WHO recommendation on antenatal anti-D immunoglobulin prophylaxis

WHO recommendation on antenatal anti-D immunoglobulin prophylaxis



Antenatal prophylaxis with anti-D immunoglobulin in non-sensitized Rh-negative pregnant women at 28 and 34 weeks of gestation to prevent RhD alloimmunization is recommended only in the context of rigorous research.

(Context-specific recommendation –research)


Publication history

First published: December 2016

Updated: No update planned

Assessed as up-to-date: December 2016



  • This context-specific recommendation relates to anti-D prophylaxis during pregnancy and not the practice of giving anti-D after childbirth, for which there is high-certainty evidence of its effect of reducing RhD alloimmunization in subsequent pregnancies (1). Anti-D should still be given postnatally when indicated.
  • Determining the prevalence of RhD alloimmunization and associated poor outcomes among women in LMIC settings, as well as developing strategies to manage this condition, is considered a research priority.



Rhesus (Rh) negative mothers can develop Rh antibodies if they have an Rh-positive newborn, causing haemolytic disease of the newborn (HDN) in subsequent pregnancies. Administering anti-D immunoglobulin to Rhnegative women within 72 hours of giving birth to an Rh-positive baby is an effective way of preventing RhD alloimmunization and HDN (1). However, Rhesus alloimmunization occurring in the third trimester due to occult transplacental haemorrhages will not be prevented by postpartum anti-D.



The ANC recommendations are intended to inform the development of relevant health-care policies and clinical protocols. These recommendations were developed in accordance with the methods described in the WHO handbook for guideline development (2). In summary, the process included: identification of priority questions and outcomes, retrieval of evidence, assessment and synthesis of the evidence, formulation of recommendations, and planning for the implementation, dissemination, impact evaluation and updating of the guideline.

The quality of the scientific evidence underpinning the recommendations was graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) (3) and Confidence in the Evidence from Reviews of Qualitative research (GRADE-CERQual) (4) approaches, for quantitative and qualitative evidence, respectively. Up-to-date systematic reviews were used to prepare evidence profiles for priority questions. The DECIDE (Developing and Evaluating Communication Strategies to support Informed Decisions and Practice based on Evidence) (5) framework, an evidence-to-decision tool that includes intervention effects, values, resources, equity, acceptability and feasibility criteria, was used to guide the formulation and approval of recommendations by the Guideline Development Group (GDG) – an international group of experts assembled for the purpose of developing this guideline – at three Technical Consultations between October 2015 and March 2016.

To ensure that each recommendation is correctly understood and applied in practice, the context of all context-specific recommendations is clearly stated within each recommendation, and the contributing experts provided additional remarks where needed.

In accordance with WHO guideline development standards, these recommendations will be reviewed and updated following the identification of new evidence, with major reviews and updates at least every five years.

Further information on procedures for developing this recommendation are available here.


Recommendation question

For this recommendation, we aimed to answer the following question:

  • For non-sensitized RhD-negative pregnant women (P), is routine prophylactic antenatal anti-D administration (I) compared with no anti-D (C) effective for preventing Rhesus alloimmunization (O) and improving outcomes?


Evidence summary

The evidence on the effects of antenatal anti-D prophylaxis was derived from a Cochrane review that included two RCTs involving over 4500 Rh-negative pregnant women (6). Most participants were primigravidas. Both trials compared antenatal anti-D prophylaxis with no antenatal anti-D prophylaxis. One trial used a dose of 500 IU, the other used 250 IU, given at 28 and 34 weeks of gestation. Data were available for 3902 pregnancies, and more than half the participants gave birth to Rh-positive newborns (2297). All women with Rh-positive newborns received postpartum anti-D immunoglobulin as per usual management. The primary outcome was the presence of Rh-antibodies in maternal blood (a proxy for neonatal morbidity). No maternal ANC guideline outcomes (including maternal satisfaction and sideeffects) and few perinatal guideline outcomes were reported in these trials.

Fetal and neonatal outcomes

Evidence on the effect of antenatal anti-D on RhD alloimmunization during pregnancy, suggestinglittle or no difference in effect, is very uncertain. In addition, the evidence on the effect on postpartum RhD alloimmunization and alloimmunization up to 12 months postpartum among women giving birth to Rh-positive newborns (n = 2297 and 2048, respectively) is very uncertain, partly because events were rare. Evidence on the effect of antenatal anti-D on neonatal morbidity (jaundice) from one trial (1882 neonates) is also very uncertain, partly because events were rare. No other ANC guideline outcomes were reported in the review.


Additional considerations

Low-certainty evidence from the Cochrane review suggests that Rh-negative women who receive antenatal anti-D are less likely to register a positive Kleihauer test (which detects fetal cells in maternal blood) during pregnancy (1 trial, 1884 women; RR: 0.60, 95% CI: 0.41–0.88) and at the birth of a Rh-positive neonate (1 trial, 1189 women; RR: 0.60, 95% CI: 0.46–0.79). In the Cochrane review, the rate of RhD alloimmunization during pregnancy, the postpartum period and up to 12 months later among women in the control group was 0.6%, 1.1% and 1.5%, respectively. Rates of RhD alloimmunization in subsequent pregnancies were not reported in the trials. There is no evidence on optimal dose of antenatal anti-D prophylaxis and various regimens are used. There are two ongoing studies listed in the Cochrane review, which may help to clarify issuesaround effects and dosage once completed. Only 60% of Rh-negative primigravidas will have an Rh-positive newborn, therefore 40% of Rhnegative women will receive anti-D unnecessarily with antenatal anti-D prophylaxis (6).


A single dose of anti-D can cost around US$ 50 (500 IU) to US$ 87 (1500 IU) (139), depending on the brand and local taxes; therefore, the cost of antenatal prophylaxis for two 500 IU doses could be as much as US$ 100 per woman. Additional costs will include screening for blood typing in settings where Rh blood tests are not currently performed.


The contribution of RhD alloimmunization to perinatal morbidity and mortality in various LMIC settings is uncertain and it is not known whether antenatal anti-D for non-sensitized Rh-negative women will impact on equity.


Anti-D immunoglobulin is derived from human plasma and is administered by injection, which may not be acceptable to all women. Qualitative evidence indicates that engagement may be limited if tests and procedures are not explained properly to women, or when women feel their beliefs, traditions and social support mechanisms are overlooked or ignored by health-care professionals (high confidence in the evidence) (7).


In a number of LMIC settings providers feel that a lack of resources, both in terms of the availability of the medicines and the lack of suitably trained staff to provide relevant information, may limit implementation of recommended interventions (high confidence in the evidence) (8). Anti-D needs refrigeration at 2–8°C, which may not be feasible in some LMIC settings.


Further information and considerations related to this recommendation can be found in the WHO guidelines, available at:




Implementation considerations

  • The successful introduction of evidence-based policies related to antenatal care into national programmes and health care services depends on well-planned and participatory consensus-driven processes of adaptation and implementation. These processes may include the development or revision of national guidelines or protocols based on this recommendation.
  • The recommendation should be adapted into locally-appropriate documents and tools that are able to meet the specific needs of each country and health service. Modifications to the recommendation, where necessary, should be justified in an explicit and transparent manner.
  • An enabling environment should be created for the use of this recommendation, including changes in the behaviour of health care practitioners to enable the use of evidence-based practices.
  • Local professional societies may play important roles in this process and an all-inclusive and participatory process should be encouraged.
  • Antenatal care models with a minimum of eight contacts are recommended to reduce perinatal mortality and improve women’s experience of care. Taking this as a foundation, the GDG reviewed how ANC should be delivered in terms of both the timing and content of each of the ANC contacts, and arrived at a new model – the 2016 WHO ANC model – which replaces the previous four-visit focused ANC (FANC) model. For the purpose of developing this new ANC model, the ANC recommendations were mapped to the eight contacts based on the evidence supporting each recommendation and the optimal timing of delivery of the recommended interventions to achieve maximal impact.


Research implications

The GDG identified this priority question related to this recommendation

  • What is the prevalence of Rh alloimmunization and associated poor outcomes among pregnant women in LMIC settings? Can cost-effective strategies be developed to manage this condition in LMICS and improve equity?


Related links

WHO recommendations on antenatal care for a positive pregnancy experience

(2016) - full document and evidence tables

Managing Complications in Pregnancy and Childbirth: A guide for midwives and doctors

Pregnancy, Childbirth, Postpartum and Newborn Care: A guide for essential practice

WHO Programmes: Sexual and Reproductive health

Maternal Health




  1. Crowther C, Middleton P. Anti-D adminstration after childbirth for preventing rhesus alloimmunization. Cochrane Database Syst Rev. 1997;(2):CD000021
  2. WHO handbook for guideline development, 2nd edition. Geneva: World Health Organization; 2014 (http://www.who.int/kms/handbook_2nd_ ed.pdf, accessed 6 October 2016).
  3. GRADE [website]. The GRADE Working Group; 2016 (http://gradeworkinggroup.org/, accessed 27 October 2016).
  4. GRADE-CERQual [website]. The GRADECERQual Project Group; 2016 (https://cerqual. org/, accessed 27 October 2016).
  5. The DECIDE Project; 2016 (http://www.decide-collaboration.eu/, accessed 27 October 2016).
  6. McBain RD, Crowther CA, Middleton P. Anti-D administration in pregnancy for preventing Rhesus alloimmunization. Cochrane Database Syst Rev. 2015;(9):CD000020.
  7. Downe S, Finlayson K, Tunçalp Ö, Gülmezoglu AM. Factors that influence the use of routine antenatal services by pregnant women: a qualitative evidence synthesis. Cochrane Database Syst Rev. 2016;(10):CD012392
  8. Downe S, Finlayson K, Tunçalp Ö, Gülmezoglu AM. Factors that influence the provision of good quality routine antenatal care services by health staff: a qualitative evidence synthesis. Cochrane Database Syst Rev. 2016


Citation: WHO Reproductive Health Library. WHO recommendation on antenatal anti-D immunoglobulin prophylaxis. (December 2016). The WHO Reproductive Health Library; Geneva: World Health Organization.