Abstract

Introduction: Severe hemolytic disease of the fetus and newborn (HDFN) due to red cell alloimmunization is a frequent cause of recurrent fetal loss. This condition becomes critical when standard treatments like intrauterine transfusion (IUT) or immune-modulating therapies such as therapeutic plasma exchange (TPE) and intravenous immunoglobulin (IVIG) are unavailable or not administered in a timely manner. This case report emphasizes the potential benefits of early TPE and IVIG administration.

Case Presentation: A 28-year-old Rhesus D (RhD) negative woman (G3P2) experienced recurrent fetal loss due to severe HDFN and had a history of RhD alloimmunization and fetal loss in her second pregnancy. In her third pregnancy, high anti-D titers (1:2,024) were identified at weeks 12 and 16. Despite the need, TPE and IVIG were not administered properly due to the patient missing follow-ups and the absence of IUT facilities, culminating in macerated intrauterine death (IUD) at 27 weeks.

Discussion: The failure to implement early TPE and IVIG interventions, alongside systemic treatment inadequacies, contributed to the adverse pregnancy outcome. This case accentuates the necessity of accessible and timely intervention in pregnancies complicated by high anti-D titers.

Conclusion: For RhD alloimmunized pregnancies with high anti-D titers, early administration of TPE and IVIG before 20 weeks of gestation is crucial in reducing fetal morbidity and mortality. This case underscores the importance of early intervention and continuous monitoring in managing sensitized pregnancies.

Introduction

Maternal red blood cell (RBC) alloimmunization may lead to the production of harmful antibodies that cause hemolytic disease of the fetus and newborn (HDFN), resulting in fetal morbidity and mortality. Severe HDFN can lead to hydrops fetalis and significant jaundice, potentially resulting in kernicterus, permanent brain damage, or infant death. In contrast, mild HDFN typically causes only mild neonatal jaundice, which is often effectively treated with phototherapy alone1. Before the introduction of anti-D immunoglobulin (RhIG) in 1968, it was estimated that HDFN affected approximately 1% of all pregnancies worldwide, with anti-D being a major contributor to fetal morbidity and mortality2. Approximately 0.1 to 0.4% of pregnant women remain sensitized despite the implementation of RhIG, likely due to antigens other than RhD3.

The related morbidity and mortality of HDFN due to anti-D have significantly reduced after routine antenatal and postnatal RhIG prophylaxis. However, Rhesus D (RhD) alloimmunization still occurs due to failure in identifying the mother’s Rhesus status or detecting fetal-maternal hemorrhage (FMH), and non-compliance with RhIG prophylaxis guidelines. These were evidenced in our published data on RBC alloimmunization and HDFN in pregnant Malay women, besides reported cases of severe anti-D HDFN in primigravida women4, 5.

The risk and management of HDFN have improved with advanced diagnostic methods and treatment modalities. Nowadays, the fetal RhD genotype can be detected with a high-sensitivity method using polymerase chain reaction (PCR) techniques on free fetal DNA (ffDNA) extracted from maternal plasma, eliminating the need for paternal testing6. Detailed ultrasonography scanning (USS) and Doppler assessment of fetal middle cerebral artery-peak systolic velocity (MCA-PSV) have significantly increased the success of accurately diagnosing HDFN without placing the fetus at risk7. Meanwhile, therapeutic plasma exchange (TPE), intravenous immunoglobulin (IVIG) injections, and intrauterine transfusion (IUT) have provided excellent outcomes in treating severe HDFN7, 8. Here we report the case of a woman with recurrent fetal loss due to high anti-D titers and highlight the benefit of administering TPE and IVIG as early as 20 weeks of gestation to avoid sudden intrauterine death (IUD). However, the patient missed the opportunity to undergo those treatments and our institution also lacked the experience to perform an IUT.

CASE PRESENTATION

A 28-year-old gravida 3 para 2 (G3P2) patient with RhD negative status was referred to our healthcare institution for fetal monitoring and pregnancy management. She had one surviving child from her first pregnancy in 2015, when she was 22 years old. RhD alloimmunization was detected in her second pregnancy in 2017, at the age of 24, when she delivered a macerated fetus at 38 weeks with a high anti-D titer of 1:>4,096. Her RhD negative status was identified as a rr (cde/cde) phenotype during her first pregnancy. Her husband’s blood type was O RhD positive with a R1R1 (CDe/CDe) phenotype. She claimed that she was given only one dose of antenatal anti-D prophylaxis during her first and second pregnancy at 28 weeks gestation, and no postnatal prophylaxis was given. She also said she did not receive any blood transfusion, suffered miscarriage, or experienced FMH events during her first pregnancy. With regard to her RhD alloimmunization, she and her husband were provided counseling on future pregnancy plans and the possible complications that entailed. Thus, she chose to remain in voluntary subfertility for four years by taking intramuscular Depo Provera. However, after three years, in October 2021, she was referred to our institution at 16 weeks of gestation when complications arose in her latest pregnancy.

The patient had early antenatal booking at six weeks gestation (July 2021) and uneventful follow-ups at a district hospital. However, a positive indirect antiglobulin test at the 12th week of gestation detected a high anti-D titer of 1:2048 (September 2021). She was referred to our center on the 16th week (October 2021), where another test also yielded the same result (Table 1). Initially, she was scheduled for bi-weekly check-ups and adhered to the schedule very well. Detailed ultrasound scanning was performed at 21 weeks gestation, which showed good fetal growth, but there was a presence of minimal pericardial effusion with no cardiomegaly or pleural effusion. Despite having a high anti-D titer, fetal MCA-PSV Doppler assessment remained normal throughout the follow-up. After the obstetrician and transfusion team discussion, it was decided to proceed with therapeutic plasma exchange (TPE) to reduce her anti-D titer during her next follow-up appointment (in early December 2021). In the meantime, referral to a maternal-fetal specialist for intrauterine transfusion (IUT) was planned in case her MCA-PSV Doppler assessments showed abnormal results.

However, TPE could not be carried out as the patient missed her follow-up appointment for unknown reasons after 23 weeks gestation (December 2023). Later, the clinicians were informed of the termination of her pregnancy at 27 weeks (January 2022) after she delivered a macerated stillborn by induction at a district hospital near her home. Her postnatal recovery went well physically and mentally because she was already aware of the poor outcome. On further discussion, she and her husband were still keen to attend appointments at our institution for future pregnancies. Details of the patient’s pregnancies are summarised in Table 2.

Table 1.

Summary of patient’s immunohaematological test results

Test Patient Husband ABO/RhD Blood group A RhD negative A RhD positive Rh phenotype rr (cde/cde) R1R1 (CDe/CDe) Antibody screening Positive Not applicable Antibody identification Anti-D Not applicable Anti-D titre 1:2048 (at 12 and 16 week gestation) Not applicable

Table 2.

Chronology of the patient’s pregnancies and outcomes

Pregnancy Year Gestation (weeks) Anti-D status Anti-D prophylaxis Foetal monitoring Management / pregnancy outcome 1 2015 37 Not detected Given at 28 weeks Not given postnatal IUGR and oligohydramnios of unknown cause Boy, 1.4 kg via LSCS at 37 weeks due to acute foetal distress, the only surviving child. 2 2017 28 Unknown Given at 28 weeks Unknown Girl, 2.8 kg, vaginal delivery. MSB at 38 th week of gestation. 37-38 Detected, Anti-D titre of 1: > 4,096 Not given postnatal IUD after 37 weeks 3 (current) 2021 July-September 6-15 Detected, anti-D titre of 1:2,048 at 12 th week Not given, not indicated Booking and follow-up at district hospital. Foetal growth corresponding to age. Referred to our centre at 16 weeks gestation. Oktober-December