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Health technology assessment

Determination of fetal rhesus D status from maternal plasma of rhesus negative women

  • Year: 2014
  • Authors Arentz-Hansen H, Brurberg KG, Kvamme MK, Stoinska-Schneider A, Hofmann B, Ormstad SS, Fure B.
  • ISSN (digital): 1890-1298
  • ISBN (digital): 978-82-8121-931-1

It is likely that NIPT gives a very accurate RhD typing of the fetus. The documentation is of high quality.



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Key message

Approximately 15 percent of Norwegian women are Rhesus D (RhD)-negative. During pregnancy and birth, there is a danger that these women produce antibodies against fetal blood cells (alloimmunization), if the fetus is RhD-positive. These antibodies may cross the placenta and cause hemolytic disease of the fetus, which may become life threatening. Today, all RhD-negative pregnant women are closely followed-up during pregnancy, and the newborns are routinely tested for RhD-type at birth. Upon detection of an RhD-positive child, the mother will get anti-D prophylaxis within 72 hours after birth to prevent the formation of anti-D antibodies that may cause problems in subsequent pregnancies.

Alloimmunization may occur throughout the whole pregnancy, especially during the last trimester. Therefore, in the Guidance for obstetrics 2014 published by the Norwegian Gynecological Association, it is recommended that anti-D prophylaxis should be offered RhD-negative women also during pregnancy, if they carry an RhD-positive fetus. With a blood sample from the pregnant woman, it can be tested whether the fetus is RhD-negative or -positive. The technology is based on analysis of free fetal DNA present in the woman's blood during pregnancy, and is often referred to as non-invasive prenatal testing (NIPT). The result of NIPT can be used to provide targeted prophylactic treatment to the pregnant women who can benefit from it, and to avoid unnecessary treatment of pregnant women with RhD negative fetuses.

In this report, we summarize research studies on diagnostic accuracy of NIPT, as well as clinical effectiveness and health economic and ethical consequences of introducing NIPT for fetal RhD typing in all RhD-negative pregnant women. The main findings are:

Diagnostic accuracy

  • It is likely that NIPT gives a very accurate RhD typing of the fetus. The documentation is of high quality.

Clinical effectiveness

  • We identified no systematic reviews on clinical effectiveness of introducing NIPT for fetal RhD typing in all RhD-negative pregnant women.

Health economic evaluation

  • Introduction of a program with NIPT-guided anti-D prophylaxis will give an additional cost of approximately 4 million Norwegian kroner per year. The cost per avoided RhD-alloimmunization is approximately 106,000 Norwegian kroner. These numbers are based on effectiveness data from a Swedish cohort study.

Ethics

NIPT is an ethically controversial technology. NIPT for RhD typing, when used after the legal time limit for abortion has passed, avoids many of the ethical issues, but alternative or extended applications may be ethically challenging.

Summary

Background

Approximately 15 percent of Norwegian women are Rhesus D (RhD)-negative. During pregnancy and birth, there is a danger that these women produce antibodies against fetal blood cells (alloimmunization), if the fetus is RhD-positive. These antibodies can cross the placenta and cause hemolytic disease of the fetus, which may become life threatening. Today, all RhD-negative pregnant women are closely followed-up during pregnancy, and the newborns are routinely tested for RhD-type at birth. Upon detection of an RhD-positive child, the mother will receive anti-D prophylaxis within 72 hours after birth to prevent the formation of anti-D antibodies that may cause problems in subsequent pregnancies. Anti-D prophylaxis is also given to RhD-negative women within 72 hours after invasive procedures (amniocentesis, chorion biopsy, breech repositioning) or abortion. 

Alloimmunization may occur throughout the whole pregnancy, especially during the last trimester. Therefore, in the Guidance for obstetrics 2014 published by the Norwegian Gynecological Association it is recommended that, anti-D prophylaxis should be offered RhD-negative women also during pregnancy, if they carry an RhD-positive fetus. With a blood sample from the pregnant woman, it can be tested whether the fetus is RhD-negative or -positive. The technology is based on analysis of free fetal DNA present in the woman's blood during pregnancy, and is often referred to as non-invasive prenatal testing (NIPT). The result of NIPT can be used to provide targeted prophylactic treatment to the pregnant women who can benefit from it, and to avoid unnecessary treatment of pregnant women with RhD-negative fetuses.

An alternative strategy practiced in some countries, is to offer prophylaxis to all RhD-negative pregnant women without testing whether the fetus is RhD-negative or -positive. This strategy has been chosen in England, while countries like the Netherlands, Denmark and Iceland have introduced systems for NIPT-guided prophylaxis.

Objectives

In this report, we summarize research studies on diagnostic accuracy of NIPT, as well as clinical effectiveness and health economic and ethical consequences of introducing NIPT for fetal RhD typing in all RhD-negative pregnant women.

Method                      

Diagnostic accuracy

We communicated the results of a systematic review (SBU Alert-report 2011), and updated with more recent primary studies including more than 500 participants. To summarize the primary studies, we used a bivariate analysis model to estimate the "Summary ROC curve".

Clinical effectiveness

Due to time constraints, we restricted the literature searches to systematic reviews. This prioritization was made because the commissioner of this project was most interested in knowing about the diagnostic accuracy of NIPT for RhD typing.

Health economic evaluation

We performed a cost-effectiveness analysis (CEA) to estimate the health economic consequences of introducing a program with screening of all RhD-negative pregnant women with NIPT and selected anti-D prophylaxis, compared with either current practice or a program where anti-D prophylaxis is given to all RhD-negative pregnant women. The effect estimate in the analysis is based on a recent Swedish cohort study, comparing screening of RhD-negative pregnant women with NIPT and selected prophylaxis (n = 9,380) with a historical control group who was not given anti-D during pregnancy (n = 18,546). In our health economic analysis, the health effect is incidence of RhD alloimmunization.

The Guidance for obstetrics 2014, suggest testing with NIPT in gestational week 25, in Norway. In this report, we will therefore primarily focus on test results around this time point.

Results

Diagnostic accuracy

We identified one systematic review from 2011 (SBU Alert report) of medium quality reporting that NIPT provides a very accurate RhD typing of fetuses of RhD-negative women. Our search for primary studies identified six studies, including more than 500 participants in each study, carried out after 2011. We therefore performed new meta-analysis estimating the sensitivity and specificity of NIPT for fetal RhD typing to 99.84% (95% CI 99.73 to 99.91) and 96.86% (95% CI 95.53 to 97.80), respectively around 25 weeks of gestation.

Clinical effectiveness

We identified no systematic reviews on clinical effectiveness of introducing NIPT for fetal RhD typing in all RhD-negative pregnant women.

Health economic evaluation

Introduction of a program with NIPT-guided anti-D prophylaxis (i.e. screening of all RhD-negative pregnant women with NIPT and selected anti-D prophylaxis) will give an additional cost of approximately 4 million Norwegian kroner per year. A program offering anti-D prophylaxis to all RhD-negative pregnant women will give an additional cost of approximately 3,5 million Norwegian kroner per year. The cost per avoided RhD alloimmunisation is approximately 106,000 Norwegian kroner by NIPT-guided anti-D prophylaxis, and about 88,000 Norwegian kroner offering anti-D prophylaxis to all RhD-negative pregnant women. Since the cost estimate is based on relative risk of RhD alloimmunization with NIPT-guided anti-D prophylaxis versus current practice, as described in the Swedish cohort study, the result is linked with uncertainty. Within a 95 percent confidence interval for the effect estimate, the cost per avoided RhD alloimmunization vary between 367,020 Norwegian kroner and 73,404 Norwegian kroner. The costs are presented in a societal perspective.

Ethics

NIPT is an ethically controversial technology. NIPT for RhD typing, when used after the legal time limit for abortion has passed, avoids many of the ethical issues, but alternative or extended applications may be ethically challenging.

Discussion

In this HTA report, we have sought to quantify the benefits and costs associated with the introduction of a new program for NIPT-guided anti-D prophylaxis for RhD-negative pregnant women in Norway.

The results of the included systematic review showed high diagnostic accuracy of NIPT, but since the review was old and there were some uncertainties linked to the results, we decided to update the SBU report by including large primary studies published from 2011 (including two studies from the SBU report, both from 2008). This gave us the possibility to calculate an estimate for both sensitivity and specificity for NIPT for fetal RhD typing.

We identified no systematic reviews on clinical effectiveness of introducing NIPT-guided prophylaxis. However, we identified systematic reviews suggesting that it may be effective to offer anti-D prophylaxis to all RhD-negative pregnant women, but these reviews were not included since they did not meet our predefined inclusion criteria. Based on the estimates we have on diagnostic accuracy of NIPT for fetal RhD typing, it seems likely that the effectiveness of NIPT-guided anti-D prophylaxis is similar to the effectiveness achieved by giving anti-D prophylaxis to all RhD-negative pregnant women.

Since we did not identify any systematic reviews on clinical effectiveness of introducing NIPT- guided prophylaxis, our economic evaluation was based on a recent Swedish cohort study. The effect estimate was incidence of alloimmunization. In this study, the number of alloimmunizations were approximately halved. There are uncertainties associated with the effect estimates, and alloimmunization is used as a surrogate endpoint for clinical effectiveness.

The cost per avoided alloimmunization is likely to be overestimated. The follow-up cost of children with sequelae of RhD alloimmunization is expected to decrease over time following introduction of NIPT-guided anti-D prophylaxis or anti-D prophylaxis to all RhD-negative pregnant women and this is not included in the analysis.

Conclusions

  • It is likely that NIPT gives a very accurate RhD typing of the fetus. The documentation is of high quality.
  • We identified no systematic reviews on clinical effectiveness of introducing NIPT for fetal RhD typing in all RhD-negative pregnant women.
  • Introduction of a program with NIPT-guided anti-D prophylaxis will give an additional cost of approximately 4 million Norwegian kroner per year. The cost per avoided RhD-alloimmunization is approximately 106,000 Norwegian kroner. These numbers are based on effectiveness data from a Swedish cohort study.
  • NIPT is an ethically controversial technology. NIPT for RhD typing, when used after the legal time limit for abortion has passed, avoids many of the ethical issues, but alternative or extended applications may be ethically challenging.
  • By introducing NIPT-guided anti-D prophylaxis, around 40 % of RhD-negative pregnant women will avoid unnecessary treatment, compared with a program offering prophylaxis to all RhD-negative pregnant women.

Need for further research:

  • By introducing a program with NIPT-guided prophylaxis, it will be important with a systematic implementation and monitoring of the program.

There is a need for a systematic overview of the clinical effectiveness of NIPT for fetal RhD typing of all RhD-negative pregnant women.