Early Intravenous Immunoglobulin (IVIG) Therapy and Non Invasive Fetal Monitoring in Rh Alloimmunization (AI) and Pregnancy
Authors: Ambika Santhosh , Wong Glenn , Salhotra Amandeep , Falzon Maria , Zwirello Lucy Bayer- , Parameswaran Rekha 
Published: April 2020

High titer (HT), ≥1:32, anti-E, anti-c and anti-D Rh antibodies can cause hemolytic disease of the newborn (HDN). Maternal IVIG therapy may reduce need for intrauterine and exchange transfusions in HDN. Minimal data exists regarding optimal timing of therapy initiation, dose and frequency and fetal outcomes. Late administration of IVIG therapy beyond gestational age of 16 weeks have not been shown to improve fetal outcome. We describe the clinical course of 3 pregnant women with Rh AI. Two women with high titer Rh AI were treated with early IVIG dose of 1 gm/kg/week. A third woman with low titer Rh AI did not receive IVIG. Fetal status was monitored non-invasively with weekly Fetal Doppler ultrasound measurement of peak systolic velocity (PSV) of the middle cerebral artery (MCA). Patient 1 was a 38 year old Caucasian female with high anti- D (&gt; 1:500) and history of HDN; second baby required 3 exchange transfusions and third baby required 3 intrauterine transfusions during pregnancy and 2 exchange transfusions post delivery. IVIG weekly infusion was started on week 11. Amniocentesis done at week 21 showed that baby was Rh(D) positive and the Kleihauer-Bethke test was negative. Serial fetal MCA PSV done weekly till labor induction did not show evidence of significant fetal anemia. The IVIG infusions were completed on 33rd week and the patient delivered healthy baby by cesarean section on the 35th week. The baby did not receive any intra uterine or exchange transfusions.

Patient 2 was a 37 year old caucasian woman with anti-c AI. The patient’s husband is c antigen positive and she had seroconversion during her third pregnancy which manifested as positive antibody screen in a routine type and screen with her third delivery which was uneventful. She subsequently had a miscarriage of her fourth pregnancy at 9 weeks. Her peak anti –c titer was 1: 128. She received IVIG infusion from week 11 to week 33 with stable anti-c titer of 1: 64. Serial MCA PSV assesments did not reveal significant fetal anemia. She had a normal vaginal delivery on week 34 with a healthy baby not requiring any exchange transfusions. Patient 3 was a 41 year old caucasian woman with low titer anti-E AI (1:8). No IVIG was administered as her titers remained low during her pregnancy course. Her titers were monitored every 2 weeks; peak antibody titer was 1:8. Fetal anemia was ruled out with Serial MCA PSV assesments. She delivered a healthy baby by Ceserean section at 38 weeks, 4 days.

Patient 1 Patient 2 Patient3 Gravid status G4 P2103 G5 P3013 G8, P4034 Blood group A- A+ O+ Antibody identification Anti D Anti c Anti E H/o documented HDN Yes No No Number of doses of IVIG 23 23 NA Age of Gestation IVIG started 10 weeks 11 weeks NA Cumulative dose of IVIG 1580 gms 1750 gms NA Peak antibody titer 1048 128 8 Serial Fetal Peak MCA velocity Normal Normal Normal Intra uterine/Exchange transfusions none None None Pregnancy outcome normal fetus normal fetus normal fetus IVIG adverse effects Headache, fatigue None N/A

Patient 1

Weeks of gestation Anti D Titer IVIG –Cumulative No. of doses MCA PSV (cm/s) MoM= Multiples of Median 9 1:512 12 1:1048 1 17 1:512 7 20 1:512 10 21 (0.83 MoM) 21 1:512 11 28 (1.04 MoM) 22 1:512 12 21.3 (0.76 MoM) 23 1:512 13 28.1 (0.96 MoM) 24 1:512 14 22 (0.71 MoM) 25 1:512 15 25 (0.77 MoM) 26 1:512 16 32 (0.95 MoM) 27 1:512 17 28 (0.79 MoM) 28 1:512 18 35 (0.94 MoM) 30 1:512 20 45 (1.11 MoM) 32 1:512 22 61 (1.37 MoM) 33 1:512 23 51.9 (1.1 MoM)

Patient 2

Weeks of gestation Anti c Titer IVIG – Cumulative number of doses MCA PSV (cm/s) MoM= Multiples of Median 11 1:128 1 14 1:64 4 20 1:64 10 22 1:64 11 22.3 (0.79 MoM) 24 1:64 13 23.7 (0.77 MoM) 25 1:64 14 22.7 (0.70 MoM) 26 1:64 15 30.1 (0.89 MoM) 27 1:64 16 34.3 (0.97 MoM) 29 1:64 18 37.9 (0.98 MoM) 30 1:64 19 33.3 (0.82 MoM) 31 1:64 20 27.9 (0.65 MoM) 32 1:64 21 28 (0.62 MoM) 33 1:64 22 59 (1.26 MoM) 34 1:64 23 35 (0.71 MoM)

Patient 3

Weeks of gestation Anti E Titer IVIG - Cumulative No. of doses MCA PSV (cm/s) MoM= Multiples of Median Median – 1.29 MoM = No fetal anemia 1.29 – 1.5 MoM = Mild anemia &gt;1.5 MoM = Severe anemia 12 1:8 0 19 1:8 0 26 1:8 0 28 1:8 0 40.6 (1.07 MoM) 29 1:4 0 39.7 (1.02 MoM) 32 1:4 0 42 (0.94 MoM 34 1:4 0 55 (1.12 MoM)

Conclusion- Early initiation of weekly IVIg therapy at dose of 1 gm/kg at gestational age of 10 to 11 weeks in high titer (≥ 1:32) maternal Rh AI is well tolerated and can eliminate the need for invasive fetal monitoring, intrauterine transfusion and exchange transfusion.