Hemolytic disease of the fetus and newborn due to Rh(D) incompatibility: A preventable disease that still produces significant morbidity and mortality in children

Abstract

In the mid-20th century, Hemolytic Disease of the Fetus and Newborn, caused by maternal alloimmunization to the Rh(D) blood group antigen expressed by fetal red blood cells (i.e., "Rh disease"), was a major cause of fetal and neonatal morbidity and mortality. However, with the regulatory approval, in 1968, of IgG anti-Rh(D) immunoprophylaxis to prevent maternal sensitization, the prospect of eradicating Rh disease was at hand. Indeed, the combination of antenatal and post-partum immunoprophylaxis is ~99% effective at preventing maternal sensitization to Rh(D). To investigate global compliance with this therapeutic intervention, we used an epidemiological approach to estimate the current annual number of pregnancies worldwide involving an Rh(D)-negative mother and an Rh(D)-positive fetus. The annual number of doses of anti-Rh(D) IgG required for successful immunoprophylaxis for these cases was then calculated and compared with an estimate of the annual number of doses of anti-Rh(D) produced and provided worldwide. Our results suggest that ~50% of the women around the world who require this type of immunoprophylaxis do not receive it, presumably due to a lack of awareness, availability, and/or affordability, thereby putting hundreds of thousands of fetuses and neonates at risk for Rh disease each year. The global failure to provide this generally acknowledged standard-of-care to prevent Rh disease, even 50 years after its availability, contributes to an enormous, continuing burden of fetal and neonatal disease and provides a critically important challenge to the international health care system.

Fig 1. IgG anti-Rh(D) doses actually administered annually, as compared with minimum and optimum thresholds for immunoprophylaxis.

The GBD Super Regions are indicated along the x-axis and the annual number of doses of IgG anti-Rh(D) are indicated along the y-axis. The annual numbers of IgG anti-Rh(D) doses actually administered in each GBD Super Region are indicated by filled-in black diamonds. The minimum threshold number of annual IgG anti-Rh(D) doses (i.e., the number required to provide post-partum immunoprophylaxis only) is indicated by the blue line; the optimum threshold number of annual IgG anti-Rh(D) doses (i.e., the number required to provide both antenatal and post-partum immunoprophylaxis only) is indicated by the green line. The “acceptability area” is indicated in light green.

Fig 2. Heat-map representing each country’s gap in providing post-partum Rh(D) immunoprophylaxis.

The “gap” is the proportion of annual doses of IgG anti-Rh(D) not administered post-partum divided by those that should have been administered to prevent maternal Rh(D) sensitization. The size of the gap is indicated by various colors; dark green: fully satisfied; light green: gap between 0 and 30%; yellow: gap between 30 and 50%; light orange: gap between 50 and 80%; dark orange: gap greater than 80%; white: data not available because statistics are not tracked in these countries; gray: IgG anti-Rh(D) provided through a national volunteer program [22] and, therefore, not tracked in the MIDAS database.