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
- Timing of Administration
- Route of Administration
- Maternal RhD variant typing
- Indications for RAADP in unsensitised RhD-negative women
- Conclusion
- References
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).
Table 1 | International Guidelines on Routine Antenatal Anti-D Prophylaxis (RAADP)
| Guideline (Year) | Country | Schedule | Dose (IU) | Route | Timing (wks) | Maternal RhD Variant Typing | Maternal RhD Variant Management | Foetal RhD Genotyping (material, technique, timing wks, recommendation) | Key Notes |
|---|---|---|---|---|---|---|---|---|---|
| FIGO/ICM (2021) | INT | Universal | Single: 300 μg (1500); (does not exclude Two-dose: 625 × 2 (1250)) | IM | Single: 28; (does not exclude Two-dose: 28 and 32–34) | Recommended | Weak D types 4.0/4.1 → treat as RhD negative; others → refer to haematology or transfusion medicine specialist | cfDNA with real-time PC recommend | Strongly recommended; midwife empowerment emphasized; subtype-based management. |
| ACOG PB181 (2017) | USA | Universal | 300 μg (~1500) | IM | Single: 28 | NA | NA | NA | |
| ACOG Practice Advisory (2024) | USA | Targeted | Variable, based on availability | IM / IV (for emergency use) | Single: 28 or as needed | Recommended | Weak D and variants → refer to haematology; avoid RhIg in sensitized women | cfDNA with real-time PCR at ≥11 wks recommended | Addressing RhIg shortages: prioritizing postpartum RhIg, use of NIPT to minimize usage, and conservation strategies in case of shortages. |
| BSH (2024) | UK | Targeted (based on foetal RhD status) | Single: 1500; Two dose: 500 × 2 (1000) | IM / IV | 1-dose: 28; 2-dose: 28 & 34 | Recommended | Weak D types 1–3 → no anti-D prophylaxis; Others → treat as RhD negative and refer to haematology | cfDNA with real-time PCR at ≥11 wks recommended universally | Based on NICE DG25; minimizes unnecessary RhIg; supersedes BSH 2016; RCOG refers to BSH |
| NICE TA156 (2008) CG190 (2015) | UK | Universal | Single: e.g. 1500 Two-dose: e.g. 500 × 2 (1000) | IM (preferred) / IV (may be used, especially for sensitising events or where IM is contraindicated) | Single: 28–30; Two-dose: 28 & 34 | NA | NA | NA | |
| NICE NG201 (2021) | UK | Universal | Single: e.g. 1500 Two-dose: e.g. 500 × 2 (1000) | IM / IV | Single: 28–30; Two-dose: 28 & 34 | NA | NA | NA, but DG25 (2016), cited as applicable guidance, states: cfDNA with real-time PCR recommended (“should be used”)¹ | |
| RCOG GTG 22 (2011, archived)&sup5; | UK | Universal (non targeted) | Single: 1500 | IM / IV | Single: 28 | NA | NA | Mentions cffDNA as emerging but no formal recommendation | Archived; clinicians directed to BSH; cites implementation study Soothill et al. 2014 (BJOG) for NHS implementation of targeted anti-D prophylaxis using cfDNA |
| RANZCOG C-Obs 6 (2023) | AU New Zealand | Universal | Two-dose: 625 × 2 (1250) | IM | Two-dose: 28 & 34 | Recommended | Weak D → treat as RhD positive; Preformed Anti-D antibodies: Do not administer RhIg | cfDNA with real-time PCR at > 11+0 wks recommended | |
| NBA (2024) | AU | Targeted | Two-dose: 625 × 2 (1250) &sup4; | IM | Two-dose: 28 & 34 (second dose ±2 i.e. 32–36) | Recommended | Weak D types 1–3 → treat as RhD positive (i.e. no anti-D prophylaxis); Partial D / other variants → refer to haematology or transfusion medicine specialist | cfDNA with real-time PCR at ≥11 wks strongly recommended | Targeted approach with genotyping to guide the use of RhD immunoglobulin. First dose recommended at 28 weeks; second dose based on foetal RhD status. |
| SOGC (2024) | Canada | Universal | Single: 1500 Two-dose: 120 μg (~600) × 2 (240 μg – 1200) | IM / IV | Single: 28 Two-dose: 28 & 34 | Recommended | Weak D types 1–3 → treat as RhD positive (i.e. no anti-D prophylaxis); Other variants → no anti-D prophylaxis recommended. | cfDNA foetal RHD genotyping available via referral labs; not routine due to cost and access constraints | Repeat dose >40 wk: insufficient data |
| SASOG (2022) | South Africa | Universal | Single: 1500; Two-dose: 500 × 2 | IM (preferred) / IV (if necessary) | Single: 28–30; Two-dose: 28 & 34 | NA | NA | CfDNA with PCR at ≥ 10 wks recommended |
Notes:
1. As per NICE DG25 (2016), cited by NG201 (2021) as the applicable guidance on foetal RHD genotyping.Abbreviations:
ACOG: American College of Obstetricians and Gynecologists (USA); AU = Australia; BCSH = British Committee for Standards in Haematology; BSH: British Society for Haematology; CA = Canada; CH = Switzerland; DE = Germany; FIGO: International Federation of Gynecology and Obstetrics; FMH: Fetomaternal Haemorrhage; GT: Green-top Guideline (RCOG); ICM: International Confederation of Midwives; INT = International; IM: Intramuscular; IU: International Units; IV: Intravenous; NA: Not Addressed; NBA: National Blood Authority (Australia); NG: NICE Guideline; NICE: National Institute for Health and Care Excellence (UK); NIPT: Non-Invasive Prenatal Testing; PB: ACOG Practice Bulletin; RCOG: Royal College of Obstetricians and Gynaecologists (UK); SOGC: Society of Obstetricians and Gynaecologists of Canada; TA: NICE Technology Appraisal; UK = United Kingdom; WHO: World Health Organization; WIRhE: Women’s Initiative for Rh disease Elimination; wks: weeks (gestational age).
1. As per NICE DG25 (2016), cited by NG201 (2021) as the applicable guidance on foetal RHD genotyping.Abbreviations:
ACOG: American College of Obstetricians and Gynecologists (USA); AU = Australia; BCSH = British Committee for Standards in Haematology; BSH: British Society for Haematology; CA = Canada; CH = Switzerland; DE = Germany; FIGO: International Federation of Gynecology and Obstetrics; FMH: Fetomaternal Haemorrhage; GT: Green-top Guideline (RCOG); ICM: International Confederation of Midwives; INT = International; IM: Intramuscular; IU: International Units; IV: Intravenous; NA: Not Addressed; NBA: National Blood Authority (Australia); NG: NICE Guideline; NICE: National Institute for Health and Care Excellence (UK); NIPT: Non-Invasive Prenatal Testing; PB: ACOG Practice Bulletin; RCOG: Royal College of Obstetricians and Gynaecologists (UK); SOGC: Society of Obstetricians and Gynaecologists of Canada; TA: NICE Technology Appraisal; UK = United Kingdom; WHO: World Health Organization; WIRhE: Women’s Initiative for Rh disease Elimination; wks: weeks (gestational age).
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.
References
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