Direct antiglobulin test for the prediction of neonatal hyperbilirubinemia needing an intervention: a systematic review and diagnostic test accuracy meta-analysis

Abstract

Importance:

The direct antiglobulin test (DAT) is commonly used as a screening test for predicting significant neonatal hyperbilirubinemia requiring intervention. However, evidence for this approach is limited.

Objective:

The aim of this study was to evaluate the diagnostic utility of DAT in predicting the need for phototherapy and double volume exchange transfusion (DVET) in neonates with ABO and Rhesus (Rh) incompatibility conditions.

Methods:

MEDLINE, Embase, CENTRAL, CINAHL, and Web of Science were searched from inception until 1 February 2024. Randomized controlled trials (RCTs) and non-RCTs were eligible for inclusion. Two reviewers screened the titles and abstracts blinded to each other. A Bayesian bivariate random-effects model was employed for the diagnostic test accuracy meta-analyses. Risk of bias was assessed using Quality Assessment for Studies of Diagnostic Accuracy 2 and certainty of evidence (CoE) was adjudged according to the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) guidelines.

Results:

In total, 53 studies were included in the systematic review and 28 were synthesized in the meta-analysis. For the need for phototherapy outcome, the pooled sensitivity [95% credible interval (CrI)] and specificity (95% CrI) of DAT in ABO incompatibility (18 studies, n = 10,110) were 56.1% (44.5%–67.8%) and 83.6% (71.6%–90.8%). For Rh incompatibility (three studies, n = 491), the sensitivity and specificity were 40.4% (12.2%–81.7%) and 89.9% (72.7%–94.6%). The CoE was predominantly low. For the need for DVET outcome, the pooled sensitivity and specificity of DAT in ABO incompatibility (three studies, n = 2,652) were 83.6% (35.8%–99.6%) and 74.5% (40.3%–92.7%). For Rh incompatibility (two studies, n = 240), the sensitivity and specificity were 80.3% (34.2%–97.3%) and 68.0% (25.3%–92.1%). The CoE was predominantly very low.

Conclusion:

In ABO and Rh incompatibility, DAT probably has moderate specificity and low sensitivity for predicting the need for phototherapy. For DVET, though DAT is possibly a better predictor due to its acceptable sensitivity, the predictive interval was wide. Thus, we do not suggest the routine use of DAT screening to predict the need for phototherapy and DVET. However, it may be used as a second-tier investigation for risk stratification of high-risk neonates.

Systematic Review Registration:

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022297785, PROSPERO (CRD42022297785).

1 Introduction

Neonatal hyperbilirubinemia (NNH) is a common diagnosis in neonates, requiring treatment in the initial postnatal days (1). While the majority of these neonates needing treatment are managed with phototherapy, a small proportion may require additional therapies such as intravenous immunoglobulin (IVIG) and double volume exchange transfusion (DVET). Despite the availability of effective interventions, the risk of serious adverse outcomes including kernicterus, cerebral palsy, hearing loss, and even mortality remains a significant concern (2). These adverse outcomes could be prevented by the timely identification and treatment of neonates at risk of developing severe NNH.

Evidence-based guidelines have recommended the use of various screening tools for early identification and treatment of NNH (1, 3). Despite the incorporation of these tools into clinical practice, instances of serious adverse outcomes secondary to NNH have been reported. This is often attributed to factors such as challenges in identifying high-risk neonates, limitations of the screening tools, and adaptation of policies such as early discharge from healthcare facilities. As a result, regional guidelines suggest risk stratification based on gestational age, bilirubin levels, and the presence of various other morbidities such as sepsis, asphyxia, and ABO, Rhesus (Rh), and other blood group incompatibilities (1, 4, 5). The inclusion of additional tests such as the direct antiglobulin test (DAT) has also been recommended (1, 5).

DAT is commonly performed in suspected cases of hemolytic disease of the newborn due to ABO or Rh incompatibility (6). However, the current clinical guideline does not recommend routine testing of umbilical cord blood for DAT in ABO and Rh incompatibility (5). As the evidence for the same is contentious, many centers continue to use routine DAT testing as a screening test to identify at-risk neonates (6–10).

Thus, we conducted a systematic review and diagnostic test accuracy (DTA) meta-analyses with an aim to evaluate the diagnostic utility of DAT in predicting NNH requiring treatment in neonates with ABO and Rh incompatibility conditions.

2 Methods

The protocol was registered with PROSPERO (CRD42022297785) (11), and the reporting is in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy Studies (PRISMA-DTA) (12).

2.1 Study eligibility

Randomized controlled trials (RCTs), non-RCTs, and conference abstracts were eligible for inclusion. Studies that evaluated the diagnostic performance of DAT in predicting the need for treatment of NNH in various mother-neonate blood group pairs, including but not exclusively ABO and Rh incompatibility, were also eligible for inclusion. Case reports, traditional reviews, and systematic reviews were excluded. There were no language restrictions.

2.2 Patient population

We included studies conducted in different healthcare settings in late preterm and term neonates. Studies reporting on preterm neonates of <34 weeks' gestation, NNH secondary to enzyme deficiency, sepsis, liver disorders, and those who had received fetal therapy were excluded.

2.3 Index test

A DAT was performed on umbilical cord blood or during the first 14 days of postnatal life. We included studies that had used the two commonly used methods of DAT measurement (gel or tube agglutination methods). For the generation of the 2 × 2 table, we considered a weakly positive DAT as a positive test.

2.4 Reference standard

A serum bilirubin test was performed in the first 14 days of postnatal life.

2.5 Target condition

We considered the following outcomes: the need for phototherapy, DVET, and IVIG therapy in the first 14 days, irrespective of the treatment thresholds recommended by different guidelines. We did not include outcome parameters such as clinical jaundice and significant hyperbilirubinemia not requiring intervention.

2.6 Information sources

We conducted a comprehensive search of MEDLINE, Embase, CENTRAL, CINAHL, and Web of Science from inception till 1 February 2024. (AS, VK) (Supplementary Table 1). In addition, we searched the bibliographies of included studies and review articles to identify potentially eligible studies for inclusion.

2.7 Study selection and data extraction

All the study titles and abstracts were screened independently in duplicates by two authors (TA, TB) using an online software platform (Rayyan QCRI, Doha) (13). Data extraction was independently performed by the two investigators (VR, VK) using a preformed data extraction form, and disagreements were resolved by consensus. We recorded data items, including blood group, timing of DAT measurement, outcomes, and test accuracy measures [true positives (TPs), true negatives (TNs), false positives (FPs), and false negatives (FNs)].

2.8 Study quality assessment

The risk of bias and applicability concerns of the included studies were assessed using the Quality Assessment for Studies of Diagnostic Accuracy 2 tool (QUADAS-2) (14). Two authors (VK, PK) independently assessed the quality of the studies.

2.9 Data synthesis

Data synthesis was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy (15). We estimated individual sensitivities and specificities, along with their 95% confidence intervals using DTA measures. These findings are presented using forest plots and the summary receiver operating characteristic (SROC) space. In addition, we used a Bayesian bivariate random-effects approach to estimate median pooled sensitivity and specificity, along with 95% credible intervals (CrI). Bayesian analysis was performed using METABayesDTA version 1.4 and R software version 4.3.1 (R Foundation for Statistical Computing, Vienna, Austria) using the “meta4diag' and “meta” packages (16, 17). Vague priors were used. A Stan sampler with two chains, 500 warm-up iterations, and 1,500 total iterations was utilized. Model fit was assessed by visualizing the correlation residual plot and the frequency table probability residual plot. Model convergence was confirmed by examining the trace and density plots.

A meta-analysis was performed for each outcome: the need for phototherapy, the need for DVET, and the requirement of IVIG therapy. Within each outcome, the DTA measures were estimated for specific maternal and neonatal blood group combinations. For the DTA meta-analysis, we included only studies with ABO or Rh incompatibility, as these are the two commonly encountered clinical scenarios. Studies that evaluated DAT in blood group scenarios other than ABO or Rh incompatibility were included in the narrative review. ABO or Rh blood group incompatibilities were categorized into ABO incompatibility [Mother blood group (MBG): O; Rh positive and baby blood group (BBG): A or B irrespective of Rh status], Rh incompatibility (MBG: A, or B or AB or O with Rh negative and BBG: A or B or AB or O with Rh positive), or ABO/Rh incompatibility (MBG: O with Rh positive and BBG: A or B with Rh positive or negative OR MBG: A, B, AB, O with Rh negative and BBG: A or B or AB or O with Rh positive).

2.9.1 Subgroup and sensitivity analysis

Heterogeneity was explored using subgroup analysis of the covariates, DAT testing methods and treatment thresholds, as per the guidelines. We performed a post-hoc sensitivity analysis by excluding studies with applicability concerns in the patient selection domain. For publication bias, we examined the regression coefficient line for plot asymmetry. A funnel plot of the log diagnostic odds ratio against 1/(effective sample size)^1/2 was generated. For assessing the certainty of the evidence, we used GRADEPro, following GRADE guidelines for DTA meta-analysis for each target condition and blood group combination (18).

3 Results

3.1 Study selection

After the removal of duplicates, 1,409 titles and abstracts were screened. Of these, 73 were selected for full-text review. Among them, 51 were included in the systemic review. Of the included studies, 28 were synthesized in a DTA meta-analysis, and 23 studies were included in the narrative review (Figure 1). The excluded studies with valid reasons for their exclusion are listed in Supplementary Table 2.

Figure 1

3.2 Characteristics of included studies

A total of 28 studies (n = 20,935) (10, 19–44) were included in the meta-analysis, with 20 studies (10, 19, 26, 28, 30, 32–44) (n = 11,385), 3 studies (10, 22, 29) (n = 491), and 9 studies (10, 20, 21, 23–25, 27, 31) (n = 9,561) assessed DAT in the ABO, Rh and ABO/Rh incompatibility scenarios, respectively. Only two studies (23, 25) included late preterm along with term neonates, while the others only included term neonates. Furthermore, 16 studies (20, 22, 24, 25, 28–33, 36, 39–42, 45) did not specify the method of DAT assessment, 7 studies (10, 19, 23, 27, 35, 37, 38) utilized the gel method, and 5 studies (21, 26, 34, 43, 44) used the column agglutination method. Most DAT assessments were performed with cord blood samples (10, 19, 20, 22–31, 33–37, 40–44), while two studies (21, 38) performed the assessments during the initial postnatal days. Of the included studies, 28 studies (10, 19–44) (n = 20,162) reported the outcome measure of the need for phototherapy, 7 studies (19, 22, 27, 29, 31, 32, 44) (n = 3,338) were on DVET, and 2 studies (19, 45) (n = 1,005) were on IVIG therapy. The characteristics of the included studies synthesized in the meta-analysis are provided in Table 1, and those in the narrative review are summarized in Appendix I in the Supplementary Material.

3.3 Risk of bias and applicability

Overall, the studies were adjudged to have a moderate risk of bias (Table 2). The common reason to adjudge studies as having a high risk of bias was in the domain of reference standard, as the DAT result was not blinded to the clinicians. For patient selection, high risk was attributed to the non-consecutive inclusion of neonates. Applicability concerns in the patient selection domain were related to the selective inclusion of neonates by prior testing. The proportion of studies assessed to have an overall risk of bias of “low,” “high,” or “unclear” is presented in Figure 2.

Figure 2

3.4 Main results

We have summarized the study-specific sensitivity and specificity of all the included studies for the target conditions: the need for phototherapy (Supplementary Figures 1, 2), DVET (Supplementary Figures 3, 4), and IVIG therapy (Supplementary Figures 5, 6), employing forest plots and the SROC curves.

For the primary target condition, the need for phototherapy, a total of 28 studies (n = 20,162) (10, 19–44) were included. In the meta-analysis of studies evaluating DAT in ABO incompatibility (18 studies; n = 10,110) (10, 19, 26, 28, 30, 32–43), the posterior median sensitivity and specificity were 56.1% (95% CrI: 44.5%–67.8%) and 83.6% (95% CrI: 71.6%–90.8%), respectively. For the Rh isoimmunization scenario (three studies; n = 491) (10, 22, 29), the pooled sensitivity and specificity were 40.4% (95% CrI: 12.2%–81.7%) and 89.9% (95% CrI: 72.7%–94.6%), respectively. Studies that had evaluated DAT in ABO/Rh incompatibility (nine studies; n = 9,561) (10, 20, 21, 23–25, 27, 31) yielded a pooled sensitivity and specificity of 35.8% (95% CrI: 19.6%–57.0%) and 82.5% (95% CrI: 61.9%–93.1%), respectively (Figures 3, 4, Table 3).

Figure 3

Figure 4

For the target condition, the need for DVET, a total of seven studies (n = 3,338) (19, 22, 27, 29, 31, 32, 44) were included. In ABO incompatibility settings (three studies; n = 2,652) (19, 32, 44), the pooled sensitivity and specificity were 83.6% (95% CrI: 35.8%–99.6%) and 74.5% (95% CrI: 40.3%–92.7%). In Rh incompatibility (two studies; 240 infants) (22, 29), the pooled sensitivity and specificity were 80.3% (95% CrI: 34.2%–97.3%) and 68.0% (95% CrI: 25.3%–92.1%). Whereas for ABO/Rhesus incompatibility (two studies; n = 446) (27, 31), the pooled sensitivity and specificity were 50.1% (95% CrI: 13.9%–85.5%) and 89.0% (95% CrI: 67.0%–94.9%) (Table 3 and Supplementary Figure 7).

For the target condition, the need for IVIG (two studies; n = 1,005) (19, 45), we could not perform a meta-analysis as only a limited number of studies on each blood group scenario had reported on this outcome.

3.4.1 Subgroup analysis

3.4.1.1 Treatment thresholds

Subgroup analysis was conducted for the need for phototherapy for the studies which used the American Academy of Pediatrics (AAP) threshold chart in the ABO (nine studies, n = 3,231) (19, 26, 28, 30, 35, 36, 38, 39) and ABO/Rh incompatibility (six studies, n = 7,807) (20, 21, 23, 25, 27) scenarios. Whereas subgroup analyses were performed for studies using National Institute for Health and Care Excellence (NICE) threshold charts in the Rh (two studies, n = 483) (10, 29) and ABO/Rh (two studies; n = 1,611) (10, 24) incompatibility scenarios. There were no significant differences in the subgroup analyses except for an improvement in sensitivity when using AAP charts for the need for phototherapy in ABO incompatibility scenarios. The sensitivity and specificity were 80.3% (95% CrI: 34.2%–97.3%) and 68.0% (95% CrI: 25.3%–92.1%), respectively (Supplementary Table 3).

3.4.1.2 DAT method

The subgroup analysis based on the method used for DAT measurement (gel vs. tube method) showed no significant difference for the outcomes of phototherapy and DVET in any of the blood group scenarios (Supplementary Table 3).

3.4.2 Post-hoc sensitivity analysis

We also performed a post-hoc sensitivity analysis by excluding studies with applicability concerns in patient selection (21, 22, 27, 37). For the need for phototherapy, we found no differences from the primary analysis for ABO incompatibility (17 studies, n = 10,012) (10, 19, 26, 28, 30, 32–36, 38–43), Rh incompatibility (two studies, n = 483) (10, 29), and ABO/Rh incompatibility (seven studies, n = 9,076) (10, 20, 23–25, 31) (Supplementary Table 4).

3.4.3 Certainty of evidence

The certainty of evidence for the outcome measure, the need for phototherapy, was very low for the pooled sensitivity in ABO, Rh, and ABO/Rh incompatibility. This was primarily due to inconsistency, followed by the risk of bias and imprecision. In contrast, the certainty of evidence for specificity varied between low to moderate in ABO, Rh, and ABO/Rh incompatibility, mainly due to the risk of bias and inconsistency. For the outcome measure, the need for DVET, the certainty of evidence for sensitivity was very low. For specificity, it remained very low to low across ABO, Rh, and ABO/Rh incompatibility scenarios. Downrating the certainty of evidence was done mainly due to the risk of bias and inconsistency (Table 4).

3.4.4 Publication bias

For the outcome measures, the need for phototherapy and DVET, we did not detect publication bias as Deek's plot for asymmetry was not statistically significant (Supplementary Figures 8, 9).

4 Discussion

In our systematic review and DTA meta-analysis, we found that the DAT had low sensitivity but moderate specificity in predicting the need for phototherapy in ABO and Rh incompatibility scenarios. The evidence certainty for sensitivity ranged from very low to low, while for specificity, it was low to moderate. For the outcome measure, the need for DVET, the DAT showed varied sensitivity and specificity across ABO and Rh incompatibility scenarios, with the evidence certainty ranging from very low to low for both sensitivity and specificity.

The sensitivity of DAT for predicting the need for phototherapy was 56.1% in ABO incompatibility, 40.4% in Rh incompatibility, and 35.8% in studies that had evaluated either ABO or Rh incompatibility pairs, with only modest changes in specificity in the aforementioned groups, which was moderate. In addition, the predictive interval for Rh and ABO/Rh incompatibility was as low as 14%, indicating that the DAT is a poor predictor of the need for phototherapy in these scenarios. The poor predictive ability of DAT in Rh and ABO/Rh incompatibility could likely be attributed to a false positive rate of approximately 15% due to the routine use of maternal anti-D immunoglobulin in Rh-negative mothers and the passive transfer of these immunoglobulins to infants (46). The specificity of DAT for predicting the need for phototherapy was 83.6%, 89.9%, and 82.5% in ABO, Rh, and ABO/Rh incompatibility, respectively. However, not accounting for other causes of NNH, such as G6PD deficiency and extravasation, likely could have impacted the specificity of DAT. In contrast, the sensitivity and specificity of the DAT for predicting the need for DVET varied markedly across different blood group incompatibility scenarios. For ABO and Rh incompatibility, the sensitivity was above 80%, while the specificity was relatively lower.

To illustrate the practical implications of our study findings, we could consider 1,000 neonates with ABO incompatibility with a 20% probability [based on Gabbay et al. 2023 (20)] of them needing phototherapy for NNH. In this scenario, there would be 243 positive test results. However, 131 (41%) neonates would be falsely diagnosed as having ongoing hemolysis (false positive), whereas, among the 757 negative DAT results, 88 (12%) would be incorrect diagnoses (false negative). This high rate of false positives could lead to delayed discharge, additional investigations, an increased burden on the healthcare system, and heightened parental anxiety. On the other side, false negatives pose a significant risk, as high-risk neonates might be discharged earlier and followed up less frequently, placing the infants at risk of significant hyperbilirubinemia. In addition, the cost implications are considerable. Nevertheless, the moderate specificity of DAT for ABO incompatibility would allow 669 (88%) out of the 757 cases with negative results to have the correct diagnosis (true negatives). This improved specificity may facilitate early discharge and reduce costs.

The studies we included had a moderate risk of bias, especially in the reference standard domain. This was due to the non-blinding of the DAT test results to clinicians, which could significantly influence the need for an intervention. In addition, there was uncertainty in the flow and timing domain due to the poor reporting of the included studies.

Our review has crucial clinical implications, as it is the first comprehensive review addressing the utility of DAT in the management of neonates with blood group incompatibility. Previously, conflicting evidence on the utility of DAT led to varied recommendations by academic bodies. The AAP recommends a routine umbilical cord blood DAT for all mothers with a history of antenatal antibody screen being positive or unknown or with an Rh-negative blood group (1). The NICE advises against using routine umbilical cord blood DATs to predict significant NNH (4). As a DAT has a low sensitivity in most situations, a DAT may not be used as a screening tool for predicting the need for NNH treatment. Our findings imply that a negative DAT result in an incompatibility scenario can reasonably identify neonates who are less likely to require treatment for NNH and may be restricted to at-risk neonates to assess their risk stratification. Moreover, the sensitivity and specificity of a DAT in the prediction of DVET varied markedly with a wide predictive interval and very low to low evidence certainty. Therefore, we do not suggest the use of the DAT as a screening test for predicting severe hyperbilirubinemia requiring DVET.

Despite including several studies, the certainty of evidence remained very low to low for sensitivity and low to moderate for specificity for the need for phototherapy outcome measure, implying the need for future studies with improved study designs.

4.1 Strengths and limitations

To the best of our knowledge, this is the first systematic review to assess the predictive ability of DAT for determining the need for an intervention in NNH. We conducted a thorough literature search and performed clinically relevant analyses based on various blood group combinations, including various subgroup and post-hoc sensitivity analyses. We adhered to the standards recommended by the Cochrane Screening and Diagnostic Tests Methods group and followed the PRISMA reporting guidelines. We assessed the certainty of evidence as guided by the GRADE working group. However, our study had some limitations. Initially, we planned to include all blood group combinations in the meta-analyses, but we restricted the analysis to clinically relevant incompatibility scenarios. We were unable to do many of the pre-planned subgroup analyses such as based on gestational age and DAT strength due to the non-availability of data. We could not evaluate the effect of the updated AAP guidelines on phototherapy and DVET on the sensitivity and specificity of DAT, as none of the included studies evaluated these thresholds. Finally, we did not account for ethnic differences or consider other causes of significant hyperbilirubinemia.

5 Conclusions

In ABO and Rh incompatibility, DAT probably has moderate specificity but low sensitivity for predicting the need for phototherapy. For the need for DVET, DAT is possibly a poor predictor as the sensitivity and specificity varied markedly across blood groups with wide predictive intervals. Thus, we do not suggest the use of DAT as a screening test for predicting hyperbilirubinemia requiring either phototherapy or DVET.

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