Gestational Alloimmune Liver Disease in Pregnancy and the Neonate

A 33-year-old Gravida 2 Para 0100 at 11 weeks’ gestation presents for a maternal-fetal medicine consultation due to a history of prior loss from suspected gestational alloimmune liver disease (GALD). She underwent in vitro fertilization with negative preimplantation genetic testing for aneuploidy. Her prenatal laboratory tests were unremarkable, and she had low-risk noninvasive prenatal testing. Her medical history is significant for hypothyroidism, for which she takes levothyroxine.In the prior pregnancy, the patient presented at 20 weeks’ gestation for an anatomy ultrasonography at which time a fetal demise was identified. There was evidence of fetal hydrops on ultrasonography. The patient underwent dilation and evacuation. An evaluation to discern the etiology of the demise, including an autopsy, fetal microarray, antiphospholipid antibody testing, infectious serologies, and blood cell typing with Kleithauer-Betke testing, was all unremarkable. The autopsy suggested that although the fetal demise likely occurred at 18–19 weeks’ gestation, the fetus only measured 15 weeks’ gestation at the time of the demise, suggesting early-onset fetal growth restriction. The autopsy also demonstrated hemosiderin deposition in the fetal liver and pancreas, a finding highly suggestive of GALD. Because of the 90% to 95% recurrence rate of GALD,1,2 the maternal-fetal medicine physician recommended treatment with weekly intravenous immunoglobulin (IVIG) starting at 14 weeks’ gestation in any future pregnancies. After meeting with genetic counseling, the fetal tissue was tested for genetic diseases associated with hemosiderin deposition and GALD, which was unrevealing.Six months after this intrauterine loss, the patient became pregnant again and opted for IVIG treatment.The patient began IVIG infusions of 1g/kg weekly starting at 12 weeks’ gestation. She did not have any reactions to IVIG infusions such as headaches, rashes, nausea, or vomiting. She underwent an early anatomic ultrasonography at 16 weeks’ gestation, a follow-up anatomy ultrasonography at 20 weeks’ gestation, and growth ultrasonographies every 2 weeks that showed consistent growth at approximately the 50th percentile and a normal-appearing fetal liver. She was vaccinated for tetanus, diphtheria, acellular pertussis vaccine, and influenza, but the patient declined the respiratory syncytial virus vaccine, given the lack of data about coadministration of this vaccine with IVIG treatment; she planned to give Nirsevimab to her infant post birth. The patient started weekly antenatal testing with fetal nonstress tests and amniotic fluid indices at 32 weeks’ gestation.The patient underwent induction of labor and had a successful vaginal delivery at 38.1 weeks’ gestation complicated by a postpartum hemorrhage of 1.4 L for which she received uterotonic medications and treatment with an intrauterine vacuum device. She did well postpartum, and her postpartum hemoglobin was stable at 10.5g/dL. Her IVIG infusions were discontinued.A live male neonate was delivered via spontaneous vaginal delivery at 38.1 weeks’ gestation weighing 3400 g with an Apgar score of 8 and 8 at 1 and 5 minutes, respectively. He was admitted for monitoring in the neonatal intensive care unit because of the maternal history of GALD. Laboratory tests, including hepatic panel and coagulation profile, were not indicative of GALD and were only significant for indirect hyperbilirubinemia requiring phototherapy. He received breast milk via bottle and breastfeeding. He received Nirsevimab before discharge. He was discharged with plans to follow up with gastroenterology.GALD is a rare cause of severe fetal and neonatal liver disease resulting in fetal growth restriction, oligohydramnios, fetal distress, fetal hydrops, stillbirth, neonatal liver failure, neonatal multiorgan damage, and neonatal death.1,3,4 GALD has a high recurrence rate; of patients who have had a pregnancy previously diagnosed with GALD, approximately 90% to 95% of future pregnancies will be affected.1,2 Without any treatment, 14% to 25% of future pregnancies result in an intrauterine fetal demise, and 80% result in neonatal demise, making this an important disease to diagnose, treat, and prevent.3,5GALD is caused by alloimmunization of pregnant persons to an unknown antigen located on fetal hepatocytes. It is estimated to affect 4 in 100 000 births in the United States per year.6 GALD alloimmunization can occur antenatally and result in adverse outcomes similar to neonatal alloimmunization thrombocytopenia. Some studies suggest that alloimmunization in GALD may occur as early as 12 weeks’ gestation in the incident pregnancy, with the onset of fetal liver injury typically occurring around 24 weeks’ gestation.4,7Alloimmunization is thought to result in the deposition of IgG antibodies from the pregnant person into the fetal liver.3,4 These antibodies cause activation of the terminal complement cascade, resulting in severe fetal hepatocyte damage.3,7 The hepatocyte damage results in low hepcidin, a hormone that downregulates iron absorption and storage, resulting in increased iron uptake and deposition in hepatic and extrahepatic tissues.3 The iron or hemosiderin deposition causes fetal liver injury similar to that of adult patients with hereditary hemochromatosis who have inflammation of the liver with progression to fibrosis and cirrhosis.3,4,7Fetal hepatic and extrahepatic iron deposition commonly results in the phenotypic pattern known as neonatal hemochromatosis (NH). NH appears similar to hereditary hemochromatosis with ascites, jaundice, hepatomegaly, respiratory distress, and multiorgan failure.4,8,9 A diagnosis of NH is made when siderosis, or iron deposits, is noted in the extrahepatic tissues4 and can be detected on magnetic resonance imaging (MRI), through biopsies of extrahepatic tissue (most commonly the salivary gland), or via evaluation of liver pathology on autopsy. Although NH is frequently caused by GALD, NH can result from other etiologies such as trisomy 21, parvovirus, or cytomegalovirus perinatal infections.10Unfortunately, GALD is rarely diagnosed during pregnancy because the ultrasonography findings associated with GALD are often nonspecific findings such as fetal growth restriction and oligohydramnios.11 Other fetal ultrasonography findings associated with GALD include hepatomegaly, an irregular or nodular liver, echogenic bowel or kidneys, ascites, pericardial or pleural effusions, hydrops, placental edema, and intrauterine fetal demise11–14; these fetal ultrasonography findings often indicate advanced disease. If the maternal obstetric history is suggestive of GALD, a fetal MRI may show evidence of an atrophic liver and/or extrahepatic siderosis, but these findings are neither sensitive nor specific.10,11 It is also possible to perform cordocentesis antenatally to obtain a diagnosis.15 Because many pregnancies with ultrasonography abnormalities, such as fetal hydrops, also exhibit signs of fetal distress, many of these patients are often delivered preterm, and so prenatal initiation of IVIG in this population has not been studied.Although antenatal diagnosis of GALD is difficult, the high recurrence rate and the availability of an effective preventive treatment make postnatal or postmortem diagnosis important for initiating prophylactic IVIG treatment in future pregnancies. The initiation and standardization of antenatal IVIG administration has drastically reduced the risk of adverse outcomes for pregnancies likely to be affected by GALD. Administration of IVIG to pregnant persons in pregnancies at risk for GALD has decreased the rate of fetal loss from 1 in 4 pregnancies to 1 in 188 pregnancies.5 IVIG is thought to work by preventing further formation of antibodies from the pregnant person, binding and neutralizing the already circulating antibodies, and preventing immune activation and inflammation in the fetal liver.5,16 The timing of initiating antenatal IVIG administration has been investigated, with equivalent outcomes seen when started at either 14 or 18 weeks’ gestation.5Common side effects of IVIG in the pregnant person include headaches, flushing, nausea and vomiting, diarrhea, swelling at the infusion site, rash, and fatigue. While most of these side effects are mild and self-resolving, other, more serious adverse effects have been reported, including thromboembolic events, acute liver or kidney injury, aseptic meningitis, neutropenia, and autoimmune hemolytic anemia.17 A slow infusion rate may help to prevent the hyperviscosity associated with thromboembolic events, and regular laboratory evaluations can help detect thrombocytopenia, liver or kidney damage, and anemia.17 There is one case report of a drug-induced liver injury occurring in a pregnant patient receiving IVIG for a prior pregnancy loss complicated by GALD.18 In this case report, the patient’s liver injury was treated with steroids, although she ultimately went into preterm labor within days of the liver injury. Serious side effects of IVIG are rare and must be weighed against the treatment benefit in pregnancies at risk for recurrent GALD.Most neonatal cases of GALD with or without NH present with severe, early-onset liver disease, often within a few hours of birth. Neonatal signs of GALD include ascites, diffuse edema, jaundice, purpura, bruising, hepatomegaly, lethargy, hypotonia, oliguria, hypotension, and sepsis-like symptoms.3,8,19 Laboratory findings are often consistent with liver failure, including hyperbilirubinemia, thrombocytopenia, coagulopathy, hypoglycemia, hypoalbuminemia, metabolic abnormalities, and characteristically with normal or only mildly elevated liver transaminases3,8,9 (Table 1). The severe onset of neonatal liver failure within hours of birth is typical in GALD and less common in other metabolic, genetic, or infectious causes of liver disease. Diagnosis in the neonate is primarily made on pathology from salivary gland or liver biopsy showing positive staining of the terminal complement complex, although MRI may sometimes show extrahepatic siderosis and may aid in quicker diagnosis.10,19 Because diagnosis can take days, a high index of suspicion should lead to initiation of treatment while awaiting a confirmatory pathology diagnosis.Before neonatal disease-directed treatment, neonatal GALD had a survival rate of only 17% to 20%.2,20 Innovations have evolved a treatment of neonatal GALD consisting of a combination of high-dose IVIG administered at 1g/kg with an exchange transfusion.5,8,20,21 The IVIG works to prevent any further complement activation and liver damage, whereas the exchange transfusion removes the residual antibodies in the neonate’s blood.8 A standardized protocol for these treatments does not yet exist, but commonly an exchange transfusion is performed, immediately followed by IVIG administered at 1 to 2 g/kg and repeated weekly IVIG, as needed.8,20,22These 2 neonatal treatments, IVIG and exchange transfusion, have improved the survival rate of neonates with GALD to 75% to 80%.20,21 They have also proven effective in reversing liver damage and reducing the need for liver transplantation. Fortunately, of those neonates that survive the neonatal period, the majority have normal liver function and reassuring outcomes throughout their childhood.20,23 Given the success of these treatments, it is essential for neonatologists to consider a diagnosis of GALD in neonates presenting with severe, early-onset liver failure, particularly with normal or mildly low transaminitis because early initiation has drastically shown to improve outcomes in infants with GALD.24GALD is a rare cause of adverse fetal and neonatal outcomes resulting from alloimmunization from an antibody from the pregnant person to an unknown antigen on fetal hepatocytes. For pregnant patients at risk of recurrent GALD, treatment with weekly antenatal IVIG leads to a high likelihood of successful outcomes, as described in this case.American Board of Pediatrics Neonatal-Perinatal Content SpecificationRecognize maternal medical disorders and medications affecting the fetus and newborn infant.Known prenatal fetal interventions and assessment of fetal well-being.Understand hyperbilirubinemia and how it pertains to neonatal liver failure.