Pregnancy, a state of profound physiological and hormonal changes, is associated with a spectrum of changes in the skin and appendages. More than 90% of pregnant women experience one or more forms of skin changes. Up to 20% of women experience pruritus during their pregnancy.
Specific dermatoses of pregnancy are the afflictions of the skin that appear during pregnancy and resolve with parturition. Pruritus gravidarum, a specific dermatosis of pregnancy, is a condition of the skin in gravid women represented by itching and only secondary lesions in the form of excoriations with or without evidence of cholestasis. Pruritus gravidarum and intrahepatic cholestasis of pregnancy are terms used interchangeably in the medical literature with pruritus gravidarum characterizing the patients with pruritus in the absence of hyperbilirubinemia.
A single exact etiology of pruritus gravidarum has not been established yet. Hormonal and genetic factors have been ascribed to play a strong role in its causation. The disease starts in the third trimester, a time of peak hormonal concentration, and resolves with parturition. It also reappears in subsequent pregnancies supporting the hormonal basis for the disease causation.
Pruritus gravidarum has a heterogeneous incidence with distinct ethnic and geographical differences. This ethnic and geographical pooling of cases points towards an underlying genetic basis for the disease. Heterozygous mutations in the multidrug resistance 3 genes (MDR3), also known as ABCB4, has been implicated in the disease pathogenesis. The MDR3 gene encodes the transport protein- canalicular phosphatidylcholine translocase.
Pruritus gravidarum has a varying incidence across the globe. Incidence rates ranging from <1 to 27.6% have been reported. An incidence rate of 22.1% was seen in Chilean women of Araucanian Indian descent; the prevalence increasing directly with the degree of 'ethnic purity.' In European countries, incidence rates varied between 0.5 to 1.5%, with Scandanavian women contributing to the highest incidence rates. In the US, the highest incidence of 5.6% was seen in the Hispanic population in Los Angeles; a 0.32% incidence rate was seen in Connecticut. In Indian-Asian and Pakistani-Asian, the incidence was 1.2 to 1.5%. A higher incidence was reported during the winter.
Pruritus occurs secondary to increased levels of bile acids within the skin and in the serum. The exact mechanism by which bile acids induce pruritus is not well understood. Bile salts, due to their detergent properties, can lead to the release of histamine and proteolytic enzymes through the solubilization of lipid cellular membranes. The release of histamine and other enzymes can lead to the activation of free nerve endings, thus leading to pruritus.
The levels of bile acids rise secondary to hormonal and genetic factors. Hormones like estrogen and progesterone, whose levels increase through the course of pregnancy, have a cholestatic effect, and reduce the hepatic excretory function. Cholestasis can also occur owing to the mutations in the MDR3 gene.
The skin biopsy findings in pruritus gravidarum are usually non-specific; epidermal ulceration is seen.
Itching, an irritating sensation that evokes the impulse to scratch, is the predominant complaint in pruritus gravidarum. The itching begins in the late second to the early third trimester; itching onset as early as eight weeks of gestation has been described. A study found the onset of symptoms to coincide with a urinary tract infection in at least 50% women.
Itching is usually intermittent at the outset and goes on to become constant. Pruritus begins first in the abdomen and spreads to involve the entire trunk and the palms and soles. The itching ranges from mild to severe and bothers the patients most in the night. Icterus, if it does manifest, follows pruritus by at least four weeks in only about 20% of cases. If icterus is present, patients may develop steatorrhea leading to fat malabsorption. Symptoms persist through the course of pregnancy, resolve with childbirth, and recur with subsequent gestation.
The examination does not show any primary lesions in pruritus gravidarum. In fact, the diagnosis of pruritus gravidarum is rejected if any primary lesions are present. Excoriations and scratch marks secondary to itching are the typical examination findings.
Since pruritus in the absence of primary skin-lesions is the cardinal feature of pruritus gravidarum, the importance of a thorough history and a complete physical examination cannot be overemphasized.
The key laboratory finding in pruritus gravidarum is an increase in the concentration of serum bile acids. Usually, it is the first and only laboratory finding. The rise in serum bile acid levels follows pruritus. Cholic acid levels increase more than chenodeoxycholic acid levels, thus skewing the cholic/chenodeoxycholic ratio. The cholic/chenodeoxycholic ratio was 3.4 in women with pruritus gravidarum as compared to 1.1 in pregnant women without the condition.
Serum aminotransferases may be increased but do not exceed 1000 unit/L, distinguishing this condition from viral hepatitis. Alkaline phosphate levels, although elevated, are not specific for pruritus gravidarum due to the production of the placental isoenzyme. Hyperbilirubinemia points towards the diagnosis of intrahepatic cholestasis of pregnancy.
Ultrasonography of the liver does not show any abnormalities. Histopathology may show cholestasis without inflammation, but a liver biopsy is not needed for diagnosis.
The goal of treatment should be focused on the alleviation of symptoms. Mild symptomatic cases may be treated with reassurance, antipruritic preparations like calamine lotion, soothing oatmeal baths, menthol in aqueous cream, and weak steroidal ointments. Patients should be reassured and advised to avoid anxiety and irritating clothing. A diet with low-fat content and rest should be encouraged.
Patients should also be counseled regarding the temporary nature of the disease and prompt resolution of their symptoms following delivery. First-generation antihistamines like diphenhydramine, chlorpheniramine, pheniramine, or tripelennamine are safe during pregnancy and may be used as adjunctive therapy.
Severe or intractable pruritus with concomitant biochemical abnormalities can be treated with ursodeoxycholic acid (UDCA). UDCA, a hydrophilic bile acid, removes other hydrophobic salts from enterohepatic circulation by replacing them. UDCA can be used at a dose of 15mg/kg/day and helps control pruritus while correcting the biochemical abnormalities. UDCA has no teratogenic effects and works faster than other drugs available.
Other drugs that may be used include cholestyramine, S-adenosyl-D-methionine, oral corticosteroids, nonerythemogenic UVB radiation, and phenobarbital. These drugs are implicated more in the treatment of intrahepatic cholestasis of pregnancy, but since pruritus gravidarum and intrahepatic cholestasis of pregnancy share many features, these drugs are worth mentioning here.
Pruritus is a common complaint of pregnancy, so it is important to rule out other causes of pruritus including but not limited to: specific dermatoses of pregnancy, atopic dermatitis, scabies, pediculosis, neurodermatitis, contact dermatitis, and drug eruptions. If the patient has concomitant liver function abnormalities, other causes of liver dysfunction should be ruled out: viral hepatitis, acute fatty liver of pregnancy, HELLP syndrome, and drug-induced liver damage.
The prognosis for pruritus gravidarum is excellent with rapid subsidence of symptoms after parturition. After 24-48 hours of delivery, pruritus and icterus typically resolve but may last up to four weeks. Normalization of bile acid levels occurs in 4-6 weeks. Pruritus gravidarum may recur in 40-70% of women in subsequent pregnancies. Estrogen-containing preparations may also cause recurrences in some cases.
Complications vary for the mother and the fetus. Complications to the mother may include malabsorption or postpartum bleeding following reduced levels of vitamin K owing to liver abnormalities. A study found an increased incidence of gall bladder disease, including cholelithiasis in such patients. Complications to the fetus include premature birth, intrauterine asphyxia, meconium-stained amniotic fluid, and low birth weight. A study found bile acid levels 40 micromol/L or more to be statistically significant for increased adverse events in the fetus. Fetal complications are believed to arise from placental anoxia.
Patients should be advised to refrain from scratching to avoid secondary lesions and reduce the risk of hyperpigmentation. Patients should be asked to followup with their clinicians when their symptoms are uncontrollable and bothersome. Patients should be reassured regarding the prognosis and the fetal risks involved. These patients should also be advised to avoid estrogen-containing oral contraceptives or use them in the lowest doses possible.
The management of a patient with pruritus gravidarum requires an interprofessional team consisting of an obstetrician, dermatologist, hepatologist, maternal-fetal medicine specialist, and the nursing team. The management team must focus on making the patient as comfortable as possible while monitoring the fetus of any complications. The patient should be counseled appropriately regarding the complications of the disease. Patient preferences for delivery and management options should be discussed beforehand and considered appropriately while making management decisions.
|||Kar S,Krishnan A,Shivkumar PV, Pregnancy and skin. Journal of obstetrics and gynaecology of India. 2012 Jun; [PubMed PMID: 23730028]|
|||Bergman H,Melamed N,Koren G, Pruritus in pregnancy: treatment of dermatoses unique to pregnancy. Canadian family physician Medecin de famille canadien. 2013 Dec; [PubMed PMID: 24336540]|
|||Shanmugam S,Thappa DM,Habeebullah S, Pruritus gravidarum: a clinical and laboratory study. The Journal of dermatology. 1998 Sep; [PubMed PMID: 9798344]|
|||Lammert F,Marschall HU,Glantz A,Matern S, Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. Journal of hepatology. 2000 Dec; [PubMed PMID: 11131439]|
|||Dixon PH,Weerasekera N,Linton KJ,Donaldson O,Chambers J,Egginton E,Weaver J,Nelson-Piercy C,de Swiet M,Warnes G,Elias E,Higgins CF,Johnston DG,McCarthy MI,Williamson C, Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking. Human molecular genetics. 2000 May 1; [PubMed PMID: 10767346]|
|||de Vree JM,Jacquemin E,Sturm E,Cresteil D,Bosma PJ,Aten J,Deleuze JF,Desrochers M,Burdelski M,Bernard O,Oude Elferink RP,Hadchouel M, Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proceedings of the National Academy of Sciences of the United States of America. 1998 Jan 6; [PubMed PMID: 9419367]|
|||Geenes V,Williamson C, Intrahepatic cholestasis of pregnancy. World journal of gastroenterology. 2009 May 7; [PubMed PMID: 19418576]|
|||Reyes H,Gonzalez MC,Ribalta J,Aburto H,Matus C,Schramm G,Katz R,Medina E, Prevalence of intrahepatic cholestasis of pregnancy in Chile. Annals of internal medicine. 1978 Apr; [PubMed PMID: 637428]|
|||Lee RH,Goodwin TM,Greenspoon J,Incerpi M, The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population. Journal of perinatology : official journal of the California Perinatal Association. 2006 Sep; [PubMed PMID: 16761011]|
|||Laifer SA,Stiller RJ,Siddiqui DS,Dunston-Boone G,Whetham JC, Ursodeoxycholic acid for the treatment of intrahepatic cholestasis of pregnancy. The Journal of maternal-fetal medicine. 2001 Apr; [PubMed PMID: 11392594]|
|||Abedin P,Weaver JB,Egginton E, Intrahepatic cholestasis of pregnancy: prevalence and ethnic distribution. Ethnicity [PubMed PMID: 10887460]|
|||Varadi DP, Pruritus induced by crude bile and purified bile acids. Experimental production of pruritus in human skin. Archives of dermatology. 1974 May; [PubMed PMID: 4828535]|
|||Sasseville D,Wilkinson RD,Schnader JY, Dermatoses of pregnancy. International journal of dermatology. 1981 May; [PubMed PMID: 7016769]|
|||Dacus JV,Muram D, Pruritus in pregnancy. Southern medical journal. 1987 May; [PubMed PMID: 3554534]|
|||Shornick JK, Dermatoses of pregnancy. Seminars in cutaneous medicine and surgery. 1998 Sep; [PubMed PMID: 9759674]|
|||Reyes H, The spectrum of liver and gastrointestinal disease seen in cholestasis of pregnancy. Gastroenterology clinics of North America. 1992 Dec; [PubMed PMID: 1478743]|
|||Roger D,Vaillant L,Fignon A,Pierre F,Bacq Y,Brechot JF,Grangeponte MC,Lorette G, Specific pruritic diseases of pregnancy. A prospective study of 3192 pregnant women. Archives of dermatology. 1994 Jun; [PubMed PMID: 8002643]|
|||McKenzie AW, Skin disorders in pregnancy. The Practitioner. 1971 Jun; [PubMed PMID: 4325807]|
|||Berg B,Helm G,Petersohn L,Tryding N, Cholestasis of pregnancy. Clinical and laboratory studies. Acta obstetricia et gynecologica Scandinavica. 1986; [PubMed PMID: 3727939]|
|||Kenyon AP,Piercy CN,Girling J,Williamson C,Tribe RM,Shennan AH, Obstetric cholestasis, outcome with active management: a series of 70 cases. BJOG : an international journal of obstetrics and gynaecology. 2002 Mar; [PubMed PMID: 11950183]|
|||Diken Z,Usta IM,Nassar AH, A clinical approach to intrahepatic cholestasis of pregnancy. American journal of perinatology. 2014 Jan; [PubMed PMID: 23359238]|
|||Bacq Y,Sapey T,Bréchot MC,Pierre F,Fignon A,Dubois F, Intrahepatic cholestasis of pregnancy: a French prospective study. Hepatology (Baltimore, Md.). 1997 Aug; [PubMed PMID: 9252146]|
|||Rolfes DB,Ishak KG, Liver disease in pregnancy. Histopathology. 1986 Jun; [PubMed PMID: 3525371]|
|||Elling SV,Powell FC, Physiological changes in the skin during pregnancy. Clinics in dermatology. 1997 Jan-Feb; [PubMed PMID: 9034654]|
|||Wong RC,Ellis CN, Physiologic skin changes in pregnancy. Journal of the American Academy of Dermatology. 1984 Jun; [PubMed PMID: 6376552]|
|||Palma J,Reyes H,Ribalta J,Hernández I,Sandoval L,Almuna R,Liepins J,Lira F,Sedano M,Silva O,Tohá D,Silva JJ, Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a randomized, double-blind study controlled with placebo. Journal of hepatology. 1997 Dec; [PubMed PMID: 9453428]|
|||Pillarisetty LS,Sharma A, Pregnancy Intrahepatic Cholestasis 2020 Jan; [PubMed PMID: 31855347]|
|||Sherard GB 3rd,Atkinson SM Jr, Focus on primary care: pruritic dermatological conditions in pregnancy. Obstetrical [PubMed PMID: 11435950]|
|||Winton GB,Lewis CW, Dermatoses of pregnancy. Journal of the American Academy of Dermatology. 1982 Jun; [PubMed PMID: 7047596]|
|||Furhoff AK, Itching in pregnancy. A 15-year follow-up study. Acta medica Scandinavica. 1974 Nov; [PubMed PMID: 4440518]|
|||Johnston WG,Baskett TF, Obstetric cholestasis. A 14 year review. American journal of obstetrics and gynecology. 1979 Feb 1; [PubMed PMID: 312017]|
|||Glantz A,Marschall HU,Mattsson LA, Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates. Hepatology (Baltimore, Md.). 2004 Aug; [PubMed PMID: 15368452]|
|||Laatikainen T,Ikonen E, Serum bile acids in cholestasis of pregnancy. Obstetrics and gynecology. 1977 Sep; [PubMed PMID: 896101]|