Routine antenatal anti-D prophylaxis (RAADP) involves the administration of an appropriate dose of anti-Rh(D) immunoglobulin (RhIG) to non-sensitised RhD-negative women during pregnancy. This intervention has been shown to significantly reduce the incidence of RhD sensitisation and haemolytic disease of the foetus and newborn (HDFN). Without RAADP, it is estimated that approximately 1%–2% of RhD-negative women at risk become sensitised (Pilgrim, Lloyd-Jones, & Rees, 2009). All major international guidelines consistently recommend RAADP for unsensitised RhD-negative women to prevent red cell alloimmunisation.

One-Dose versus Two-Dose Protocols

Various national and international guidelines endorse either a single-dose or two-dose RAADP regimen. The standard single-dose approach typically involves 1500 IU, while the two-dose regimen includes 500–625 IU at each administration.

It has been hypothesised that administering two smaller doses may maintain a higher circulating concentration of RhIG towards term, compared with a single larger dose administered earlier. Consistent with this hypothesis, a meta-analysis found that administering 1250 IU (250 μg) of RhIG at both 28 and 34 weeks’ gestation was associated with an odds ratio of 0.19 (95% CI 0.03–0.53) for Rh sensitisation in Rh-negative women, whereas a single dose of 1500 IU (300 μg) given between 28 and 30 weeks yielded an odds ratio of 0.42 (95% CI 0.17–0.73), indicating greater efficacy of the two-dose regimen in reducing the risk of sensitisation (Turner, Lloyd-Jones, & Anumba, 2012).

Nevertheless, a cohort study conducted in the United Kingdom reported lower compliance rates with the two-dose regimen compared to the one-dose protocol (White, Cheng, & Penova-Veselinovic, 2019). 

Considering the additional cost and the risk of reduced compliance associated with the two-dose regimen, and the demonstrated efficacy of the single dose, despite evidence suggesting it may be less effective than the two-dose regimen in reducing the risk of Rh sensitisation, many guidelines recommend the single-dose RhIG schedule as a valid and effective option (table 1).

Timing of Administration

The guidelines are consistent in recommending administration at 28 weeks’ gestation in the case of a single-dose regimen, aligning with the period of increased risk of FMH. In two-dose regimens, a second administration is typically advised at approximately 34 weeks (Table 1).

Route of Administration

RhIg can be administered via either the intramuscular (IM) or intravenous (IV) route. Most guidelines recognise both methods as clinically appropriate. A systematic review, incorporating two randomised controlled trials, found no significant difference in clinical outcomes between IM and IV administration at 28 weeks (Hamel et al., 2020). Nevertheless, IM remains the preferred route in most settings, while IV is reserved for specific circumstances such as institutional protocol, clinical judgement, or patient preference (SOGC, 2018; FIGO/ICM, 2021; SASOG, 2022).

Maternal RhD variant typing

Maternal RhD variant typing is increasingly advocated. Current guidelines advise that women with weak D types 1–3 be managed as RhD-positive, thereby eliminating the need for anti-D prophylaxis. Conversely, women with partial D phenotypes or rare variants should undergo molecular characterisation and be referred to haematology or transfusion medicine specialists (BSH, 2024; NBA, 2024; SOGC, 2024). 

Indications for RAADP in unsensitised RhD-negative women

Some guidelines, such as the American College of Obstetricians and Gynecologists (ACOG, 2017), advocate universal RAADP for all unsensitised RhD-negative women. However, there is growing international consensus favouring the use of non-invasive prenatal testing (NIPT) for foetal RhD genotyping via cell-free foetal DNA (cfDNA) from maternal plasma. This approach enables targeted RAADP administration only to women carrying RhD-positive foetuses, thereby conserving RhIg and avoiding unnecessary immunoglobulin exposure (BSH, 2024; NBA, 2024; SOGC, 2024; RANZCOG, 2023). Countries with established laboratory infrastructure have incorporated cfDNA-based foetal RhD genotyping into national antenatal care protocols, including the United Kingdom, Australia, Canada, and the Netherlands (NICE, 2021; NBA, 2024; RANZCOG, 2023; NVOG, 2021). The International Federation of Gynecology and Obstetrics (FIGO), while recognising the utility of a targeted RAADP strategy, continues to support the universal approach as well, thereby ensuring that recommendations remain adaptable to the capacities of local healthcare systems (FIGO, 2021).

This variation in recommendations reflects broader differences across countries in terms of resource availability, infrastructure to support cfDNA testing, and policy priorities regarding cost-effectiveness, equity of access, and immunoglobulin stewardship (BSH, 2024; FIGO, 2021; SOGC, 2018; NICE, 2021).

Conclusion

While universal RAADP remains standard where molecular diagnostics are unavailable or impractical, international guidelines increasingly endorse a targeted, genotype-informed approach that enhances clinical precision and limits unnecessary prophylaxis in women unlikely to benefit (BSH, 2024; FIGO, 2021; WHO, 2023). This strategy supports responsible stewardship of limited RhIg supplies while ensuring equitable access.