ABO and RhD blood groups and gestational hypertensive disorders: a population-based cohort study
Prof M Reilly, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, 171 77 Stockholm, Sweden. Email email@example.com
Please cite this paper as: Lee B, Zhang Z, Wikman A, Lindqvist P, Reilly M. ABO and RhD blood groups and gestational hypertensive disorders: a population-based cohort study. BJOG 2012;119:1232–1237.
Objective To examine the association between ABO and RhD blood groups and gestational hypertensive disorders in a large population-based cohort.
Design Cohort study. Risks of gestational hypertensive disorders, pre-eclampsia, and severe pre-eclampsia, estimated by odds ratios for maternal ABO blood group and RhD status.
Setting National health registers of Sweden.
Population All singleton deliveries in Sweden born to first-time mothers during the period 1987–2002 [total n = 641 926; any gestational hypertensive disorders, n = 39 011 (6.1%); pre-eclampsia cases, n = 29 337 (4.6%); severe pre-eclampsia cases, n = 8477 (1.3%)].
Methods Using blood group O as a reference, odds ratios of gestational hypertensive disorders, pre-eclampsia, and severe pre-eclampsia were obtained from logistic regression models adjusted for potential confounding factors.
Main outcome measures Gestational hypertensive disorders, pre-eclampsia, and severe pre-eclampsia.
Results Compared with blood group O, all non-O blood groups had modest but statistically significantly higher odds of pre-eclampsia. Blood group AB had the highest risk for pre-eclampsia (OR = 1.10, 95% CI 1.04–1.16) and severe pre-eclampsia (OR = 1.18, 95% CI 1.07–1.30). RhD-positive mothers had a small increased risk for pre-eclampsia (OR = 1.07, 95% CI 1.03–1.10).
Conclusions In the largest study on this topic to date, women with AB blood group have the highest risks of gestational hypertensive disorders, pre-eclampsia, and severe pre-eclampsia, whereas women with O blood group have the lowest risks of developing these disorders. Although the magnitude of increased risk is small, this finding may help improve our understanding of the etiology of pre-eclampsia.
Gestational hypertensive disorders are the leading cause of maternal mortality in developed countries, and are responsible for approximately 16% of all maternal deaths.1 Most of these deaths are attributed to pre-eclampsia, especially when the condition progresses into severe pre-eclampsia or eclampsia.2 With the improvement in the early diagnosis of pre-eclampsia and better accessibility to antenatal care, diagnosis of pre-eclampsia has increased during the last two decades in many developed countries, with a rate of approximately 3% of pregnancies in the USA, and more than 4% in Norway.3,4 These improvements in diagnosis have not yet been accompanied by a substantial reduction in the case fatality rates,5 and the etiology of this disease is still poorly understood. However, it is suspected that pre-eclampsia may result from changes in vascular ischaemic function,6 which can be influenced by ABO blood group.7
Although some case–control studies have shown a higher risk of pre-eclampsia for blood group AB,8,9 a meta-analysis in 2008 concluded that the risks for pre-eclampsia were not significantly different in pregnant women with the different ABO blood groups.10 However, the 17 studies included in this meta-analysis had substantial limitations that make it difficult to collectively interpret the available studies. Problems included: relatively small sample sizes (14 of 17 studies had <400 cases); a lack of recent data (11 out of 17 studies were conducted before 1990); a lack of control for any potential confounding factors; and non-uniform case definitions of pre-eclampsia. In addition, the various ethnic origins and differential ABO blood group distributions of the study subjects in the meta-analysis, covering six European countries, two countries from the Middle East, and the USA, could have resulted in further heterogeneity of associations. For all studies in the meta-analysis, the risk of pre-eclampsia in each blood group was estimated by comparison with all other blood groups combined (e.g. blood group A versus non-A), which would be expected to dilute any association.
Given the conflicting evidence and all of the concerns with the prior studies, a single, large cohort study in a single country with strict outcome definition and covariate control is needed to accurately assess the pre-eclampsia risk in different blood groups. Prior to our study, the largest study of ABO blood group and pre-eclampsia was a 1974 Russian case–control study with 1557 cases of ‘late toxemia of pregnancy’.11 In this paper, we use 15 years of population register data covering the entire country of Sweden to conduct a cohort study of more than 600 000 pregnant women and investigate whether ABO and RhD blood groups are associated with gestational hypertensive disorders and pre-eclampsia.
The Swedish Medical Birth Register, which was founded in 1973, records the details of all deliveries, and in addition to the mother’s national identity number, collects demographic information, including maternal age, country of birth, and smoking habits. Founded in 1964, the Swedish Hospital Discharge Register has gradually expanded coverage, and since 1987 has covered all Swedish public in-patient care facilities. Hospital discharges are recorded using the Swedish version of the WHO International Classification of Diseases 9th revision (ICD-9) from 1987 to 1996, and ICD-10 coding thereafter.
Pregnant women in Sweden routinely undergo ABO/RhD typing and red blood cell (RBC) antibody screening at their first antenatal appointment. In our previous work we have compiled all available maternal ABO/RhD typing and RBC antibody screening data since 1982, and we use this resource to identify the ABO blood group and RhD status of the pregnant women in this study.12
Definition of study cohort and outcome
From the Medical Birth Register we extracted 650 388 records of first-time singleton deliveries between 1987 and 2002. After excluding records with duplicate/triplicate information, missing or invalid country of birth, and missing or invalid blood group, the final study cohort consisted of 641 926 (98.7%) mothers and their singleton pregnancies.
In order to identify pregnancies complicated by gestational hypertensive disorders, or pre-eclampsia (which includes cases that progressed to severe pre-eclampsia or eclampsia), we linked the mothers extracted above to the Hospital Discharge Register for hospitalisation records occurring during the pregnancy interval, defined as an admission occurring from (and including) 273 days before delivery up to (and including) the day of delivery. We identified all diagnoses of gestational hypertensive disorders or pre-eclampsia using the ICD-9 (1987–1996 cohorts) and ICD-10 (1997–2002 cohorts) codes for these hospitalisation records, and defined three outcomes representing different levels of disease severity:
- 1 Gestational hypertensive disorders: any gestational hypertensive disorder during the pregnancy (ICD-9, 642; ICD-10, O13, O14, O15).
- 2 Pre-eclampsia: a diagnosis of pre-eclampsia, eclampsia, or severe pre-eclampsia during pregnancy (ICD-9, 642E, 642F, 642G, 642H; ICD-10, O14, O15).
- 3 Severe pre-eclampsia: a diagnosis of severe pre-eclampsia at any time during the pregnancy (ICD-9, 642F; ICD-10, O141).
The women in each of these three groups were compared with the reference group of mothers who had no record of any gestational hypertensive disorder during the pregnancy.
Descriptive statistics are provided for each of the three disease groups (i.e. gestational hypertensive disorders, any pre-eclampsia, and severe pre-eclampsia) and the healthy (reference) group. For each of the three disease outcomes, the association with blood group was estimated by the odds ratio from logistic regression models using the healthy group as a reference, with adjustment for various covariates. Model 1 included categories for maternal age in years (<20, 20–24, 25–29, 30–34, 35–39, ≥40), country of origin (Sweden, other Nordic country, or non-Nordic country), calendar year of delivery (1987–1991, 1992–1996, or 1997–2002), and smoking status at first antenatal visit (none, 1–9 cigarettes/day, ≥10 cigarettes/day). Model 2 included the covariates from model 1 in addition to the following known risk factors for pre-eclampsia: maternal history of in-patient diagnosis of hypertension or diabetes (prior to the pregnancy) and body mass index (BMI), calculated from height and weight at the first antenatal visit (<20, 20–24.9, 25–29.9, ≥30). Because data on height and weight were not available until 1992, the study sample for model 2 consisted of the 426 982 mothers of infants delivered from 1992 to 2002.
SAS 9.2 (SAS Institute, Cary, NC, USA) and its sql capabilities were used to extract the data from the original sources, and STATA 11.1 (StataCorp, College Station, TX, USA) and R 2.11 (http://www.r-project.org) were used for data analysis.
Description of study sample
A total of 641 926 mothers with their first-time singleton deliveries were extracted from the database. Most women (93.9%) had no diagnosis of gestational hypertensive disorders; 39 011 (6.1%) mothers were diagnosed with gestational hypertensive disorders, including 29 337 (4.6%) with pre-eclampsia and 8477 (1.3%) with severe pre-eclampsia. The characteristics of the women included in the study are described in Table 1. The major blood groups were type A (45.4%) and type O (37.9%), with types B and AB being relatively rare (11.6 and 5.2%, respectively). Overall, 84.7% of the mothers were RhD-positive, with little or no variation by ABO group. The blood group distribution for these women is similar to that of the general Swedish population.13 The mean age at delivery was 27 years, and a large majority of the women (86.3%) were born in Sweden.
Table 1. Selected characteristics of mothers by ABO blood group for first singleton pregnancies in Sweden, 1987–2002
| RhD group (%) |
| Age [mean (SD)]||27.2 (4.8)||27.2 (4.8)||27.2 (4.8)||27.1 (4.9)||27.1 (4.8)|
| Country of birth (%) |
|Other Nordic countries||2.9||2.7||2.8||3.6||3.7|
| Smoking at first antenatal visit (%) |
|Does not smoke||76.6||76.9||76.2||77.2||76.3|
|10 + cigarettes/day||5.6||5.4||5.7||5.3||5.7|
| BMI at first antenatal visit (%) * |
| Previous inpatient history of (%) |
| Gestational hypertensive disorders [n(%)]**|
|Any gestational hypertensive disorders||39 011 (6.1)||14 691 (6.0)||17 804 (6.1)||4437 (6.0)||2079 (6.2)|
|Pre-eclampsia||29 337 (4.6)||10 793 (4.4)||13 532 (4.6)||3409 (4.6)||1603 (4.8)|
|Severe preeclampsia||8477 (1.3)||3088 (1.3)||3876 (1.3)||1021 (1.4)||492 (1.5)|
Association of pre-eclampsia with ABO and RhD blood groups
Using mothers who had no diagnosis of any gestational hypertensive disorders as the reference group, we estimated the association between blood group and the outcomes of interest (gestational hypertension, pre-eclampsia, and severe pre-eclampsia) using odds ratios and 95% confidence intervals from logistic regression models (see Table 2). After adjusting model 1 for age, country of origin, calendar year, smoking, and RhD status, when compared with blood group O, women of blood group AB had an increased risk of gestational hypertensive disorders (OR 1.05, 95% CI 1.00–1.10) and pre-eclampsia (OR 1.10, 95% CI 1.04–1.16), and an even higher increased risk for severe pre-eclampsia (OR 1.18, 95% CI 1.07–1.30). This trend of increasing odds ratios with severity of disease outcome was also apparent for blood groups A and B. Overall, blood group O had the lowest odds for any of the outcomes. Similar results were obtained from model 2, which adjusted for model 1 covariates and for BMI, diabetes, and hypertension: for example, women of blood group AB had an increased risk of severe pre-eclampsia (OR 1.20, 95% CI 1.08–1.35).
Table 2. Adjusted odds ratios with 95% confidence intervals of any gestational hypertensive disorders, any pre-eclampsia, and severe pre-eclampsia in a first, singleton pregnancy
| Model 1 (1987–2002 birth cohorts)|
| Type O (reference)||1.00||1.00||1.00|
| Type A||1.00 (0.97–1.02)||1.03 (1.01–1.06)*||1.04 (0.99–1.09)|
| Type B||1.03 (0.99–1.06)||1.07 (1.02–1.11)**||1.11 (1.03–1.19)**|
| Type AB||1.05 (1.00–1.10)*||1.10 (1.04–1.16)***||1.18 (1.07–1.30)***|
| RhD− (reference)||1.00||1.00||1.00|
| RhD+||1.06 (1.03–1.09)***||1.07 (1.03–1.10)***||1.04 (0.98–1.11)|
| Model 2 (1992–2002 birth cohorts)|
| Type O (reference)||1.00||1.00||1.00|
| Type A||1.01 (0.99–1.04)||1.04 (1.00–1.07)*||1.04 (0.98–1.10)|
| Type B||1.01 (0.97–1.06)||1.01 (0.96–1.07)||1.07 (0.98–1.16)|
| Type AB||1.06 (1.01–1.13)*||1.12 (1.05–1.21)***||1.20 (1.08–1.35)***|
| RhD− (reference)||1.00||1.00||1.00|
| RhD+||1.06 (1.02–1.10)**||1.06 (1.02–1.11)**||1.03 (0.96–1.11)|
Compared with RhD-negative women, RhD-positive women had a small increased risk of gestational hypertensive disorders (model 1 OR 1.06, 95% CI 1.03–1.09) and pre-eclampsia (OR 1.07, 95% CI 1.03–1.10). The risks for non-O blood group and RhD-positive status were additive, as there was no evidence of statistical interaction, so that of all ABO/RhD blood groups, O− blood group had the lowest estimated risks of gestational hypertensive disorders, whereas blood group AB+ had the highest risk. For example, compared with blood group O−, AB+ had 1.23 times the odds (95% CI 1.10–1.38) of developing severe pre-eclampsia.
We investigated the association between ABO and RhD blood groups and gestational hypertensive disorders, pre-eclampsia, and severe pre-eclampsia for a total of 641 926 first-time pregnant women with singleton deliveries in the largest study to date. Our results indicate that women with blood group AB have the highest risk of pre-eclampsia, and especially severe pre-eclampsia, whereas women with blood group O have the lowest risk. In addition, RhD-positive women have a slightly higher risk of developing pre-eclampsia.
This large study of registry data has numerous strengths. The availability of national population-based registry data enabled us to use strict criteria in defining our study cohort: we selected only nulliparous mothers with a singleton delivery and valid information for ABO and RhD blood group and country of birth, and as our reference group, we chose pregnant women with no diagnosis of any gestational hypertensive disorders. By analysing three hierarchical outcomes––any gestational hypertensive disorders, any pre-eclampsia, and lastly severe pre-eclampsia––we were able to investigate potential trends in effects that would suggest greater biological plausibility. However, because of our reliance on ICD coding for outcome definition [e.g. an ICD code for HELLP (haemolysis, elevated liver enzymes and low platelet count) was not available until ICD-10] and low occurrence of other outcomes such as eclampsia, we could not assess with statistical precision any results for more specific outcomes beyond those presented. Another limitation is that outcome misclassification may occur because of a reliance on ICD codes during a calendar period when changes were implemented. Previous validation efforts in the Hospital Discharge Register that compared ICD-9 codes with an expert medical record review indicate high positive predictive values for the outcomes, with 84% of pregnancies with ICD codes for gestational hypertension classified as having the disorder, and 93% of pregnancies with ICD codes for pre-eclampsia classified as such during record review.14,15 However, ICD-10 diagnoses in the register have not been validated, but we conducted a sensitivity analysis where we restricted our sample to deliveries in the ICD-9 era (1987–1996), and found similar estimates of associations (results not shown). Whereas only in-patient diagnoses of hypertension and diabetes before pregnancy were available, these represent the most severe cases and we found no evidence of confounding. Finally, although the study was nationally representative, caution is warranted in extrapolating findings to other populations, given the varied incidence of both gestational hypertensive disease and distribution of ABO blood groups around the world.
Our findings of an increased risk of pre-eclampsia for non-O blood groups are consistent with a recent case–control study from Finland of 927 women, including 248 cases of pre-eclampsia,8 which reported that women with blood group AB had a higher risk for pre-eclampsia than non-AB women (OR 2.1), with the risk being larger for severe pre-eclampsia (OR 2.3). Although this study narrowed the ethnic origins of the pregnant women by selecting only those who spoke Finnish or Swedish, and who lived in Finland, the data did not exclude multiple deliveries, which are associated with an increased risk of pre-eclampsia,16,17 nor did the investigators limit the parity of the mothers, despite the well-known higher prevalence in first pregnancy and higher risk in subsequent pregnancies for women whose first pregnancy was affected.17,18
Our results appear to have biological plausibility. One suggested mechanism of how blood group influences the risk of gestational hypertensive disorders is through the maternal immune response. A laboratory study of over 1000 women found that placental protein 13 (PP13), an early biomarker of pre-eclampsia with suspected function in the maternal–fetal immune interface, differentially binds to erythrocytes from distinct ABO groups, with strongest binding to blood group AB.7 In addition, compared with O group, A, B, and AB groups are associated with an increased risk of thrombotic events, although this relationship is debated.19 Finally, ABO blood groups may differ in the occurrence of known vascular risk factors for pre-eclampsia, such as endothelial dysfunction,20 insulin resistance,21 and hypercholesterolemia.22 ABO blood groups display differences in levels of endothelial cell markers, including von Willebrand factor, E-selectin, and thrombomodulin.20 Recent genome-wide association studies indicate that genetic variants at the ABO locus are associated with soluble E-selectin,21,23 P-selectin, and ICAM-1,24 vascular inflammatory agents that are associated with hypertension and type-2 diabetes.25,26 However, of a diverse panel of inflammatory biomarkers, including E-selectin, P-selectin, and ICAM-1, a recent study found that only E-selectin levels were higher in pre-eclampsia cases versus controls.27
In summary, in the largest study to date of blood groups and pre-eclampsia, we found evidence indicating that women of non-O blood groups, especially blood group AB+, have an increased risk of gestational hypertensive disorders, pre-eclampsia, and severe pre-eclampsia. Although associations were modest in magnitude, the consistent risks from models with different levels of covariate adjustment and the increase in risk for more severe outcomes suggest biological plausibility. Whereas some strong risk factors for pre-eclampsia have been identified, the etiology of this leading cause of maternal mortality is still poorly understood, and much recent research effort is being directed at investigating biomarkers,28–30 whose effect on pre-eclampsia may be modified by ABO blood group.7 Our study suggests that investigations of factors associated with pre-eclampsia should consider the contribution of ABO blood group in order to help improve our understanding of the underlying mechanism of this disease.
Disclosure of interests
None to declare.
Contribution to authorship
This study was planned jointly by B.L. and M.R. Data were discussed jointly by all authors. B.L. and Z.Z. drafted the article. All authors contributed to critical revision for important intellectual content, and gave final approval of the version to be published.
Details of ethics approval
The study was approved by the Stockholm regional ethics committee (ref. no. 2008/672-32).
The work performed was supported by a grant from the Swedish Research Council (VR): contract number, 60521601; project number, K2007-54X-20327-01-2. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the article.
We thank Gustaf Edgren (Karolinska Institute, Department of Medical Epidemiology and Biostatistics) for compiling the blood group information in the SCANDAT database and Jing Fan (Karolinska Institute, Department of Public Health Sciences) for assistance with data extraction.