Correspondence

Fetal Sex and Hemolytic Disease from Maternal Red-Cell Alloimmunization

N Engl J Med 1998; 338:1699-1700June 4, 1998

Article

To the Editor:

Fetal anemia secondary to maternal Rh alloimmunization is a major cause of intrauterine and postnatal morbidity and mortality. The relations between fetal sex and the antenatal course and outcome of Rh alloimmunization have been unclear.

In mice, male fetal cells in the maternal circulation may trigger a strong maternal rejection response.1 Transplantation studies in humans suggest that male recipients tolerate female tissue well, whereas female recipients tend to reject transplants from male donors.2 The male-specific H-Y antigen may induce a T-cell reaction in the female immune system.3 We hypothesized that male fetuses are more severely affected by maternal Rh alloimmunization and reviewed 86 consecutive singleton pregnancies with RhD-positive fetuses (43 male and 43 female) and maternal anti-D titers higher than 1:16.

Fifty-one fetuses (59 percent) received one or more intravascular, intrauterine transfusions. Parity, the number of previous affected pregnancies, and the maternal anti-D titers did not vary significantly between the women with male fetuses and the women with female fetuses. The women with male fetuses had more previous pregnancies (median, 2.0 vs. 1.0; P=0.03). The gestational age at the time of the first intrauterine transfusion was younger for male fetuses than for female fetuses (24.5 vs. 30.0 weeks, P= 0.004).

Multiple linear regression analysis with stepwise selection, with the fetal hematocrit (corrected for gestational age) at the time of the first transfusion as the dependent variable and fetal sex, gestational age at first transfusion, maternal anti-D titer, gravidity, parity, and history of previous affected children as independent variables, showed that fetal sex (P=0.005) (Figure 1Figure 1Umbilical-Cord Hematocrit before Initial Intrauterine Transfusion, According to Fetal Sex.) and maternal anti-D titer at first transfusion (P=0.031) were predictors of the fetal hematocrit. Hydrops was present in 17 fetuses (16 males and 1 female; relative risk for males, 16.0; 95 percent confidence interval, 2.2 to 115.4). Mortality was higher for male fetuses than for female fetuses (21 percent vs. 7 percent; relative risk, 3.0; 95 percent confidence interval, 0.87 to 10.3).

A predominance of males has been reported among Rh-positive infants causing alloimmunization in their Rh-negative mothers.4 Walker and Mollison noted in 1957 that the neonatal death rate from kernicterus was twice as high among boys as among girls.5 We propose that male fetuses are more severely affected by maternal Rh alloimmunization than female fetuses. The mechanism is unclear, but it may be that male fetuses are “rejected” by their mothers.

Barbara Ulm, M.D.
Martin R. Ulm, M.D.
Simon Panzer, M.D.
University Hospital of Vienna, 1090 Vienna, Austria

5 References

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   Bonney EA, Matzinger P. The maternal immune system's interaction with circulating fetal cells. J Immunol 1997;158:40-47
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   Pennisi E. Long-sought H-Y antigen found. Science 1995;269:1515-1516
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   de Bueger M, Bakker A, Van Rood JJ, Van der Woude F, Goulmy E. Tissue distribution of human minor histocompatibility antigens. J Immunol 1992;149:1788-1794
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   Woodrow JC, Donohoe WT. Rh-immunization by pregnancy: results of a survey and their relevance to prophylactic therapy. BMJ 1968;4:139-144
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   Walker W, Mollison PL. Haemolytic disease of the newborn: deaths in England and Wales during 1953 and 1955. Lancet 1957;1:1309-1314
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Citing Articles (2)

Citing Articles

1. 1

   B. Ulm, L. Kirchner, G. Svolba, B. Jilma, J. Deutinger, G. Bernaschek, S. Panzer. (1999) Immunoglobulin administration to fetuses with anemia due to alloimmunization to D. Transfusion 39:11, 1235-1238
   CrossRef

2. 2

   Barbara Ulm, Gerhard Svolba, Martin R. Ulm, Gerhard Bernaschek, Simon Panzer. (1999) Male fetuses are particularly affected by maternal alloimmunization to D antigen. Transfusion 39:2, 169-173
   CrossRef