Impact of Antepartum Anemia on Maternal and Perinatal Outcomes in Women with Placenta Accreta Spectrum: A Multicenter Study

Introduction

Placenta accreta spectrum (PAS) is a severe obstetric disease characterized by abnormal placental adherence or invasion into the uterine wall, which can lead to life-threatening maternal hemorrhage and significant perinatal morbidity.^1–3 With rising global cesarean section (CS) rates, the incidence of PAS has increased markedly in recent years.¹ PAS management remains challenging due to its association with massive blood loss, complex surgical procedures, high demand for transfusion and multidisciplinary care.

Antepartum anemia is a common condition during pregnancy. According to the World Health Organization, an estimated 37% of pregnant women worldwide were affected.⁴ A study reported a significantly higher incidence of anemia in women with PAS compared to those without (60.4% vs 23.3%).⁵ Anemia has been linked to adverse maternal and perinatal outcomes in the general obstetric population, such as low birth weight, preterm birth, postpartum hemorrhage and so on.⁶ In the context of PAS, antepartum anemia may have two clinically related but distinct implications. First, it may serve as a marker of more severe placental disease, because deeper placental invasion, coexisting placenta previa, and recurrent antepartum bleeding may contribute to lower hemoglobin (HGB) levels. Second, anemia may also represent a potentially modifiable perioperative risk factor, because reduced HGB reserves may impair physiological tolerance to blood loss and increase the likelihood of transfusion.^5,7 Although anemia has been studied in general obstetric populations and PAS-related hemorrhage,^5,8 limited evidence has specifically evaluated whether antepartum anemia is associated with broader maternal and perinatal outcomes within a PAS population after accounting for PAS severity and placenta previa.

Therefore, we conducted this multicenter cohort study to investigate the association between antepartum anemia and maternal-perinatal outcomes in women with PAS, identify independent risk factors for adverse outcomes, and help optimize clinical management in this population.

Materials and Methods

This is a multicenter, retrospective cohort study. We retrospectively collected cases from September 2016 to July 2025 at three Chinese medical centers: Peking Union Medical College Hospital, Shandong Provincial Hospital Affiliated to Shandong First Medical University, and Qilu Hospital of Shandong University Dezhou Hospital. The inclusion criteria were as follows: (1) confirmation of PAS during delivery or by postoperative pathology, (2) age ≥ 18 years old, (3) singleton pregnancy, (4) delivery at ≥ 28 weeks of gestation. The exclusion criteria were: (1) coexisting inherited or acquired coagulation disorders, (2) multiple gestation, (3) intrauterine fetal death, (4) incomplete medical records.

Maternal and perinatal data were obtained from electronic medical records at the participating centers. Maternal baseline characteristics included age, gestational age at delivery, gravidity, number of prior CS, and history of intrauterine procedures (including induced abortion, uterine curettage, and hysteroscopy), as well as hypertensive disorders of pregnancy (HDP) and gestational diabetes mellitus (GDM). Obstetric characteristics included PAS subtypes, placenta previa subtypes, antenatal corticosteroid administration, ultrasound features, vaginal bleeding during pregnancy, mode of delivery and emergency delivery. Maternal outcomes included operating time, bladder injury, hysterectomy, estimated blood loss (intrapartum and within 24 hours postpartum), packed red blood cells (PRBCs) transfusion, return to the operating room, intensive care unit (ICU) admission, postpartum infection, deep venous thrombosis (DVT), disseminated intravascular coagulation (DIC), pulmonary embolism (PE), and length of hospital stay. Perinatal outcomes included birthweight, preterm birth, neonatal intensive care unit (NICU) admission, and perinatal death. Patients with missing information on key baseline characteristics, such as HGB, PAS diagnosis, or maternal and perinatal outcomes, were excluded. The final analytic cohort consisted of complete cases, with no missing values in the variables. No imputation was performed.

HGB levels were obtained from the last complete blood count prior to delivery and reported in g/L. According to the World Health Organization criteria, anemia in the third trimester was defined as HGB < 110 g/L.⁹ PAS was classified according to the Chinese Guidelines for Diagnosis and Management of Placenta Accreta Spectrum Disorders (2023) based on the depth of trophoblast invasion: accreta (invasion into superficial myometrium), increta (invasion into deep myometrium), and percreta (penetration through serosa).¹⁰ In cases with mixed grades, the most severe grade was used. Diagnosis was confirmed by intraoperative findings of failure of spontaneous placental separation or by histopathology. Complete placenta previa was defined as placenta completely covering the internal cervical os. Partial placenta previa was defined as the placenta partially covers the internal cervical os and marginal placenta previa was defined as the placental edge reaches the margin of the internal cervical os but does not cover it. Low-lying placenta was defined as a placental edge within 20 mm of the internal cervical os.

The composite adverse maternal outcome was defined as the occurrence of at least one of the following: major obstetric hemorrhage (estimated blood loss ≥ 2000 mL or transfusion of > 4 units of PRBCs), ICU admission, or severe peripartum morbidity, including bladder injury, DIC, DVT, PE, postpartum infection, or unplanned return to the operating room.^11–13 The composite adverse perinatal outcome was defined as any of the following: preterm birth (< 37 weeks of gestation), perinatal death, or NICU admission.

Women were categorized into an anemia group (HGB < 110 g/L) and a non-anemia group (HGB ≥ 110 g/L) based on pre-delivery HGB levels. Categorical variables are presented as frequencies and percentages [n (%)], and continuous variables as median with interquartile range. Group comparisons were performed using the Chi-square test, Fisher’s exact test, or the Mann–Whitney U test, as appropriate. To minimize baseline imbalance, propensity score matching (PSM) was performed using a 1:1 nearest neighbor matching algorithm with a caliper width of 0.2. Variables entered into the propensity score model were selected primarily based on clinical relevance and prior evidence. These variables included maternal age, gestational age at delivery, gravidity, number of prior CS, PAS subtypes, placenta previa subtypes, antenatal corticosteroid administration, ultrasound features, mode of delivery and vaginal bleeding during pregnancy. Covariate balance before and after matching was assessed using standardized mean differences (SMD), with an SMD < 0.15 considered indicative of good balance. After matching, all variables met this threshold (Table 1). Subsequent analyses were conducted in the matched cohort. Univariable and multivariable logistic regression analyses were used to identify independent risk factors for composite adverse maternal and perinatal outcomes. Candidate variables for regression models were selected according to clinical relevance, prior literature, and univariable associations (P < 0.2). Multicollinearity was assessed using variance inflation factor (VIF), with VIF < 5 indicating no significant collinearity among the independent variables. All variables had VIF values below 2.5 (Table S1). A forward stepwise selection method was used to build the multivariable model. Results are reported as odds ratio (OR) with 95% confidence intervals (CIs), and a two-sided P value < 0.05 was considered statistically significant.

Table 1 Characteristics of Women in Before and After Matching Cohorts

All statistical analyses were performed using IBM SPSS Statistics (version 27.0), and PSM was conducted using R software (version 4.3.2).

Results

A total of 984 women were included, of whom 316 (32.1%) were classified into the anemia group and 668 (67.9%) into the non-anemia group (Figure 1). Baseline characteristics are presented in Table 1. Among the cohort, 469 women (47.7%) had placenta accreta, 455 (46.2%) had placenta increta, and 60 (6.1%) had placenta percreta. Placenta previa was present in 541 women, including 416 (76.9%) with complete placenta previa, 44 (8.1%) with partial placenta previa and 81 (15.0%) with marginal placenta previa or low-lying placenta. Advanced maternal age (≥ 35 years) was observed in 426 women (43.3%). The median gestational age at delivery was 264 days (approximately 37 weeks and 5 days). A history of ≥ 2 prior CS was reported in 13.5% of women, and the median number of intrauterine procedures was 1. Antepartum vaginal bleeding occurred in 28.0% of women. Overall, 267 women (27.1%) underwent vaginal delivery and 717 (72.9%) underwent cesarean delivery, including 168 emergency procedures.

Figure 1 Flowchart. Abbreviation: PAS, placenta accreta spectrum.

Comparison of Baseline Characteristics

Compared with the non-anemia group, women with anemia were less likely to be of advanced maternal age (38.3% vs 45.7%, P = 0.033) and had a lower median gestational age at delivery (256 vs 268 days, P < 0.001). They were more likely to have ≥ 2 prior CS (23.4% vs 8.8%, P < 0.001), more gravidity (91.1% vs 72.8%, P < 0.001). Notably, the anemia group had more severe PAS (increta/percreta: 79.4% vs 39.5%, P < 0.001), a higher prevalence of placenta previa (86.4% vs 40.1%, P < 0.001), more ultrasound features suggestive of PAS and increased antepartum vaginal bleeding (49.1% vs 18.1%, P < 0.001). What’s more, they also had greater use of antenatal corticosteroids (51.9% vs 18.4%, P < 0.001) and a higher rate of cesarean delivery (94.0% vs 62.9%, P < 0.001). No significant differences were observed between groups in the number of intrauterine procedures, HDP, GDM, or emergency delivery.

After PSM, covariate balance was substantially improved between the anemia and non-anemia groups. All post-matching SMDs were below 0.15, indicating acceptable balance across measured baseline covariates (Table 1 and Figure S1).

Association Between Antepartum Anemia and Maternal-Perinatal Outcomes

Before matching, women with anemia had significantly worse maternal outcomes (Table 2), including longer median operating time (87 vs 59 minutes, P < 0.001), greater median blood loss (1000 vs 450 mL, P < 0.001), and higher median transfusion requirements (4 vs 0 units, P < 0.001). They also had higher rates of bladder injury (5.4% vs 2.4%, P = 0.022) and DIC (1.3% vs 0.1%, P = 0.039), as well as a longer median postpartum hospital stay (5 vs 4 days, P < 0.001). The composite adverse maternal outcome was significantly more frequent in the anemia group (46.5% vs 16.6%, P < 0.001).

Table 2 Maternal and Perinatal Outcomes in Before and After Matching Cohorts

After matching, most maternal outcomes showed no significant differences between groups. However, women with anemia still required significantly more blood transfusions (median 4 vs 2 units, P < 0.001) and had a higher incidence of composite adverse maternal outcomes (42.2% vs 30.7%, P = 0.006).

In the unmatched cohort, neonates in the anemia group had higher rates of preterm birth (60.1% vs 27.1%), lower median birthweight (2900 g vs 3100 g), and higher NICU admission rates (48.7% vs 28.1%) (all P < 0.001). The composite adverse perinatal outcome was also more frequent in the anemia group (63.9% vs 35.9%, P < 0.001). However, after matching, no significant differences were observed between groups in any perinatal outcomes.

Independent Risk Factors for Composite Adverse Maternal Outcome

In the matched cohort, univariable analysis identified multiple factors associated with composite adverse maternal outcomes (Table 3).

Table 3 Univariable Logistic Regression Analysis of Risk Factors Associated with Composite Adverse Maternal and Perinatal Outcomes

Multivariable analysis demonstrated that anemia (OR 1.84, 95% CI 1.22–2.78, P = 0.004), placenta increta/percreta (OR 25.56, 95% CI 5.62–116.26, P < 0.001), vascular lacunae (OR 2.56, 95% CI 1.65–3.95, P < 0.001), and hypervascularity of the uterine serosa-bladder interface (OR 2.47, 95% CI 1.50–4.08, P < 0.001) were independent risk factors (Table 4).

Table 4 Multivariable Logistic Regression Analysis of Risk Factors Associated with Composite Adverse Maternal and Perinatal Outcomes

Gestational age at delivery was identified as a protective factor (OR 0.98 per day, 95% CI 0.96–0.99, P = 0.007), with each additional day associated with a 2% reduction in risk.

Independent Risk Factors for Composite Adverse Perinatal Outcome

Anemia was not significantly associated with adverse perinatal outcomes (OR 1.14, 95% CI 0.82–1.61, P = 0.437) (Table 3) and was not retained in the final model.

Multivariable analysis identified gestational age at delivery as a strong protective factor (OR 0.65, 95% CI 0.60–0.71, P < 0.001). Cesarean delivery was associated with a markedly lower risk of adverse perinatal outcomes compared with vaginal delivery (OR 0.01, 95% CI 0.002–0.06, P < 0.001), whereas emergency delivery was associated with increased risk (OR 3.75, 95% CI 1.24–11.37, P = 0.020) (Table 4).

Discussion

In this retrospective study of 984 women with PAS, we found that antepartum anemia is a prevalent condition, affecting 32.1% of the cohort. The anemia group had a significantly higher proportion of placenta increta and percreta, a higher prevalence of placenta previa, and a higher rate of vaginal bleeding during pregnancy. Antepartum anemia is associated with more blood transfusions even after adjusting for potential confounders through PSM and is significantly associated with composite adverse maternal outcome. Notably, while anemia was initially associated with poorer perinatal outcomes in the unmatched cohort, these differences vanished after matching.

The higher prevalence of severe PAS, placenta previa, and antepartum bleeding among women with anemia indicates that anemia may partly reflect more advanced disease. In the matched cohort, most maternal outcomes were not significantly different between groups, whereas transfusion requirement remained higher among women with anemia. After balancing key confounders including PAS severity and placenta previa, the composite adverse maternal outcome remained significantly higher in the anemic group than in the non-anemic group (42.2% vs 30.7%, P = 0.006). Because the primary composite adverse maternal outcome included transfusion of > 4 units of PRBCs, and anemia is clinically associated with transfusion requirement, the observed association between antepartum anemia and the composite maternal outcome should be interpreted cautiously. Therefore, our findings mainly indicate that antepartum anemia is associated with increased transfusion-related maternal risk and greater perioperative blood resource demand, rather than providing definitive evidence that anemia directly increases all severe maternal morbidities. Multivariable analysis confirmed anemia as an independent risk factor, supporting its clinical significance as a modifiable risk factor. These findings underscore the importance of enhanced blood preparation and perioperative management in anemic patients.

However, after PSM, most maternal outcomes, including estimated blood loss, ICU admission and DIC, showed no significant differences between the anemic and non-anemic groups. This finding may be explained by several factors. Firstly, PSM balanced key confounders such as PAS severity and placenta previa, which are major determinants of maternal morbidity.¹⁴ Secondly, in patients with severe PAS, the extent of placental invasion and surgical difficulty likely overshadow the contribution of anemia to outcomes such as operative time and blood loss.¹⁵ Thirdly, standardized multidisciplinary protocols at the participating centers, including proactive hemostatic strategies and timely intervention, may have reduced the incidence of complications such as infection, DIC, PE and DVT.¹⁶ The low event rates of these outcomes may have limited statistical power to detect modest differences between groups.

Preterm birth in the context of PAS should be interpreted cautiously. In this population, preterm birth may result from planned delivery, substantial antepartum hemorrhage, or emergency cesarean delivery, rather than reflecting a direct effect of anemia. In our study, the initial difference in perinatal outcomes disappeared after PSM, and anemia was not identified as an independent risk factor for the composite adverse perinatal outcome. These findings suggest that adverse perinatal outcomes in PAS are more likely driven by confounding factors (such as PAS severity, placenta previa, and bleeding-related obstetric indications) than by anemia itself. This contrasts with the more complex relationship observed in general obstetric populations. In a general obstetric population in China, Shi et al reported a J-shaped association, where mild anemia appeared protective against fetal growth restriction and stillbirth, whereas moderate to severe anemia increased these risks.¹⁷ Another study found a U-shaped association between hemoglobin concentration and adverse maternal-perinatal outcomes, in which the risk of preterm birth was more than doubled at a HGB concentration of 70 g/L (risk ratio 2.04, 95% CI 1.20–3.48).¹⁸ Both studies highlighted the adverse impact of severe anemia on fetal outcomes in general obstetric populations. However, the limited number of women with severe anemia in our cohort restricted our ability to perform severity-based subgroup analyses, which may have masked a potential dose-response relationship.

The multivariable analysis further confirmed established strong predictors of adverse outcomes in PAS. Consistent with previous literature,^19,20 PAS subtypes, particularly increta and percreta, were associated with an increased risk of adverse maternal outcomes. In addition, specific ultrasound signs, including placental lacunae and hypervascularity of the uterine serosa-bladder interface, were identified as independent risk factors. These imaging features reflect the depth of placental invasion and aberrant vascularity, providing objective criteria for preoperative risk assessment.^21–24

Notably, gestational age at delivery emerged as a protective factor. For stable PAS women without other complications, appropriately prolonging gestation may confer benefits for both maternal and neonatal outcomes. Rosenthal et al demonstrated that delaying planned delivery until 36–37 weeks of gestation in such women did not increase the risk of adverse maternal outcomes, while significantly improving neonatal outcomes.²⁵ Similar findings were reported by Morlando et al.²⁶ In contrast, emergency delivery was associated with a significantly increased risk of adverse perinatal outcomes. This finding aligns with prior literature and underscores the critical importance of planned, multidisciplinary care in the management of PAS.^27,28

The main strength of this study is its multicenter design, which enhances sample representativeness and generalizability of the findings. The use of PSM effectively balanced confounding factors between groups, thereby reducing selection bias. Additionally, the application of composite outcome measures comprehensively captures clinically significant adverse events, avoiding the limitations of relying on single outcome indicators.

However, there are also several limitations. Firstly, the retrospective design inherently confers a lower level of evidence compared to prospective studies. Although PSM balanced known confounders, there may still be unmeasured confounding factors, such as nutritional status, iron supplementation, and surgical team expertise, that could influence the results. Secondly, the diagnosis of anemia was based on the last complete blood count prior to delivery, which may partly reflect acute antepartum bleeding rather than a stable baseline state. Because this was a retrospective multicenter study, earlier antepartum HGB values were not uniformly available across centers or measured at standardized gestational time points. Therefore, we were unable to perform a reliable sensitivity analysis based on earlier HGB measurements. This potential reverse-causation issue should therefore be considered when interpreting the association between anemia and maternal outcomes. Thirdly, the low incidence of certain outcomes, such as perinatal death, may have resulted in insufficient statistical power. Additionally, the limited number of women with severe anemia in our cohort precluded stratified analysis by anemia severity. Finally, as the data were derived from three tertiary hospitals in China, caution is warranted when extrapolating these findings to regions with different healthcare resources and settings.

Conclusions

In women with PAS, antepartum anemia is independently associated with increased adverse maternal risk, mainly through increased transfusion requirements, and is not associated with adverse perinatal outcomes. Integrating anemia screening and correction into PAS clinical management pathways may help improve maternal prognosis and reduce the burden on blood resources in regions with limited supply. For women in whom antepartum anemia cannot be corrected before delivery, adequate preoperative blood preparation is essential.