Targeted Anti-D, The First Irish Perspective

C.A. McCormick1, L. Mulvany2, M.C. De Tavernier1

1. Department of Obstetrics and Gynaecology, Portiuncula University Hospital Ballinasloe, SAOLTA group
2. Department of Haematology, Coagulation and Blood Transfusion, Portiuncula University Hospital Ballinasloe, SAOLTA group

The use of anti-D to prevent haemolytic disease of the new-born can be regarded as one of the greatest success stories of modern medicine. Rhesus antibodies cause significant harm to rhesus positive foetuses in utero including anaemia, jaundice, hydrops fetalis and stillbirth. Deaths due to haemolytic disease of the new born have fallen dramatically. In the UK 1 in 2180 babies in 1953 died due to Rhesus haemolytic disease. 37 years later, in 1990, this figure had dropped to 1 in 62,500 1. Recent initiatives including the routine administration of anti-D at 28-32 weeks gestation have further reduced the incidence of sensitisation2.

However, it is important to remember that anti-D is a blood product and therefore can be associated with adverse events. It is a finite resource and there is potential for shortage of supply. Physiological reactions may occur on administration. In Ireland we have witnessed the devastating impact  of disease transmission through blood products3.

Anti-D is effective at preventing sensitisation following foetal maternal haemorrhage1. This is only relevant when a rhesus negative mother is carrying a rhesus positive foetus. However approximately 40% of rhesus negative women will carry rhesus negative foetuses and therefore will obtain no benefit from antenatal anti-D administration. By identifying mothers with rhesus negative foetuses, 40% of antenatal anti-D administration could be eradicated. In a retrospective review of 883 births over a 6-month period in 2016, 141 deliveries were to rhesus negative mothers. 68 of these women delivered rhesus negative babies. Therefore this 48% of rhesus negative women would have received an unnecessary blood product during their pregnancy if routine antenatal anti-D had been administered. In the 1990s it was discovered that foetal DNA could be detected in the maternal blood stream4. Amplification of this genetic material has given rise to a new wave of antenatal diagnosis. Cell free DNA can be used to identify foetal rhesus status and therefore guide antenatal management of rhesus negative women. This technique is being widely utilised across Europe. Denmark, the Netherlands and Finland have all reported sensitivities of over 99% and specificities over 97% in the years since they have implemented routine testing 5-7. The Netherland report a reduction in unnecessary ante natal anti-D administration from 40% to 1.31% 5.A recent metanalysis by Mackie et al reported sensitivities of 0.993 (95% CI 0.982-0.997) and specificity of 0.984 (CI 0.964-0.993)8. Based on this data the authors concluded that for foetal rhesus status non-invasive perinatal testing should be considered diagnostic.

With regards to false negative results, that is incorrectly identifying a rhesus positive foetus as being rhesus negative and therefore not administering anti-D, the figures are very reassuring. The NICE guidelines quote a rate of 2-4/1000 women having such a result 9. This exposes them to a risk of sensitisation similar to that of a woman before the introduction of antenatal Anti D, which was approximately 2%9. NICE also comment that current sensitisation rates are estimated at 281 per 100,000 pregnancies. If targeted anti-D administration was introduced the rate could rise by 3- i.e to 284 per 100,000 rhesus negative pregnancies. However, the rates of unnecessary anti-D administration would fall over 30% so the small risk of increased sensitisation should be balanced against the much larger risk of unnecessary blood products9.

In our unit an information sheet has been developed to inform women of the small but important risk of sensitization secondary to false negative results. To date no woman has opted out of the program. Cord bloods are being tested for ABO and Rhesus blood group for quality monitoring and to ensure minimisation of this risk.

Since introduction of targeted anti-D in July 2017 and March 2018, 212 women have been tested. 130 women were identified as carrying a Rhesus positive foetus and 82 were identified as Rhesus negative. Therefore 82 women (38%) have avoided unnecessary anti-D administration.

A cost analysis is ongoing in the department. We expect to show a significant cost saving as part of the initiative. Costs to be considered include: free foetal DNA Rhesus testing (26 euro including shipping and report), Anti D 1500 units (71 euro), workload reduction in the emergency department, maternity ward, early pregnancy unit in relation to antepartum haemorrhage, reduction in Kleihauer tests and increase in work load for OPD midwives taking samples at booking, providing patient information and following results. In conjunction with a potential cost saving there are strong ethical arguments to promote the use of free foetal DNA to reduce exposure of pregnant women to unnecessary blood products.

In conclusion, targeted anti-D has been successfully introduced in Portiuncula University Hospital. Free foetal DNA has been proven as an effective test internationally. In our experience the test is feasible, has high patient acceptability and prevents unnecessary anti-D exposure in 39% of rhesus negative women.

Conflict of Interest:
The authors declare that there is no conflict of interest.

Corresponding Author:
Ciara McCormick
Portiuncula Hospital
Ballinasloe
Galway
Ireland
Email: cmccormi@tcd.ie

References

1. Contreras, M. (1998), The prevention of Rh haemolytic disease of the fetus and newborn — general background. BJOG: An International Journal of Obstetrics & Gynaecology, 105: 7-10. doi:10.1111/j.1471-0528.1998.tb10285.x
2. Tiblad E, Taune Wikman A, Ajne G, Blanck A, Jansson Y, Karlsson A, Norlander E, Hollander BS, Westgren M. Targeted routine antenatal anti-D prophylaxis in the prevention of RhD immunisation–outcome of a new antenatal screening and prevention program. PLoS One. 2013;8(8):e70984
3. Garvey P, Murphy N, Flanagan P, Brennan A, Courtney G, Crosbie O, Crowe J, Hegarty J, Lee J, McIver M, McNulty C, Murray F, Nolan N, O’Farrell C, Stewart S, Tait M, Norris S, Thornton L. Disease outcomes in a cohort of women in Ireland infected by hepatitis C-contaminated anti-D immunoglobulin during 1970s. J Hepatol. 2017 Dec;67(6):1140-1147. doi: 10.1016/j.jhep.2017.07.034. Epub 2017 Aug 24.
4. Lo YM, Tein MS, Lau TK, Haines CJ, Leung TN, Poon PM, Wainscoat JS, Johnson PJ, Chang AM, Hjelm NM. Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am J Hum Genet. 1998;62(4):768-75.
5. de Haas M, Thurik FF, van der Ploeg CP, Veldhuisen B, Hirschberg H, Soussan AA,Woortmeijer H, Abbink F, Page-Christiaens GC, Scheffer PG, Ellen van der Schoot C. Sensitivity of fetal RHD screening for safe guidance of targeted anti-D immunoglobulin prophylaxis: prospective cohort study of a nationwide programme in the Netherlands. BMJ. 2016;355:i5789
6. Clausen FB, Steffensen R, Christiansen M, Rudby M, Jakobsen MA, Jakobsen TR, Krog GR, Madsen RD, Neilsen KR, Rieneck K, Sprogoe KM, Baech J, Dziegiel MH, Grunnet N. Routine noninvasive prenatal screening for fetal RHD in plasma of RhD-negative pregnant women-2 years of screening experience from Denmark. Prenat Diagn. 2014;34(10):1000-5
7. Haimila K, Sulin K, Kuosmanen M, Sareneva I, Korhonen A, Natunen S, Tiumala J, Sainio S. Targeted antenatal anti-D prophylaxis program for RhD-negative pregnant women – outcome of the first two years of a national program in Finland. Acta Obstet Gynecol Scand. 2017;96(10):1228-33.
8. Mackie FL, Hemming K, Allen S, Morris RK, Kilby MD. The accuracy of cell‐free fetal DNA‐based non‐invasive prenatal testing in singleton pregnancies: a systematic review and bivariate meta‐analysis. BJOG2017;124:32–46.
9. National Institute for Health and Care Excellecne High-throughput non-invasive prenatal testing for fetal RHD genotype. National Institute for Health and Care Excellence Guidance. 9 November 2016-. https://www.nice.org.uk/guidance/dg25

P917

image_pdfimage_print