Tamaki H,Ito E,Mitsuda N,Miyai K,Tanizawa O, Gestational thyrotoxicosis and hyperemesis gravidarum: possible role of hCG with higher stimulating activity. Clinical endocrinology. 1993 Apr [PubMed PMID: 8319364]|
|||Goodwin TM,Montoro M,Mestman JH,Pekary AE,Hershman JM, The role of chorionic gonadotropin in transient hyperthyroidism of hyperemesis gravidarum. The Journal of clinical endocrinology and metabolism. 1992 Nov [PubMed PMID: 1430095]|
|||Soules MR,Hughes CL Jr,Garcia JA,Livengood CH,Prystowsky MR,Alexander E 3rd, Nausea and vomiting of pregnancy: role of human chorionic gonadotropin and 17-hydroxyprogesterone. Obstetrics and gynecology. 1980 Jun [PubMed PMID: 7383455]|
|||Goldzieher JW,Moses LE,Averkin E,Scheel C,Taber BZ, A placebo-controlled double-blind crossover investigation of the side effects attributed to oral contraceptives. Fertility and sterility. 1971 Sep [PubMed PMID: 4105854]|
|||Brzana RJ,Koch KL, Gastroesophageal reflux disease presenting with intractable nausea. Annals of internal medicine. 1997 May 1 [PubMed PMID: 9139556]|
|||Fejzo MS,Sazonova OV,Sathirapongsasuti JF,Hallgrímsdóttir IB,Vacic V,MacGibbon KW,Schoenberg FP,Mancuso N,Slamon DJ,Mullin PM, Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum. Nature communications. 2018 Mar 21 [PubMed PMID: 29563502]|
|||Viljoen E,Visser J,Koen N,Musekiwa A, A systematic review and meta-analysis of the effect and safety of ginger in the treatment of pregnancy-associated nausea and vomiting. Nutrition journal. 2014 Mar 19 [PubMed PMID: 24642205]|
|||Werntoft E,Dykes AK, Effect of acupressure on nausea and vomiting during pregnancy. A randomized, placebo-controlled, pilot study. The Journal of reproductive medicine. 2001 Sep [PubMed PMID: 11584487]|
|||Madjunkova S,Maltepe C,Koren G, The delayed-release combination of doxylamine and pyridoxine (Diclegis®/Diclectin ®) for the treatment of nausea and vomiting of pregnancy. Paediatric drugs. 2014 Jun [PubMed PMID: 24574047]|
|||Koren G,Clark S,Hankins GD,Caritis SN,Umans JG,Miodovnik M,Mattison DR,Matok I, Maternal safety of the delayed-release doxylamine and pyridoxine combination for nausea and vomiting of pregnancy; a randomized placebo controlled trial. BMC pregnancy and childbirth. 2015 Mar 18 [PubMed PMID: 25884778]|
|||Koren G,Clark S,Hankins GD,Caritis SN,Miodovnik M,Umans JG,Mattison DR, Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial. American journal of obstetrics and gynecology. 2010 Dec [PubMed PMID: 20843504]|
|||McParlin C,O'Donnell A,Robson SC,Beyer F,Moloney E,Bryant A,Bradley J,Muirhead CR,Nelson-Piercy C,Newbury-Birch D,Norman J,Shaw C,Simpson E,Swallow B,Yates L,Vale L, Treatments for Hyperemesis Gravidarum and Nausea and Vomiting in Pregnancy: A Systematic Review. JAMA. 2016 Oct 4 [PubMed PMID: 27701665]|
|||Goodwin TM, Hyperemesis gravidarum. Obstetrics and gynecology clinics of North America. 2008 Sep [PubMed PMID: 18760227]|
|||Togay-Işikay C,Yiğit A,Mutluer N, Wernicke's encephalopathy due to hyperemesis gravidarum: an under-recognised condition. The Australian [PubMed PMID: 11787926]|
|||Spruill SC,Kuller JA, Hyperemesis gravidarum complicated by Wernicke's encephalopathy. Obstetrics and gynecology. 2002 May [PubMed PMID: 11975941]|
|||Kim YH,Lee SJ,Rah SH,Lee JH, Wernicke's encephalopathy in hyperemesis gravidarum. Canadian journal of ophthalmology. Journal canadien d'ophtalmologie. 2002 Feb [PubMed PMID: 11865957]|
|||Eroğlu A,Kürkçüoğlu C,Karaoğlanoğlu N,Tekinbaş C,Cesur M, Spontaneous esophageal rupture following severe vomiting in pregnancy. Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus. 2002 [PubMed PMID: 12444998]|
|||Liang SG,Ooka F,Santo A,Kaibara M, Pneumomediastinum following esophageal rupture associated with hyperemesis gravidarum. The journal of obstetrics and gynaecology research. 2002 Jun [PubMed PMID: 12214835]|
|||Garg R,Sanjay,Das V,Usman K,Rungta S,Prasad R, Spontaneous pneumothorax: an unusual complication of pregnancy--a case report and review of literature. Annals of thoracic medicine. 2008 Jul [PubMed PMID: 19561889]|
|||Walch A,Duke M,Auty T,Wong A, Profound Hypokalaemia Resulting in Maternal Cardiac Arrest: A Catastrophic Complication of Hyperemesis Gravidarum? Case reports in obstetrics and gynecology. 2018 [PubMed PMID: 30151287]|
|||Mitchell-Jones N,Gallos I,Farren J,Tobias A,Bottomley C,Bourne T, Psychological morbidity associated with hyperemesis gravidarum: a systematic review and meta-analysis. BJOG : an international journal of obstetrics and gynaecology. 2017 Jan [PubMed PMID: 27418035]|
|||Veenendaal MV,van Abeelen AF,Painter RC,van der Post JA,Roseboom TJ, Consequences of hyperemesis gravidarum for offspring: a systematic review and meta-analysis. BJOG : an international journal of obstetrics and gynaecology. 2011 Oct [PubMed PMID: 21749625]|
|||Weigel MM,Weigel RM, Nausea and vomiting of early pregnancy and pregnancy outcome. An epidemiological study. British journal of obstetrics and gynaecology. 1989 Nov [PubMed PMID: 2611169]|
|||Chin RK,Lao TT, Low birth weight and hyperemesis gravidarum. European journal of obstetrics, gynecology, and reproductive biology. 1988 Jul [PubMed PMID: 3208964]|
|||Vandraas KF,Vikanes AV,Vangen S,Magnus P,Støer NC,Grjibovski AM, Hyperemesis gravidarum and birth outcomes-a population-based cohort study of 2.2 million births in the Norwegian Birth Registry. BJOG : an international journal of obstetrics and gynaecology. 2013 Dec [PubMed PMID: 24021026]|