Gastrointestinal disease

Gastrointestinal diseases in pregnancy can be divided into diseases specific to pregnancy, for example, hyperemesis gravidarum, obstetric cholestasis, HELLP syndrome and acute fatty liver of pregnancy, and diseases incidental to pregnancy, for example, inflammatory bowel disease, dyspepsia, peptic ulcer disease and viral hepatitis. Disorders in the second category may present for the first time in pregnancy. This chapter considers the drug management of each of these conditions, with the exception of HELLP syndrome and acute fatty liver. The preferred drug treatment and the known complications associated with their use in pregnancy are also described. Where possible, studies relating to the safety of different therapeutic options are discussed.     

Diagnóstico posparto de la enfermedad de Wilson en gestante con síndrome HELLP y coagulopatía

HELLP syndrome is a clinical-analytical entity defined by microangiopathic hemolytic anemia, elevated liver enzymes, and thrombocytopenia. Liver involvement in this syndrome is common to several liver diseases. Some of these liver diseases are inherent to pregnancy (acute fatty liver of pregnancy, gestational intrahepatic cholestasis), while others are related to intercurrent disease (acute viral hepatitis) or to previous chronic liver disease. We report a case of postpartum diagnosis of chronic liver disease secondary to Wilson disease, with onset in the third trimester of pregnancy and HELLP syndrome associated with acute liver failure and coagulopathy. We review the differential diagnosis and the scientific literature on the topic.     

Inherited long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and a fetal-maternal interaction cause maternal liver disease and other pregnancy complications.

Fetal-maternal interactions are critical determinants of maternal health during pregnancy and perinatal outcome. This review explores the causative relationship of a fetal disorder of mitochondrial fatty acid oxidation, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, and the serious maternal liver diseases of pregnancy-preeclampsia, the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet counts), and acute fatty liver of pregnancy. Features of the metabolic adaptation necessitated during the fetal-neonatal transition; common phenotypes of pediatric fatty acid oxidation disorders, including neonatal hypoketotic, hypoglycemia and hepatic crisis; and clinical abnormalities of HELLP and acute fatty liver of pregnancy are presented. Evidence that a common mutation in the alpha-subunit (LCHAD) of trifunctional protein, E474Q, is always one of the mutant alleles in fetal isolated LCHAD deficiency associated with these disorders of pregnancy that cause high maternal, fetal, and newborn morbidity and mortality is reviewed. Recommendations for molecular testing for LCHAD deficiency in families with life-threatening maternal liver disease are given.     

Hyperemesis gravidarum,gastrointestinal and liver disease in pregnancy

Women of childbearing age may be affected by diseases of the gastrointestinal tract or liver; some have no effect on obstetric outcome, some are improved in pregnancy and some deteriorate. Gastrointestinal or liver disease may be caused by pregnancy and resolve following delivery e.g. hyperemesis gravidarum, pre-eclampsia, acute fatty liver of pregnancy, HELLP syndrome and obstetric cholestasis, or may present for the first time in pregnancy e.g. inflammatory bowel disease, cholelithiasis and hepatitis. These examples and other common gastrointestinal and liver disorders will be discussed giving details of diagnosis, management and effects on pregnancy outcome and also background information on normal liver physiology in pregnancy.     

Lebererkrankungen in der Schwangerschaft

A complete spectrum of maternal liver diseases occurs during pregnancy. Many, such as viral hepatitis, are not related to pregnancy. In contrast, women may develop potentially life-threatening liver diseases uniquely related to pregnancy. Beside the syndrome of Hemolysis, Elevated Liver enzymes and Low Platelets (HELLP syndrome), these include the common intrahepatic cholestasis of pregnancy and the very rare acute fatty liver of pregnancy. During the past decade the molecular pathogenesis of these two diseases has been better defined, and mutations in genes encoding the hepatocanalicular phospholipid transporter and enzymes of fatty acid β-oxidation have been identified as genetic risk factors. Furthermore, due to optimized obstetric, intensive care and hepatological management, maternal and fetal mortality have decreased significantly.     

Fetal fatty acid oxidation defects and maternal liver disease in pregnancy

OBJECTIVE: The objective was to evaluate the relationships between all types of fetal fatty acid oxidation defects and maternal liver disease, including acute fatty liver of pregnancy and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. METHODS: This was a case-control study comparing fetal fatty acid oxidation defects to the outcome of maternal liver disease. Fifty case infants with fatty acid oxidation defects were identified, with 25 matched controls collected per case. This generated a total of 50 case infants and 1,250 control infants. Pregnancies were evaluated for the presence of maternal liver disease (comprised of acute fatty liver of pregnancy, HELLP syndrome, and preeclampsia evolving into HELLP syndrome) using a conditional logistic regression model. Subgroup analysis compared long chain to short and medium chain fatty acid defects. RESULTS: Maternal liver disease was noted in 16.00% of all fatty acid oxidation defect pregnancies compared with 0.88% in the general population (odds ratio 20.4, 95% confidence interval 7.82-53.2). These pregnancies demonstrated an 18.1-fold increase in maternal liver disease when compared with our matched population controls with unaffected fetuses. All classifications of fatty acid oxidation defects were at high risk of developing maternal liver disease. Long chain defects were 50 times more likely than controls to develop maternal liver disease and short and medium chain defects were 12 times more likely to develop maternal liver disease. CONCLUSION: Maternal liver disease is significantly higher across the entire spectrum of fatty acid oxidation defects pregnancies compared with the matched control population. Notably, there is significant risk to the pregnancies with fetuses affected with short and medium chain defects, not just those with fetal long chain fatty acid oxidation defects as previously reported. Future studies should examine the pathophysiology of all infant fatty acid oxidation defects and its implications for maternal liver disease for improved future health outcomes. LEVEL OF EVIDENCE: II-2.     

Current management of the HELLP syndrome

The HELLP syndrome as part of the microangiopathic syndromes requires special attention in terms of a rapid and accurate diagnostic and differential diagnostic workup because of its possibly rapid clinical deterioration. It is defined by the classical triad of hemolysis,elevated liver enzymes and low platelet counts which may lead to prognostically relevant problems in differentiating it from thrombotic-thrombocytopenic purpura and hemolytic-uremic syndrome and other pregnancy-related and unrelated liver diseases, i.e. mainly clinical and laboratory similarities to other liver diseases such as acute fatty liver or intrahepatic cholestasis in pregnancy or pregnancy-unrelated settings like viral hepatitides. The management in the different phases of pregnancy is described in detail. Therapeutic options to prolong pregnancy are discussed as are the possibilities of prophylaxis in subsequent pregnancies and aspects of the followup.     

Acute fatty liver and HELLP syndrome: two distinct pregnancy disorders.

OBJECTIVE: to report the experience clinical, biochemical findings, complications and the maternal-perinatal outcome in patients with HELLP syndrome and acute fatty liver of pregnancy (AFLP) during the same period. MATERIALS AND METHODS: during the period between January 1996 and December 1999, medical records of patients with the discharge diagnosis of AFLP and HELLP syndrome were reviewed for presenting symptoms, laboratory findings, maternal and perinatal complications. Routine laboratory evaluation included serial measurement of liver function tests, complete blood cell count, coagulation profile and renal function tests. RESULTS: during the study period 10 patients had AFLP and 75 women had HELLP syndrome as the discharge diagnosis. Patients with HELLP syndrome had major parity than AFLP (P<0.006). The most common presenting symptom for patients with AFLP was malaise noted in all patients, nausea and/or vomiting, abdominal pain and jaundice were very common. Headache, abdominal or epigastric pain and hematuria were the most common symptoms of patients with HELLP syndrome. Women with AFLP had major hypoglycemia, hypocholesterolemia, hypotriglyceridemia, serum transaminase activity and low antithrombin III. Disseminated intravascular coagulation, acute renal insufficiency, ascites, seroma and encephalophaty were more common with AFLP. CONCLUSIONS: our opinion is that AFLP had clinical presentation, biochemical findings and complications clearly distinguished of HELLP syndrome.     

妊娠期急性肾损伤的相关进展

妊娠期间肾脏损伤风险至少增加2倍,妊娠期急性肾损伤(acute kidney injury in pregnancy,P-AKI)是一种高风险产科疾病,严重威胁母亲和胎儿的健康。尽管P-AKI在过去30年中发病率下降,我国仍有较高的发病率及致死率。P-AKI是妊娠期严重的并发症,有起病急、进展快、病情重的临床特点,常伴有呼吸、心血管及消化等系统的症状。P-AKI的相关疾病,如子痫前期、妊娠期急性脂肪肝、HELLP综合征和血栓性微血管病等临床表现相似,容易出现诊断困难。现总结近年来国内外文献,从P-AKI病理生理变化、不同地区发病率及诱因、诊断标准、P-AKI的相关疾病及预防治疗措施等进行分析,并对P-AKI的透析指征进一步分析,旨在提高大家对疾病的了解、预防和诊治,降低发病率、病死率及致残率,改善母婴结局。     

Critical care in obstetrics: pregnancy-specific conditions

This chapter summarizes the clinical presentation, pathophysiology, evaluation and management of six commonly encountered complications unique to pregnancy that require critical care management: obstetric haemorrhage; pre-eclampsia/HELLP (haemolysis-elevated liver enzymes-low platelets) syndrome; acute fatty liver of pregnancy; peripartum cardiomyopathy; amniotic fluid embolism; and trauma.     

Outcome of pregnancy with severe liver disease.

OBJECTIVES: To study the incidence, presentation, and outcome of patients with severe liver disease in an urban Indian population. METHOD: 26 patients with severe liver disease were identified in the study period of one year at a teaching tertiary care institute in Mumbai. Investigations included bedside Bleeding and Clotting Time (BT/CT), coagulation profiles and liver and renal function tests. Management was directed towards initial stabilization followed by early delivery in an intensive care setting. RESULT: 80.71% of the patients had HELLP (Hemolysis, Elevated Liver enzymes, Low Platelets) syndrome. The remaining were cases of acute fulminant hepatitis and acute fatty liver of pregnancy. The most consistent finding was thrombocytopenia (88.46%). Disseminated Intravascular Coagulopathy (DIC) was the most common complication (65%). BT/CT were 100% sensitive for the diagnosis of DIC. Maternal and perinatal mortality were 42.3% and 61.5% respectively. CONCLUSION: Intensive care facilities and an early diagnosis are essential for the management of mothers with severe liver disease. Prognosis is poor for patients with fulminant hepatitis and acute fatty liver. Screening for DIC is a must. Delay in recovery of biochemical parameters may indicate atypical disease. Patient education is essential at discharge.     

Diagnosis and management of hemolysis, elevated liver enzymes, and low platelets syndrome

Pregnancies complicated by hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome require a well-formulated management plan. The development of this syndrome after 34 weeks' gestation or with documentation of maternal or fetal compromise is an indication for delivery. Acute fatty liver of pregnancy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura may present with signs, symptoms, and laboratory abnormalities that may be confused with HELLP syndrome. Thorough investigation is warranted because of the differences in proper management among these various complications of pregnancy. Expectant management in patients with HELLP syndrome remote from term and the use of corticosteroids to improve postpartum maternal outcome remain experimental.     

Síndrome ELLP,un diagnóstico diferencial complicado

HELLP syndrome (Hemolysis, Elevated Liver enzymes, and Low Platelet count) is a thrombotic microangiopathy of pregnancy. This syndrome may be incomplete, with manifestations of only a few of its parameters: EL (elevated liver enzymes), ELLP (elevated liver enzymes and thrombocytopenia) and LP (thrombocytopenia alone). ELLP syndrome is a difficult differential diagnosis in which the main causes of thrombocytopenia in pregnancy and other diseases must be excluded. In current clinical practice, the management of ELLP is similar to that of complete HELLP syndrome. However, maternal and fetal morbidity is lower in ELLP syndrome, which may suggest the need to evaluate different protocols for these two variants of the same disease.     

Lebererkrankungen in der Schwangerschaft

Liver diseases in pregnancy can result in maternal as well as fetal complications. Intrahepatic cholestasis in pregnancy may lead to a high fetal risk of IUD, meconium-stained amniotic fluid, premature delivery, asphyxia and arrhythmia. Concerning a good fetal outcome there is no evidence-based therapy. Pruritus and elevated cholic acid can be treated and controlled well by ursodeoxycholic acid. Since there is a higher risk of intrauterine death, most common at 37+ weeks of gestation, delivery is recommended starting at 36+ weeks, even earlier when excessively high cholic acid levels occur. Acute fatty liver of pregnancy is linked to higher maternal and fetal mortality. There are regular crossovers to the HELLP syndrome. Cholelithiasis causes 6% of all jaundice in pregnancy and thus has to be considered as another differential diagnosis particularly in multiparity. If operative treatment is required for cholecystolithiasis during pregnancy the best fetal outcome is achieved in the second trimester. It is likely that in the future chronic liver diseases such as Wilson??s disease and autoimmune hepatitis will be seen more often during pregnancy since there are increasingly better options for treatment. The same applies to pregnant women who have already undergone liver transplantation. An interdisciplinary approach with hepatologists in these high-risk pregnancies is mandatory.     

妊娠期高血压疾病并发HELLP综合征终止妊娠时机及方式的探讨

目的:探讨妊娠期高血压疾病并发溶血、肝酶升高及血小板减少综合征(HELLP综合征)终止妊娠的时机和方式对母儿的影响。方法:对我院11年来31例HELLP综合征患者的临床资料进行回顾性分析。结果:31例患者当中阴道分娩仅2例,其中1例母体产后并发DIC死亡,围生儿1例死产,1例新生儿死亡。剖宫产29例,剖宫产率93.5%,其中1例母体术后并发急性肾功能衰竭死亡,1例术后并发DIC、多器官衰竭(MOST)死亡,余27例均存活,未发现明显后遗症;围生儿31例(双胎2例),其中胎死宫内3例,死产1例,新生儿死亡4例。结论:HELLP综合征严重威胁母儿的安全,适时终止妊娠是治疗HELLP综合征极其重要的手段,终止妊娠的方式首选剖宫产;终止妊娠的时机为诊断后24~48小时,具体还应依病情的严重程度及孕周的大小作出综合判断。     

Transient postpartum diabetes insipidus associated with HELLP syndrome

Diabetes insipidus in pregnancy has different causes. The association of diabetes insipidus with disturbances of liver function has been reported, however, diabetes insipidus has rarely been reported in HELLP syndrome. We present a 23-year-old primigravida with a singleton gestation complicated by HELLP syndrome who developed postpartum diabetes insipidus. Labor was induced promptly to terminate pregnancy because of intrauterine fetal death and liver dysfunction. 1-deamino-8-D-arginine-vasopressin was administered. Diabetes insipidus and liver dysfunction resolved within 2 weeks. Development of diabetes insipidus may result from increased vasopressinase activity mainly caused by deterioration of liver functions caused by HELLP syndrome. In pregnant women with liver disease as a result of any cause, the development of diabetes insipidus should be assessed with particular attention.     

Pregnancy and inborn errors of metabolism

Increasing number of patients with inborn errors of metabolism (IEM) are now reaching adulthood and are in position to reproduce. Because of the rarity of individual disorders our knowledge of risks factors associated with pregnancy is limited. Obstetrics problems in IEM can be divided into two categories: pregnancy effects on maternal metabolic disorders and relation between mother and fetus related to who of them is affected. Detrimental effects upon the fetus may be directly caused by maternal disease, as it occurs in PKU, or indirectly by maternal supplementation with harmful substrate, as occurs in galactosemia. Less commonly, fetal inborn error of metabolism may affect the mother's health. Pregnancies in which the fetus had long-chain hydroxyacyl-CoA dehydrogenase deficiency have been complicated by life-threatening HELLP syndrome (haemolysis, elevated liver enzymes and low platelets) or AFL (acute fatty liver of pregnancy) during third trimester. The management of labor and the postpartum period (for women and newborns) has to be carefully planned to avoid significant metabolic decompensation.     

Antenatal detection of abnormal liver function tests - a marker for poor perinatal outcome.

The purpose of this study was to examine (a) the incidence of liver disease diagnosed in our antenatal population, (b) the diagnostic value of initial symptoms and liver function tests (LFTs), (c) the adequacy of investigation and management of the liver disorder and (d) the obstetric and neonatal outcome in this group of patients. Women with abnormal LFTs that delivered at our hospital over a 2-year period were identified from computerised hospital records and data was obtained from chart review. Forty-six out of a total of 13 181 (0.35%) women had liver disease diagnosed in pregnancy: Diagnoses included intrahepatic cholestasis of pregnancy (13), pre-eclampsia and the HELLP syndrome (eight), acute fatty liver of pregnancy (three), hyperemesis gravidarum (one), hepatitis C (13), B (four) and hepatitis A (one), cholelithiasis (two) and hepatitis of unknown aetiology (one). Symptoms at presentation were more predictive of the final diagnosis than the initial LFT profile. Investigation of the liver disorder was incomplete in 50% of cases.One mother required intensive care for 6 weeks postpartum and three others had significant postpartum haemorrhage. There was one neonatal death and 24 neonates were admitted to the special care baby unit. Eighteen women attended for their postnatal check up at 6 weeks. Eight of these women were referred to a hepatologist. Detection of liver disease in pregnancy identifies a group at risk of poor neonatal and maternal outcome. Structured guidelines should be implemented in obstetric units to facilitate appropriate investigation, treatment and referral patterns for these women.     

HELLP syndrome and placental inflammatory pathology

HELLP syndrome, acronym for hemolysis (H), elevated liver enzymes (EL), and low platelet count (LP), is a multisystemic disease that complicates pregnancy and is considered a severe variant of hypertensive disorders in pregnancy, that causes maternal and perinatal mortality and morbidity. The pathogenesis of HELLP syndrome is not completely understood and the obstetric approach with the induction of delivery is still the only specific therapy in HELLP syndrome. It is well known that the placenta and the incomplete trophoblast invasion of spiral arteries have a central role, but especially in severe pre-eclampsia and in the HELLP syndrome there is a systemic endothelial activation and damage. In this review we emphasize the inflammatory hypothesis and the role of inflammatory cytokines deriving from placenta in pre-eclampsia and HELLP syndrome, also in the light of our recent studies on cytokines pattern.     

Maternal deaths associated with hypertensive disorders of pregnancy: a population-based study.

There were 507 deaths associated with hypertensive disorders of pregnancy (eclampsia, preeclampsia, and chronic hypertension) in South Africa over the triennium 1999-2001. Eclampsia was associated with 289 deaths, preeclampsia with 139, and the remaining 79 with chronic hypertension, hemolysis, elevated lever enzymes, and low platelet count (HELLP) syndrome, liver rupture and acute fatty liver. The major final cause of death was intracranial hemorrhage. Other causes included HELLP syndrome and liver rupture. Contributory causes include pulmonary edema, renal failure/impairment, and disseminated intravascular coagulation. Deaths from eclampsia occurred at all levels of health care, in particular, there was still a considerable number of deaths at level I hospitals. Most deaths from eclampsia occurred at low parity (parity 0 = 51%), while 13% of deaths in noneclamptics occurred in women of parity > or = 5. Similarly, most deaths from eclampsia occurred in women aged < or = 24 years, while most in the noneclamptic group were aged 25 years and greater. The most common avoidable factors were patent-oriented problems--women who either presented late for antenatal care or late to hospital when symptomatic. Administrative factors also played a major role, in that there was a delay in referral due to the unavailability of transport. The lack of protocols of management or failure to follow clinical protocols of care contributed towards avoidable medical factors. Most women presented as an emergency event and failure of resuscitation/achievement of hemodynamic stabilization constituted a significant avoidable factor. Clear protocols for management of hypertension in pregnancy at all levels of health care are required.