Differences in maternal–newborn ABO blood groups and risk of serious infant infection

Abstract

Background

During pregnancy, various maternal IgG antibodies are transferred to the developing fetus, some of which may protect the newborn against infection. If a mother and her fetus have different A, B or O (ABO) blood groups, then transferred maternal antibodies may plausibly protect the infant against infection.

Aim

To determine if maternal–newborn ABO blood group incongruence vs. congruence is associated with a lower risk of serious infection in the infant.

Design

Retrospective population-based cohort.

Methods

We used linked patient-level datasets for all singleton hospital livebirths from 2008 to 2022 in Ontario, Canada, with known maternal and newborn ABO blood groups. We used a dichotomous exposure state, either ABO blood group congruent (N = 114 507) or incongruent (N = 43 074). The main outcome of interest was the risk of serious infant infection within 27 days, and from 28 to 365 days, after birth. Cox proportional hazard models generated hazard ratios and 95% confidence intervals, and were adjusted for maternal age, world region of origin, residential income quintile and gestational age at birth.

Results

Relative to maternal–newborn congruency, incongruent ABO blood group was associated with an adjusted hazard ratio of 0.88 (95% CI: 0.80–0.97) for serious neonatal infection within 27 days of birth, and 0.93 (95% CI: 0.90–0.96) for serious infection between 28 and 365 days after birth.

Conclusions

Maternal–newborn ABO incongruence may be associated with a lower relative risk of a serious infant infection within 27 days, and from 28 to 365 days, after birth.

Introduction

The A, B or O (ABO) blood type gene indirectly encodes the ABO blood group antigens, projected via oligosaccharide chains on the surface of red blood cells (RBC), with three main allelic forms: A (A-antigens present), B (B-antigens present) and O (no antigens present).¹ Contained within the blood serum are naturally occurring IgM and IgG antibodies against A and B blood group antigens.^1,2 During later pregnancy, maternal IgG antibodies are transported across the placenta via a Fc receptor-mediated process.³ Such maternal–fetal antibody transfer is crucial for short-term passive fetal immunity occurring in utero, and within the infant up to six months after birth, until the child’s immune system is fully developed, or they become vaccinated.^3–5

The risk of infection may be reduced in the presence of certain antibodies related to ABO blood groups. For example, Escherichia coli (E. coli) bacteria appear to undergo significant phagocytosis in the presence of anti-B antibodies.⁶ Further, the severe acute respiratory syndrome-coronavirus (SARS-CoV) spike protein binds to A-antigens,⁷ and those with O blood group appear to be at a lower risk of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection.⁸

If certain anti-RBC antibodies appear protective against infection, and if these potentially protective IgG antibodies can be transferred from mother to fetus when they display dissimilar ABO blood groups (see Supplementary Table S1), then a logical question is whether maternal–fetal ABO dissimilarity (i.e. incongruence) or sameness (i.e. congruence) confers a different risk of infant infection?

Ontario’s universal healthcare system permits the systematic linkage of all maternal and child health data, including their ABO blood group status, and whether the infant is diagnosed with an infection during an emergency department (ED) or hospitalization encounter. Accordingly, this study evaluated the risk of serious infection in relation to maternal–newborn ABO blood group incongruence vs. congruence.

Materials and Methods

This population-based retrospective cohort study followed the Reporting of studies Conducted using Observational Routinely collected Data (RECORD) checklist,⁹ and considered all mothers with a singleton hospital livebirth in Ontario, Canada, between 1 April 2008 and 31 March 2022. Excluded were non-Ontario residents, those with missing gestational age at birth, infants with unknown birthweight, and mothers and/or infants with unknown ABO blood group information (Supplementary Table S2, Supplementary Figure S1).

Births in Ontario are captured using existing patient-level datasets that link a unique maternal and newborn record. Each of these datasets is described in Supplementary Table S3.

Study exposures

The main study exposure was ‘ABO blood group congruence’, defined as a dichotomous exposure state of ‘congruent’ or ‘incongruent’ for each maternal–infant pair (described in Supplementary Table S1). In the incongruent state, the mother would be exposed to a fetal foreign A or B antigen, and therefore, may produce an IgM or IgG antibody response.

Study outcomes

The primary study outcome was a ‘serious neonatal infection’, arising within 27 days after birth. A secondary study outcome was a ‘serious infant infection’, occurring from 28 days to 365 days after birth.

A serious infection was defined as a bacterial or viral infection diagnosed during the birth hospitalization period, or an infection requiring an ED visit or hospital re-admission following the birth hospitalization, during the specified periods. For any ED visit or hospital admission, the first bacterial or viral infection was analyzed, and was only considered if the main diagnostic code for the encounter was one of the infectious disease conditions listed in Supplementary Table S4.

Analyses

Maternal and infant characteristics were recorded as a number (%), mean (standard deviation, SD), or median (interquartile range [IQR]), as appropriate. Standardized differences contrasted ABO congruent and incongruent exposure groups, with a value > 0.10 considered to be important.¹⁰ Separately, to assess for selection bias, the characteristics of infants who had a recorded ABO blood group were compared to those who did not.

The number of neonates who acquired a serious infection within the first 27 days after the birth was expressed as a rate per 100 person-years. A similar approach was used for a serious infant infection from 28 days to 365 days after birth, with the denominator being those infants alive at 28 days after birth.

In the main models, unadjusted rate differences and 95% confidence intervals (95% CI) were calculated for serious infections between incongruent and congruent blood groups, with the latter as the referent. Cox proportional hazard models generated unadjusted and adjusted hazard ratios (HR) and 95% CIs, adjusting for maternal age, maternal world region of origin, maternal residential income quintile and gestational age at birth (in weeks). For the primary outcome of serious infection within 27 days after birth, time zero was the birth date. For the secondary outcome of serious infection from 28 to 365 days after birth, time zero was reset to start at day 28 after the birth. Censoring was based on death occurring before the serious infection outcome, loss of Ontario Health Insurance Plan (OHIP) eligibility, or arrival at the end of the study period (31 March 2022 or 365 days after birth). Cumulative incidence plots were generated from the adjusted models. The proportional hazard assumption was assessed graphically with log-log plots, which were met.

In a second set of models, serious neonatal and infant infections were respectively separated into those of a bacterial and viral type (Supplementary Table S4), using the aforementioned modeling approach comparing incongruent vs. congruent maternal–newborn ABO blood groups.

Additional analyses

Additional analysis 1 stratified the main model of neonatal infection by infant sex, mode of birth, timing of birth, maternal Group B Streptococcus (GBS) status and maternal premature rupture of membranes.

Persons with O blood group may be at lower risk of certain infections.^6,7,11 Accordingly, Additional analysis 2 further expanded the analysis of maternal–infant ABO congruency and infection risk to whether the infant was O blood group, or not, as outlined in Supplementary Table S5.

Additional analysis 3 was limited to a serious neonatal or infant infection diagnosed within a hospitalization, either at birth or upon re-admission to hospital.

As an infant may die before sepsis is diagnosed, Additional analysis 4 expanded the study outcome to include a composite of serious infant infection or all-cause mortality within 27 days and 28–365 days after birth.

All analyses were performed using SAS version 9.4.

Results

In all, 157 581 mother–infant pairs were included in the main cohort (10.1%), out of which 114 507 (72.7%) had ABO congruency and 43 074 had ABO incongruency (Supplementary Figure S1).

Comparing infants with and without recorded ABO blood information, mean maternal age was slightly higher among the former (31.5 vs. 30.5 years), as were the rates of premature rupture of membranes (14.7% vs. 11.5%), neonatal jaundice or hyperbilirubinemia (10.1% vs. 6.0%), hemolytic disease of the newborn (1.7% vs. 0.6%) and neonatal intensive care unit (NICU) admission (16.6% vs. 11.2%) (Supplementary Table S6). Otherwise, there were no notable differences for infants or mothers.

Infant characteristics at birth were also largely similar between the congruent and incongruent ABO blood groups, except for neonatal jaundice or hyperbilirubinemia, and hemolytic disease of the newborn (Table 1).

The primary outcome of serious neonatal infection within 27 days of birth occurred among 604 neonates in the incongruent ABO blood group (19.1 per 100 person-years) vs. 1862 neonates in the congruent group (22.2 per 100 person-years), corresponding to an unadjusted rate difference of −3.1 per 100 person-years (95% CI: −4.9 to −1.3), and an adjusted hazard ratio (aHR) of 0.88 (95% CI: 0.80–0.97) (Supplementary Figure S2; Table 2, upper).

The secondary outcome of serious infection between 28 and 365 days after the birth occurred at a rate of 18.9 per 100 person-years in the incongruent ABO blood group vs. 20.7 per 100 person-years in the congruent group, which corresponded to an unadjusted rate difference of −1.8 per 100 person-years (95% CI: −2.3 to −1.2), and an aHR of 0.93 (95% CI: 0.90–0.96) (Supplementary Figure S3; Table 2, lower).

Upon assessing the risk of a serious bacterial infection (Figure 1, upper blue), and separately, viral infection (Figure 1, lower red), the effects were largely protective in those with ABO incongruence. The exception was for the outcome of viral infection within 27 days of birth (aHR: 0.90, 95% CI: 0.80–1.02) (Figure 1, lower red). The top-10 most common types of bacterial conditions among neonates included acute upper respiratory tract infections (30.0%), bacterial sepsis (22.5%) and gastrointestinal infections (9.3%) (Supplementary Table S7, left). Top-10 viral conditions included acute upper respiratory tract infections (38.0%), acute bronchiolitis (20.0%) and gastrointestinal infections (12.1%) (Supplementary Table S7, right).

In Additional analysis 1 of a serious neonatal infection < 28 days of birth, the main effects were consistent for male and female infants (Figure 2, red), and vaginal and Caesarean births (Figure 2, blue). There was a lower associated risk of serious infection among infants with incongruent ABO blood groups born at term, but not preterm (Figure 2, green). A lower associated risk of serious infection among incongruent blood groups was only seen in newborns whose mother tested negative for GBS (Figure 2, purple). Likewise, a protective associated risk was only seen in the absence of premature rupture of membranes.

Upon considering ABO congruency as well as infant O or non-O blood group status, those with congruency and the same non-O blood group as their mothers had a higher associated risk of infection within 27 days of birth (aHR: 1.21, 95% CI: 1.10–1.35) compared to mothers and newborns both with O blood group (Additional analysis 2, Supplementary Figure S4, upper). A similar pattern was seen for serious infant infection between 28 and 365 days after birth (Supplementary Figure S4, lower).

Upon limiting the outcome to serious infections diagnosed during a birth or any subsequent hospitalization, ABO blood group incongruency was associated with a lower aHR of infection < 28 days, but not from 28 to 365 days (Additional analysis 3, Supplementary Table S8).

Expanding the study outcome to a serious infection or death, the aHR was 0.90 (95% CI: 0.82–0.98) for serious infection or death < 28 days, and 0.94 (95% CI: 0.91–0.96) for that diagnosed between 28 and 365 days (Additional analysis 4, Supplementary Table S9).

Discussion

This retrospective cohort study found that maternal–newborn ABO incongruence was associated with a 12% lower relative risk of a serious infant infection within 27 days of birth, and a 7% lower relative risk of serious infection from 28 to 365 days of life. This pattern was seen for both bacterial and viral infections, and infections solely arising during hospitalization in neonates, but not among infants born preterm, or whose mother had GBS positivity or premature rupture of membranes. The study provides preliminary evidence for a measurable neonatal and infant risk factor, that could potentially support a more accurate estimate of infant sepsis risk.^12,13

Anti-A and anti-B antibodies—found in those with either B, A or O blood groups—may heighten host immunity to Gram-negative bacteria⁷ and SARS-CoV-2 infection.¹¹ IgG antibodies are transported across the placenta, especially within the third trimester, providing short-term passive immunity to the fetus and newborn with declining protection conferred to the infant by 6 months of age.^3,14 The highest risk of serious neonatal infection seen herein was in those with congruent non-O blood groups (Supplementary Figure S4). In this situation, a mother and her infant possess similar RBC antigens and related antibodies.^1,2,15 As such, no new maternal anti-A or anti-B IgG antibodies would be generated or introduced into the fetal circulation. It remains to be determined whether the apparent protective effect of ABO incongruence is due to maternal IgG antibody transfer—something that can be systematically measured at birth in the mother and newborn. Furthermore, any waning effect could then be prospectively assessed by following the child to at least 6 months of infancy.

A slightly lower long-term risk of serious infection from 28 to 365 days was seen among infants with a non-O blood group, and whose mother had either O blood or a different non-O blood group (Supplementary Figure S4). With incongruent non-O blood groups, even small amounts of fetal blood interacting with the mother’s circulation can activate the maternal immune system.^15–17 Although the underlying mechanism is not elucidated, such IgG antibodies could, conceivably, contribute to protective immunity against infection, rather than necessarily causing minor hemolytic disease of the newborn.^18–20

Among preterm newborns, and those whose mothers tested positive for GBS or who had premature rupture of membranes, the apparent protective effect of ABO incongruence was lost. One likely explanation is that antibiotics are often empirically started in preterm newborns,²¹ and are routinely recommended in mothers with GBS positivity and premature rupture of membranes,²² especially those with prolonged rupture of membranes.²³ Thus, each of these three factors is likely a proxy for antibiotic use, the latter potentially obscuring any protective effect of ABO incongruence that was otherwise seen in the absence of these stratified variables (Figure 2).

Strengths and limitations

This study comprised a large population-based sample of hospital livebirths in Ontario over a 14-year time period, where universal healthcare permits the collection of information about maternal–infant pairs, such as ABO blood group status, and ED and hospital encounters for bacterial and viral infections. Although bacterial or viral specimens were not analyzed, the general class of infection was considered (Supplementary Table S7).

One evident major limitation is that about 90% of newborns lacked ABO blood group details (Supplementary Figure S1). This is explained by current clinical practice in Canada, in which a newborn’s blood type is generally tested if its mother is Rhesus (Rh) negative, or the infant is severely ill.^24–26 Although only 10% of maternal–infant pairs had ABO blood group data available, this group minimally differed from those who did not have ABO testing, except for neonatal hyperbilirubinemia, hemolytic disease of the newborn, and NICU admission (Supplementary Table S6). Even so, these conditions can predispose to infection, potentially introducing study selection bias.

Congruent ABO blood groups were more likely to be maternal Rh (D) negative than incongruent groups (25.1% vs. 18.0%) (Table 1). As such, Rh (D) negative mothers likely received Rho(D) immunoglobulin during the index pregnancy to prevent Rh (D) isoimmunization.²⁷ If maternal Rh (D) negativity was a true confounder, and not adjusted for herein, then the HR might have been attenuated. Information on breastfeeding practices^28,29 was also not available in the study databases. Furthermore, it is acknowledged that ABO blood group status may have been misclassified herein among the newborns, since ABO expression is not fully developed in some newborns.³⁰

Gokhale and colleagues^31,32 showed that, even in situations of maternal–neonatal ABO mismatch, a mother’s blood may be safely transfused to her newborn, without hemolysis or graft-vs.-host disease. The latter implies that, despite ABO incompatibility, maternal RBCs and corresponding maternal IgG anti-A and anti-B antibodies may be tolerated by the neonate. Hence, it also remains to be determined whether serum IgG derived from the maternal donor, and then transfused to her apparently septic or at-risk neonate, can attenuate or prevent serious neonatal infection.

A serious infant infection was based on a main diagnosis code arising within an ED visit or during a hospitalization. While most serious neonatal infections occurred during hospital admission (Supplementary Table S8), minor infections may have been missed. Differentiation between bacterial and viral infections was limited to diagnostic coding, which may have led to misclassification, including their combined presence in a given child. Certainly, a future study could ascertain invasive bacterial infections occurring in the infant, such as those isolated from blood, cerebrospinal fluid, or urine.

Conclusion

Infants whose ABO blood group was incongruent with that of their mother had a lower associated risk of serious infection. This novel study introduces a unique opportunity to better identify those infants who might be at higher risk of serious infection at birth, or soon thereafter. Both epidemiological and basic science research should elucidate the biological mechanisms involved in this relation.

Supplementary material

Supplementary material is available at QJMED online.

Acknowledgements

Parts of this material are based on data and/or information compiled and provided by: Canadian Institute for Health Information-Discharge Abstract Database (CIHI-DAD), National Ambulatory Care Reporting System (NACRS), OHIP, RPDB, MOMBABY and Ontario Laboratories Information System (OLIS). The analyses, conclusions, opinions and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred.

This Study is based in part on data provided by Better Outcomes Registry and Network (‘BORN’), part of the Children’s Hospital of Eastern Ontario. The interpretation and conclusions contained herein do not necessarily represent those of BORN Ontario.

Parts or whole of this material are based on data and/or information compiled and provided by Immigration, Refugees and Citizenship Canada (IRCC) current to September 2020. However, the analyses, conclusions, opinions and statements expressed in the material are those of the author(s), and not necessarily those of IRCC.

Author contributions

Emily Ana Butler (Conceptualization [equal], Formal analysis [lead], Funding acquisition [equal], Investigation [equal], Methodology [equal], Writing—original draft [equal], Writing—review & editing [equal]), Sonia M. Grandi (Conceptualization [equal], Formal analysis [supporting], Methodology [equal], Writing—review & editing [equal]), Lavina Matai (Data curation [equal], Resources [equal], Writing—review & editing [equal]), Xuesong Wang (Data curation [equal], Resources [equal], Writing—review & editing [equal]), Eyal Cohen (Conceptualization [equal], Funding acquisition [equal], Investigation [equal], Methodology [equal], Supervision [equal], Writing—original draft [equal], Writing—review & editing [equal]) and Joel G. Ray (Conceptualization [equal], Funding acquisition [equal], Investigation [equal], Methodology [equal], Supervision [equal], Writing—original draft [equal], Writing—review & editing [equal])

Funding

This study was supported by Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care (MLTC). This document used data adapted from the Statistics Canada Postal Code^OM Conversion File, which is based on data licensed from Canada Post Corporation, and/or data adapted from the Ontario Ministry of Health Postal Code Conversion File, which contains data copied under license from ©Canada Post Corporation and Statistics Canada. The study is also funded by the Canadian Institutes of Health Research. E.A.B. received MSc funding from The SickKids Restracomp Scholarship and the Canadian Graduate Scholarship—Master’s from CIHR.

The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Conflict of interest

None declared.

Ethics approval statement

The use of data in this project was authorized under section 45 of Ontario’s Personal Health Information Protection Act, which allows for the use of routinely collected administrative data without consent, and does not require the approval of a research ethics board.

References

Author notes