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GI and Hepatobiliary disorders in Pregnancy Ermias D (MD) Approach to Liver Disease in Pregnancy Liver disease occurs in approximately 3% of deliveries There are unique and other common liver diseases seen during pregnancy Acute fatty liver of pregnancy Intrahepatic cholestasis of pregnancy Toxemia of pregnancy – HELLP Hepatitis Gall stone disease The Liver in Normal Pregnancy Physical Examination Skin - palmar erythema and spider angiomas are usually signs of chronic liver disease, but can be normal findings in pregnancy secondary to high estrogen levels Liver In the third trimester, the enlarging uterus displaces the liver superiorly and posteriorly a palpable liver is abnormal The Liver in Normal Pregnancy Hemodynamics cardiac output increases until the 30 wk, then plateaus until delivery absolute hepatic blood flow remains unchanged, as the percentage of cardiac output to the liver decreases The Liver in Normal Pregnancy Liver function tests Albumin Alkaline Phosphatase unchanged ALT 2-4 times normal in the third trimester increases secondary to placental ALP Alkaline phosphatase may remain elevated for up to six weeks after delivery AST decreases secondary to hemodilution slightly higher in second trimester but still within normal range LDH unchanged The Liver in Normal Pregnancy Liver function tests Bilirubin Bile acids Alteration in bile composition, cholesterol super saturation, increased bile acid pool, precipitation of cholesterol crystal and stone formation. Coagulation Factors Total and Free are lower throughout pregnancy Conjugated is lower during T2 and T3 PTT/INR - unchanged Fibrinogen - slightly elevated Total cholesterol and triglycerides increase markedly during pregnancy The Liver in Normal Pregnancy Ultrasound biliary tract is usually normal Pathology standard and ultra structural examination of the liver during normal pregnancy reveals no specific abnormalities Acute Fatty Liver in Pregnancy Acute Fatty Liver of Pregnancy Affects 1 in 6,692 – 15,900 pregnancies M survival was 72%, maternal mortality of 18%, fetal mortality of 23% (earlier reports) Prompt dx, delivery and ICU mx – m survival approaches 100%, infant mortality rate <7% association with nulliparity, twin gestations, male fetus and pre-eclampsia or eclampsia Etiology Remains unknown Similar histologically and clinically to Reye’s syndrome and Jamaican vomiting sickness These diseases are characterized by microvesicular fatty infiltration of hepatocytes without inflammation or necrosis Etiology Presentation is also similar to those people with metabolic defects in the intra mitochondrial -oxidation pathway Also occurs more frequently in women whose fetuses have a deficiency of long chain 3hydroxyacyl-CoA (enzyme deficiency is similar to that in Reye’s) Clinical Manifestations Generally occurs in the third tm of pregnancy Mean gestational age is 34.5 weeks (range 28-39 weeks) The duration of prodromal symptoms and signs is variable Often presents with nausea and vomiting, followed by severe abdominal pain and headache; pruritis may occur early Clinical Manifestations RUQ tenderness with out hepatomegally Within a few days, jaundice appears, and the patient becomes somnolent and eventually comatose Hematemesis and spontaneous bleeding from hypo-prothrombinemia and DIC Oliguria, metabolic acidosis, and eventually anuria occur in approximately 50% of patients Clinical Manifestations Diabetes insipidus may also accompany the disease, but may not manifest itself until postpartum These patients may respond to dDAVP after delivery (1 deamino 8D vasopressin) Pre-eclampsia in 21-64% Clinical Manifestations If the disease is allowed to progress, labor begins and the patient delivers a stillborn infant Uteroplacental insufficiency may be the cause of fetal distress and fetal death in these patients. Clinical Manifestations During the immediate postpartum period, the mother becomes febrile, comatose and, without therapy, dies within a few days Common causes of death are: DIC, renal failure, profound hypoglycemia, and occasionally pancreatitis Lab Investigations Serum transaminases Coagulation factors INR increases before PTT because of vitamin K dependent clotting factors made in the liver fibrinogen decreases, D-dimer increases with DIC Bilirubin elevated, but usually below 500 IU/L mildly elevated Serum ammonia - elevated Serum glucose - decreased Further Investigations Liver Biopsy liver biopsy not advised for diagnosis in most cases due to coagulopathy if biopsy is necessary, FFP can be administered to correct coagulopathy pericentral microvesicular fatty change minimal inflammatory cell infiltration or hepatic necrosis periportal areas are usually preserved Histology Further Investigations Imaging - US, CT, MRI CT to detect hepatic hematoma, rupture, infarction a large number of false-negatives decreased attenuation over the liver is consistent with fatty infiltration MRI fatty infiltration can be visualized with T2-weighted images Management Once diagnosis is made, delivery should be carried out as soon as possible Need to ensure patient is stable invasive hemodynamic monitoring correct coags IV fluids containing adequate glucose if ammonia levels are elevated, treat with lactulose Management Vaginal delivery is preferable May use cervical ripening agents if needed C/S can be performed if it appears vaginal delivery cannot be carried out in a timely fashion or if patient is deteriorating Management If coagulopathy is corrected, regional anesthesia is preferable because it allows adequate assessment of LOC GA should be avoided if possible because of hepatotoxicity of some anesthetic agents Narcotic doses need to be adjusted as metabolized by the liver prognosis If delivery is carried out before hepatic encephalopathy and renal failure develop, patients recover rapidly Little risk of recurrence in subsequent pregnancies Liver disease of preeclampsia Pregnancy ass. HTNsive disorder affecting multiple organs complicates 3-10% of pregnancies Occur In the second half of pregnancy period Most commonly in primi, multiple gestation… diagnosis Sustained BP > 140/90 in previously normotensive, after 20 wk gestation 24 hrs urine protein 300mg or 30gm/dl(+1 dipstick) Hyperreflexia Edema Severe preeclampsia SBP > 160, DBP> 110 Proteinuria >2gm/24hr Serum Cr >1.2mg/dl Persistent headache, neurologic or visual disturbance Pesistent epigastric pain Platelet count < 100,000/mm3, or microangiopathic hemolyic aneamia HELLP Hemolysis, elevated liver enzymes, low platelet Described by Weinstein 1982 Underlie the development of hepatic hematoma, rapture and infarction in preeclamptic pt Upto 30% occur post delivery Dx Clinical Hemolyis – fragmented RBC, elevated LDH Elevated transaminases – variably Elevated bilirubin ---- hemolysis Glutathion S transferase, AST, D-dimer, tissue polypeptide Ag, fibronectin rise predict severe disease imaging CT, MRI To detect intrahepatic hemorrhage, infarction For pts with severe abdominal pain, neck shoulder pain, sudden drop of BP Liver Biopsy – not necessary Periportal hemorrhage, intra sinusoidal fibrin deposition, area of liver cell necrosis No pericentral microvesicular fat like AFLP No correlation with lab values of LFT DDX should be entertained pathogenisis Unknown ? Abnormality of placental fromation, trophoblast invasion and spiral artery dilations ? Lipid peroxidation, oxidative stress ? Endothelial dysfunction ? Abnormal cell permeability to Ca ? molecular variant of angiotensin management Usually resolve after delivery Post partum liver failure, sepsis, DIC and death is also possible Supportive care in ICU set up Platelet transfusions Glucocorticoid for fetal lung maturity Full recovery with out sequalae in majority Intrahepatic Cholestasis of Pregnancy Background Incidence of 1 in 1,000-10,000 pregnancies Uneven incidence worldwide High incidence in Chile and Sweden Seems to have a seasonal variation, peaking in November (cold season) Pathogenesis Cause is unknown Evidence suggests both genetic and hormonal factors play a role Genetic could explain familial cases and a higher incidence in some ethnic groups heterozygous mutations in the MDR3 gene has been found in a large consanguineous family likely autosomal dominant No HLA relation ship Pathogenesis Hormonal Estrogens estrogens are known to cause cholestasis in both experimental and clinical conditions ICP occurs mainly in the third trimester, when estrogens reach their peak also more common in twin pregnancies, which have higher circulating estrogen levels Pathogenesis Hormonal Progesterone administration of progesterone may be a risk factor for ICP the formation of large amounts of progesterone metabolites may result in saturation of the hepatic transport system utilized for biliary excretion Clinical Manifestations Generally occurs in second and third trimesters Usually begins with pruritis at night Pruritis is often generalized, but predominates on palms and soles of feet Progresses to continuous pruritis Clinical Manifestations May have excoriations due to scratching Abdominal pain is uncommon Occasionally may have dark urine and pale stool Clinical Manifestations ~2 weeks after start of symptoms, jaundice develop in 50% Accounts for 20-25% of cases of jaundice during pregnancy Jaundice is usually mild, but persists until delivery Symptoms usually abate about 2 days after delivery Differential Diagnosis for pruritis without a primary skin lesion cholestasis xerosis (dry skin) medications uremia iron deficiency leukemia HIV polycythemia lymphoma thyroid disorders diabetes visceral malignancies multiple sclerosis Lab Investigations ALP Serum total bile acids may increase to more then 10x normal Total bilirubin increases 5-10 fold mildly increased AST, ALT may increase to >1,000 U/L Lab Investigations GGT normal or slightly elevated Coagulation factors INR usually normal may be increased secondary to Vitamin K deficiency due to cholestasis or due to the use of bile acid sequestrants Diagnosis Fasting serum bile acids must be more then 3 times the upper limit of normal Clinical symptoms must also be present for diagnosis Need to exclude other causes of jaundice and pruritus including viral hepatitis, primary biliary cirrhosis and biliary tract disease Diagnosis Ultrasound reveals no biliary duct dilation, hepatic parenchyma appear normal Liver Biopsy rarely necessary for diagnosis histologically shows: centrilobular areas reveal dilated bile canaliculi these changes tend to regress after delivery Management Treatment focuses on reducing symptoms Benadryl, hydroxyzine and other antihistamines may help only slightly Antihistamines may aggravate respiratory difficulties in preterm babies Management Cholestyramine anion binding resin that interrupts the enterohepatic circulation, reducing reabsorption of bile acids dose 8-16 g/day in three to four divided doses may take up to 2 weeks to work, so should start as soon as pruritis is noted check INR qweek, as affects vitamin K absorption may cause bloating and constipation Management Ursodeoxycholic acid (UDCA) increases bile flow causes significant decrease in pruritus and decrease liver function studies dose 500 mg BID (15 – 20 – 25mg/kg/d) Management Delivery In most cases, delivery should be accomplished by 38 weeks If cholestasis is severe, delivery should be considered at 36 weeks if fetal lung maturity is documented Outcomes Perinatal Outcome Main complications are prematurity, meconuimstained amniotic fluid and intrauterine demise Probability of fetal complications is directly related to bile acid levels Fetal complications are generally not seen until bile acid levels are >40 mmol/L (further studies needed) Outcomes Perinatal Outcome Antepartum FHR testing and fetal surveillance should be undertaken May induce labour at term, or when amniotic fluid studies indicate FLM Outcomes Maternal Outcome Maternal prognosis is good Pruritis usually begins to resolve around 2 days postpartum There are generally no hepatic sequelae Recurs in 60-70% of subsequent pregnancies Recurrent episodes are variable in severity (u less severe) Outcomes Maternal Outcome May be at increased risk for gallstones OCP – administration rarely results in recurrent cholestasis, however LFTS should be checked after 3-6 months Viral hepatitis HAV - no difference with pregnancy status HEV – cause of fulminant hepatic failure in third tm, 20% mortality, associated with IUFD, abortion HBV – perinatal transmission, higher in those with HBeAg positive (90% vs 10%), Ig at birth and vaccine at first day, 1 and 6 month for the new born, lamivudine for the mother HDV – no difference from nonpreg HCV – no effect bilaterally, vertical transmission is uncommon except with high viremia, tx not possible Chronic liver diseases Usually amenorrhea and infertility Varices may worsen Autoimmune hepatitis – worsen post partum Neoplasms – may worsen, bleed Thrombosis – may worsen, hepatic vein, Transplantation – resulted in successful delivery, continue immuno supressive tx Differential Diagnosis of Liver Disease in Pregnancy Serum Bilirubin Transaminase s Coagulopat hy Histology Other Features Acute Hepatitis B >1000 >5 - Hepatocellul ar necrosis Potential for perinatal transmissio n Acute Fatty Liver <500 <5 + Fatty infiltration Coma, renal failure, hypoglycem ia Intrahepa <300 tic Cholesta sis <5, mostly direct - Dilated bile canaliculi Pruritis, increased bile acids HELLP <5 + Variable periportal necrosis HTN, edema, thrombocyt openia >500 GI disorders Physiology of pregnancy motility changes Esophageal motility in distal part decreases by a third, resting tone decreases progressively until delivery due to progesterone effect Stomach no effect on motility, delayed emptying at term, normal basal and stimulated acid secretion Intestines prolonged transit time, worsening with increasing GA, progestrone effect Increased villus height, mucosal hypertrophy, increased brush border enzymes during lactation and decrease after weaning Animal studies – increase selective amino acid and Vit B 12 absorption Nausea and vomiting 60-70% nausea, 40% vomiting in first trimester Onset 4-6wks, peak 8-12 wks, resolution by 20wk Hyperemesis gravidarum - 0.5-10/1000 preg. Often with primi, multipleg, high maternal body mass, unwanted preg, crowded living May lead to hypotension, electrolyte disturbance, …. Need hospitalization 25-40% slight transaminase and bilirubin rise Recur in subsequent preg H pylori – controversial roll Chemoreceptor trigger – mediated by hCG, thyroxin, cortisol, gestational steroid hormones, parathormon Tx – hydration, metoclopromide, prochlorperazine, vit B 6, TPN GERD 50-80% heart burn by the end of third trimester Overt esophagitis is rare Lower esophageal tone is decreased and with advance of the pregnancy intra abdominal pressure increases EGD, pH monitoring are safe but unnecessary TX- non pharmacologic antireflux measures, liquid antiacids (avoid Mg containing near term). H2RB pass the placenta but are safe, PPI are group B except omeperazole © PUD Improves Decrease use of NSAID, increase use of antiacids for n, v, cytoprotective effect of gestational steroids Course of H pylori is the same Cpx like bleeding, perforation and GOO are reported but rare EGD indicated in confusing cases Tx – sucralfate (no absorbable), antibiotics IBD IBD are common in female (by 30% > male) Fertility is affected only in crohn’s ds with pelvic inflammations, or post proctocolectomy for UC Initial IBD presentation during preg is unusual, may occur in first tm and usual is mild Disease activity before conception determines the natural course and effect on preg. Surgical mx is ass with increased m and f mortality Most drugs are safe – sulfasalazine (with folate), mesalamine is ass with interstitial nephritis in the neonates, prednisone is safe Azathioprine and 6-mercaptopurine safe in practice use Metronidazole – reports of malformation Methotrexate – teratogenic, inflixamab insufficient data appendicitis 1 in 1500 pregnancies, at any time of gestation Anatomic displacement makes dx difficult, and delayed Sx over lap eg nausea, vomiting Graded compressive US, Helical CT Tx – surgery, laparascopic Gall stone disease 2.5 – 12 % in asymptomatic preg, dx when US is done for fetal assessment Cpx are rare during preg. Cholecystitis is more common during in post partum Conservative mx with iv fluid, antibiotics analgesia, then surgery preferably laparoscopic, endoscopic common bile duct stone extraction (? Fluoroscopy use) pancreatitis Rare Due to gall stones or triglyceridemia Similar to non pregnants