Hemolytic disease of the newborn heralds hemorrhagic disease of the newborn

Abstract

Hemolytic disease of the fetus and newborn, which normally presents with unconjugated hyperbilirubinemia, has been known to cause cholestatic jaundice, albeit in rare circumstances; seen especially in the setting of Rhesus (Rh) hemolytic disease or when the mother has received intrauterine transfusion(s). Infants presenting with cholestatic jaundice in the setting of hemolytic anemia pose a clinical dilemma with regard to investigative approach and management. There are no evidence-based guidelines as to whether such infants should be managed conservatively or investigated comprehensively for other causes of cholestasis. Furthermore, whether such babies should receive chelation therapy besides supportive treatment is not known. We describe one such case where a neonate with Rh hemolytic disease presented with cholestasis and acute liver failure.

INTRODUCTION

Hemolytic disease of the fetus and newborn (HDFN) is caused by an immunologic reaction of transplacentally transferred maternal IgG antibodies against antigens on fetal red blood cells (RBCs). Most commonly, the antibodies are directed against the Rhesus D antigen [1]. The result of immunologic damage to fetal RBCs is variable and can range from mild anemia and neonatal hyperbilirubinemia requiring phototherapy to severe fetal anemia requiring postnatal exchange transfusions, intrauterine transfusions (IUTs), fetal hydrops or even intrauterine death [2]. Clinical situations with combination of more than one antibody against fetal RBCs can complicate the pregnancy course and can lead to more severe hemolytic disease [2,3]. Cholestasis in HDFN has been reported to occur with variable incidence ranging from 7% to 13% among various studies [4,5]. Infants with HDFN who receive in utero or postnatal RBC transfusions are especially at an increased risk of developing cholestasis [6]. Cholestasis in HDFN had earlier been hypothesized to occur secondary to the inspissation of bile restricting the forward flow in bile ducts [7]. However, it is now known to be caused by the direct toxicity of iron to hepatocytes in the setting of excessive hemolysis, especially when in utero or postnatal transfusions are given [8]. Excessive iron overload could predispose to liver dysfunction, hyperferritinemia, and acute liver failure, which in some cases necessitates chelation therapy.

CASE REPORT

A 13-day-old term male neonate born at 37 + 2 weeks of gestation with a birth weight of 2,800 grams to a 35-year-old gravida 4, para 3, Rh negative female by normal vaginal delivery with uneventful perinatal period was brought to neonatal emergency with parental concern of conjunctival redness for 1 week, yellowish discoloration of skin and sclerae for 3 days and persistently blood stained umbilical stump staining clothes for 2 days. The neonate had received postnatal injection of vitamin K immediately after birth and was discharged on the second day of life after immunization and serum bilirubin assessment, which was 5.1 mg/dl at 36 hours of life. He was exclusively breastfed at the hospital and at home and was receiving a vitamin D daily supplement 400 IU per day. There was a history of Rh hemolytic disease in his elder sibling, third in birth order, who had undergone double volume exchange transfusion in her neonatal period. Mother had received anti-D immunoglobulin injection after the first and second deliveries but not after the third childbirth. In the current pregnancy, indirect Coombs test was 4+ at 22 and 28 weeks, but there was no evidence of fetal anemia or hydrops based on antenatal ultrasound scans and ultrasound Doppler examinations done at 24 and 32 weeks of gestation, both of which showed normal middle cerebral artery peak systolic velocity.

At presentation, the baby was pale, icteric to the knees and elbows, had subconjunctival hemorrhage in both eyes (Figure 1), and his umbilical stump was surfaced with clotted blood. His weight was 2,950 g, and his systemic examination was normal.

Figure 1.

Conjunctival hemorrhage in the infant at presentation.

Bilirubin at admission was 19 mg/dl with direct fraction of 1 mg/dl, liver enzymes were in the normal range, and hemoglobin was 10.1 g/dl. Direct Coombs test was 2+. The baby was started on double surface phototherapy.

On the second day of admission, the baby had one episode of vomiting mixed with blood, bleeding from the umbilical stump, increased pallor, and lethargy. Investigations sent on the second day of admission showed bilirubin of 14.2 mg/dl with direct component of 4 mg/dl, serum glutamic-oxaloacetic transaminase (SGOT) of 310 IU/l, serum glutamic pyruvic transaminase (SGPT) of 145 IU/l, albumin of 4.8 g/dl, hemoglobin of 8.1 mg/dl, Platelets of 255,000/mm³ of blood, prothrombin time (PT) of 30 seconds, activated PT clotting time (aPTT) of 63 seconds, and international normalized ratio (INR) of 3.0. Baby was immediately given an injection of vitamin K and one transfusion each of fresh frozen plasma (FFP) and packed RBCs. Ultrasound of the cranium did not show any intracranial hemorrhage. The baby was started on fat-soluble vitamin replacement and ursodeoxycholic acid. Following transfusions, the bleeding diathesis abated, and a repeat coagulation profile revealed normal results with PT of 16 seconds, aPTT of 29 seconds, and INR of 1.0. Serial liver function tests over the following days of admission are presented in Table 1.

Table 1.

Liver function tests of infant during hospital stay and at follow-up.

Day of life	17	20	25	38	60
Total bilirubin (mg/dl)	10.7	9.7	9.0	5.1	3.1
Conjugated bilirubin (mg/dl)	5.4	4.5	3.8	1.7	0.9
SGOT (IU/l)	366	427	212	198	55
SGPT (IU/l)	199	253	70	78	53
Albumin (g/dl)	4.5	5.4	3.7	3.9	3.9
Globulin (g/dl)	3.4	3.8	3.1	3.2	3.1
ALP (IU/l)	427	424	466	488	444
GGT (IU/l)	144	156	188	109	90

ALP, Alkaline phosphatase; GGT, Gamma-glutamyl transferase; SGOT, Serum glutamic-oxaloacetic transaminase; SGPT, Serum glutamic pyruvic transaminase.

Ultrasound of the liver revealed normal echo pattern with normal intrahepatic biliary radicals and a well-visualized gall bladder. Serum ferritin on day 18 of life was 2,948 ng/ml, which was about ten times the normal for age. Over the course of the next few days, jaundice improved with decreasing trends of both total and direct bilirubin levels. Baby was discharged with total bilirubin of 5 mg/dl and conjugated bilirubin of 1.7 mg/dl and on follow-up at 2 months of age, liver function test revealed near normal results. Ferritin at 2 months was 1,108 ng/ml and further decreased on the next follow-up to 990 ng/ml at 3 months of age. Timeline showing disease course is presented in Figure 2.

Figure 2.

Disease course of the infant.

DISCUSSION

Our case was a 13-day well-appearing infant who presented with neonatal jaundice with Rh hemolytic disease, did not require any in utero transfusion, and had an uneventful perinatal course. The infant developed conjugated hyperbilirubinemia due to underlying hemolysis and iron overload to hepatocytes, causing liver injury with consequent bleeding diathesis. Since the coagulopathy and liver function tests improved with supportive treatment and ultrasound was not suggestive of any biliary obstruction, a conservative approach was followed. The infant was discharged after clinical and biochemical recovery and followed up with normal liver function tests and ferritin. Infants with HDFN presenting with cholestatic jaundice pose challenges with regards to underlying diagnosis as well as requirement of care beyond phototherapy and blood products. The evaluation and investigative approach to be followed is not guided by evidence-based guidelines, and decisions whether to extensively investigate or carefully follow the patient would require an individualized approach. It has been suggested that in a well-appearing infant with a history of IUTs for HDFN, it is reasonable to rule out biliary obstruction and image for the presence of gallbladder and bile ducts with minimally invasive investigation such as ultrasound [6]. Even though HDFN-associated cholestasis can be severe, the effects are transient, and there is no risk of associated chronic liver disease at 2 years of age [4]. Inadvertent phototherapy for conjugated hyperbilirubinemia increases the risk of bronze baby syndrome [9]. High to very high ferritin levels along with increased levels of transaminases may be associated with this syndrome [10]. We observed that in our case, although the mother did not receive any IUTs, ferritin levels were high. This could be because of the hemolysis of already present RBCs causing overload of iron onto the hepatocytes with consequent rise of serum ferritin. Furthermore, postnatal transfusion could also have contributed to the rise in ferritin. Coagulopathy causing significant bleeding has rarely been associated with this syndrome [5,11]. The infant in our case had liver dysfunction presenting with clinical bleeding which responded to vitamin K and FFP. Although cholestasis with hyperferritinemia has been managed conservatively, many such cases have been managed with chelation therapy in order to prevent risk of liver failure secondary to iron overload [11,12].

Although infants presenting with cholestasis beyond the second week of life should be investigated for cause of conjugated hyperbilirubinemia, those appearing well and improving with supportive management in the setting of Rh ISO immune disease can be carefully followed up after ruling out biliary obstruction, which is one of the most common causes of cholestasis in infants [6]. The same approach was followed in our case. The main limitation of our case study was that an extensive investigative approach was not followed for cholestasis; however, this was done in the light of underlying diagnosis of Rh hemolytic disease and clinical recovery with supportive management.

To conclude, cholestasis associated with HDFN seen usually is the setting of Rh hemolytic disease, can present with varying degrees of liver dysfunction ranging from mild transaminitis to acute liver failure with hemorrhagic diathesis. In the setting of cholestasis, which is usually seen following IUTs or postnatal transfusion, imaging to rule out obstructive biliary disease, besides supportive care, is essential. Additionally, hyperferritinemia with threat of iron overload to liver should be managed on a case-to-case basis with chelation therapy. Appropriate follow-up of liver function should be ensured in all cases of cholestasis.

CONFLICTS OF INTEREST

The authors declare that there are no conflicts of interest relevant to this publication.

FUNDING

None.

ETHICS APPROVAL

Consent of both father and mother of the patient has been obtained, including consent for publication of images. The authors declare that ethics committee approval was not required for this case report.