A Successful Method for Fetal Survival in Rhesus Disease

Abstract 

Introduction
Prior to immunoprophylaxis with RhIG, 7-8 percent of Rh negative women with Rh-positive, ABO-compatible infants developed anti-Rh (D) within six months of delivery; while only one percent of Rh-negative mothers delivering ABO-incompatible babies were immunized. A significant number of women in Iran become sensitized because immunoprophylaxis is not widely practiced, resulting in hemolytic diseases of the newborn.

Methods
In this paper, the small-volume (500-600 cc) plasma exchange method was investigated in treatment of 32 women with Rhesus disease. Over period of 4-16 years, these sensitized women had 157 unsuccessful pregnancies. Small-volume plasma exchange was carried out weekly from the end of their first trimester throughout their pregnancy to reduce anti-D titer.

Results
31 out of 32 mothers delivered babies successfully.

Conclusions
Small-volume plasma exchange procedure is an easy and safe method, both for the mother and the fetus and it can produce brilliant results in treatment of Rh disease. This method is inexpensive and practical, even in small blood transfusion centers.

Introduction
Fetal erythroblastosis was recognized as early as 400 BC and its pathophysiology was described in 1940.1,5 Infusion of Rho (D) Immunoglobulin as prophylaxis has reduced the disease rate^{1,2,4,8,15,17,20} from 10-17% to 0.1%.^1,3 Despite all efforts, however, fetal erythroblastosis has not been eradicated entirely.^3,4,22 According to some reports, the mortality rates of fetuses and infants of hyper sensitized mothers prior to application of proper treatment was 30% to 93%.^3,5

With new, diverse and developed treatments, the fetal mortality rate has been greatly decreased. The chance of rescue for infants of severely Rh-incompatible mothers in some centers has risen from 33% to 78.2%,^6,7 and even in some reports to 94% and 100%.^3,7,8,9,12 Intrauterine Intravenous Transfusion (IUIVT)^,31,32 Intraperitoneal Transfusion (IPT)³⁰ or Intravenous Immunoglobulin injection (IVIG)³³ have been the methods used in treatment of sensitized women. IUIVT requires advanced equipment and fetal mortality rate in each attempt is 1-9%, even if performed by the most experienced staff.^14-16,26 IUIVT therapy is practically restricted to a few advanced medical centers in the world and has never been fully used in Iran. The use of IPI or IUT therapy may result in 20% fetal mortality.³ IPT and IUIVT have been of no use for highly sensitized cases that get hydrops or fetal mortality before the 26th week. In these cases, it is recommended that either plasma exchange(10-11 liters) should be performed, or high dose immunoglobulin should be injected intravenously until the time is appropriate for blood transfusion into the fetus umbilical cord vein or peritoneal cavity.^{3,17,18,29,34,35} High volume plasma exchange has not been used frequently in the treatment of Rh disease due to its common complications (citrate toxicity, cholinesterase deficiency and problems with the replacement fluids)²⁶ and its despairing outcomes. Although the removal of several liters of plasma per week will result in transient reduction in the anti-D titer during or immediately after treatment, a chronic, significant reduction in antibody titer is difficult to achieve by this technique. Furthermore an increase in anti-D titers has been observed soon after plasma exchange was stopped.³⁹ This rebound phenomenon has been attributed to the removal of the negative feedback influence on further anti-D production by high circulating titers of anti-D antibody. High-volume plasma exchange has been regarded as costly, time consuming, and producing unreliable results.^5,6,11,24 Unfortunately the problems associated with high-volume plasma exchange have overshadowed the beneficial outcomes of small-volume plasma exchange,^7,22,23,27 inasmuch as it has not even been mentioned as therapy. In this study the simple and safe small volume plasma exchange was carried out in order to evaluate the usefulness of this method in treatment of Rh-sensitized women and to investigate the mortality rate of the fetus in these women.

Materials and methods
During 10 years (1992-2001), 32 sensitized women with history of fetal loss or affected infants were interviewed at Mashhad Blood Bank. No women were accepted for plasma exchange in the presence of contraindicating disease. Hematology tests (CBC, blood group, prothrombin time, partial thrombin time, clotting time, bleeding time, serum iron, total iron binding capacity), biochemical test (blood sugar, urea(Drug information on urea), total protein, calcium, protein electrophoresis, urine analysis) and seroimmunology tests (anti-D titer, anti-HCV, anti-HIV, anti-HTLV1, HBS antigen, indirect Coombs test) were performed in the prenatal visit for each patient. Thirty-two women were requested to participate in regular and weekly plasma exchange. From the 12th gestational week, 500-600 ml of plasma was exchanged manually in each visit using multi-unit bags in the Plasmapheresis Ward of Mashhad Blood bank and the procedure was repeated weekly until delivery. The plasma was replaced with normal saline.^7,22 Laboratory tests such as CBC, platelet, and indirect Coombs were performed weekly and TIBC, SI and protein electrophoresis were done every 8 weeks to check the degree of blood component discrepancy. Ultrasound examinations were performed in the first visit, and then every 2 or 3 weeks to confirm fetal maturity and assess various fetal and placental parameters.^5,7,9,20,22 Fetal development and thickness of placenta were considered as the criteria for terminating pregnancy. The patients were hospitalized in appropriate times for delivery. To decrease the prevalence of infant respiratory distress syndrome, 5 mg dexamethasone(Drug information on dexamethasone) IM, bid, was injected to the mothers 48 hours before cesarean section. Then the pregnant women were admitted to the Obstetric and Gynecology Ward of Ghaem Hospital (Mashhad University of Medical Sciences) for cesarean section. After delivery, the newborns were immediately transferred to intensive care unit (NICU) to prevent kernicterus.^1,3,4,21,22

Results
Tables 1 and 2 list the details of cases investigated in this study. Thirty-one out of 32 severely Rh-incompatible mothers who had small-volume plasma exchange weekly underwent cesarean section between the 34th and 38th weeks of gestation. The newborns had Apgar scores of 7-10.

Their cord hemoglobin ranged between 10-12 g/dl and their cord indirect bilirubin ranged between 3.5 and 8 mg/dl. Twenty-nine newborns were discharged in good health after 1-6 days of hospitalization following blood transfusion. Only 4 newborns did not need blood exchange. The fetus of patient number 11 developed hydrops and died in the 24th week of gestation. The initial anti-D titer of the latter patient was 1/1024 (Table 1) and plasma-exchange was not performed for her appropriately due to low weight. Two newborns with Apgar scores 7-10 also died because of malpractice during blood exchange.

Discussion
Although Rh disease has not been totally eradicated,^{3,4,12,18,19,21} researchers have been able to achieve outstanding progress in the pathophysiology, prophylaxis and treatment of this condition. Unfortunately in Iran, some Rh-negative mothers who are married to Rh-positive men do not use any preventive methods against Rh disease because of various reasons. Sensitization in these women led to fetal death or mental disorders, neural deafness, mental retardation, paralysis and other dangerous complications in their newborns. Our aim was to evaluate the usefulness of small volume plasma exchange in treatment of Rh disease. Fortunately, 31 out of 32 severely Rh incompatible women who had 157 unsuccessful pregnancies over a period of 4-16 years could deliver a relatively healthy newborn after treatment with weekly small-volume plasma exchange. Unfortunately two out of 31 infants died due to inadequate attention during blood transfusion, which reduced our rate of success in treatment from 96.8% to 90.6%. Even with this fault, our success rate was higher than those of other researcher.^1,10,23 According to our studies and observations, small-volume plasma exchange is a useful and safe method in treatment of Rh disease.^7,22 This method is not expensive and is even practical in small blood transfusion centers. The method was effective in reduction of the anti-D titer in most of the patients. In our study, the anti-D titer of 26 pregnant Rh-incompatible women decreased by as much as 30-90%. In 5 patients, only small changes were observed. As changes in the anti-D titer do not relate to the fetal state after birth,^6,7 the volume of plasma exchange was not altered for the five cases mentioned above and the procedure was continued weekly until the time for terminating the pregnancy. Obviously, if plasma exchange is not performed accurately and regularly in these severely Rh-incompatible mothers, or if their at-risk fetuses are not delivered as soon as possible, fetal mortality rate will increase Furthermore, repeated small-volume plasma exchange may prevent antibody rebound, which is common in treatment with high volume plasma exchange.

The results of this study revealed that the small-volume plasma exchange procedure is an easy and safe method both for the mother and the fetus and it can produce brilliant results in the treatment of Rh disease.

Table 1
Clinical and laboratory findings in 32 severely Rh-incompatible women treated with small-volume plasma exchange, and blood groups and Rh of their husbands and babies

Table 2
Summary of clinical and laboratory findings in 32 severe Rh-incompatible women and newborns treated with small-volume plasma exchange

1. Summary of clinical and laboratory findings in 32 severely Rh-incompatible women

2. Summary of clinical and laboratory findings in 31 newborns treated with small-volume plasma exchange