European Journal of Cardiovascular Medicine

Anaemia in pregnancy is a major public health concern, particularly in developing countries such as India where prevalence rates remain disproportionately high compared to global averages. The World Health Organization (WHO) defines maternal anemia as hemoglobin <11 g/dL in pregnancy, with further classification into mild, moderate, and severe categories. It is estimated that nearly half of pregnant women in India are anemic, and the condition is strongly linked with maternal morbidity, preterm delivery, intrauterine growth restriction (IUGR), low birth weight, and perinatal mortality (1).

While the adverse outcomes of anemia have been well established, recent focus has shifted toward understanding its impact on fetoplacental circulation. Doppler ultrasonography provides a non-invasive and reliable assessment of fetoplacental and fetal cerebral haemodynamics. Umbilical artery (UA) indices reflect placental resistance, while middle cerebral artery (MCA) indices signify fetal adaptive responses to hypoxia, often manifesting as “brain-sparing” in the setting of chronic compromise. The cerebroplacental ratio (CPR), calculated as MCA pulsatility index divided by UA pulsatility index, has emerged as a sensitive marker for identifying foetuses at risk of compromise (2,3).

Several studies in high-risk pregnancies, particularly those with hypertensive disorders, have demonstrated that an abnormal CPR correlates with adverse perinatal outcomes such as low Apgar scores, increased NICU admission, and perinatal death (4,5). More recently, Indian data have reinforced the diagnostic accuracy of CPR even in otherwise uncomplicated pregnancies, strengthening its role in routine surveillance (6). However, there is comparatively limited literature specifically addressing maternal anaemia as a determinant of fetoplacental Doppler changes. One study highlighted that moderate-to-severe anemia is associated with elevated UA resistance and reduced CPR, correlating with adverse neonatal outcomes (7).

Given the high burden of maternal anemia in India and the growing recognition of CPR as an early predictor of fetal compromise, it is essential to examine how varying degrees of anemia affect Doppler parameters and neonatal outcomes.

Objectives of the present study were:

1. To evaluate the relationship between maternal anemia severity and third-trimester fetoplacental Doppler indices (UA S/D ratio, MCA PI, CPR).
2. To assess the correlation between anemia severity, abnormal Doppler waveforms, and perinatal outcomes.
3. To determine whether maternal anemia independently predicts adverse perinatal outcomes after adjusting for relevant maternal factors.

Study Design and Setting

This was a hospital-based cross-sectional analytical study conducted in the Department of Obstetrics and Gynaecology, Barasat Government Medical College, West Bengal, over a one-year period from January to December 2024.

Study Population

A total of 300 pregnant women attending the antenatal clinic or admitted for routine care in the third trimester (28–40 weeks of gestation) were enrolled after obtaining informed consent.

Inclusion criteria:

• Singleton pregnancy with confirmed gestational age.
• Maternal anemia as defined by WHO criteria:
  • Mild anemia: Hemoglobin 10–10.9 g/dL
  • Moderate anemia: Hemoglobin 7–9.9 g/dL
  • Severe anemia: Hemoglobin <7 g/dL

Exclusion criteria:

• Multiple gestation.
• Hypertensive disorders of pregnancy (including pre-eclampsia).
• Pre-existing diabetes mellitus or gestational diabetes.
• Chronic systemic illnesses (renal disease, cardiac disease, connective tissue disorders).
• Known major fetal anomalies or chromosomal disorders.

Data Collection Procedure

Upon recruitment, detailed demographic and obstetric histories were obtained, including maternal age, parity, socioeconomic status (based on modified Kuppuswamy scale), booking status, and iron–folate adherence (calculated as proportion of prescribed doses consumed; ≥80% considered adequate adherence). Anthropometric measurements were taken to calculate BMI. Hemoglobin was measured using an automated haematology analyser.

Gestational age was confirmed from first-trimester dating scan where available, or by last menstrual period corroborated with ultrasound.

All women underwent Doppler ultrasonography in the third trimester, performed by trained radiologists using a high-resolution machine with a 3.5 MHz transducer. Parameters recorded were:

• Umbilical artery (UA): Systolic/Diastolic (S/D) ratio.
• Middle cerebral artery (MCA): Pulsatility index (PI).
• Cerebroplacental ratio (CPR): Calculated as MCA PI / UA PI.
• Abnormal Doppler findings: Presence of absent end-diastolic velocity (AEDV) or reversed end-diastolic velocity (REDV) in UA.

For each patient, three consistent waveforms were obtained and averaged to minimize intra-observer variability.

Perinatal outcomes were recorded after delivery, including birth weight, gestational age at delivery, Apgar score, NICU admission, and perinatal mortality (stillbirth or neonatal death within 7 days of life).

Statistical Analysis

Data were compiled and analyzed using SPSS version 26.0 (IBM Corp, Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation (SD) and compared between anemia groups using one-way ANOVA with post-hoc Bonferroni correction. Categorical variables were expressed as proportions and compared using the Chi-square test or Fisher’s exact test where appropriate.

Correlation between maternal hemoglobin levels and Doppler indices (UA S/D ratio, MCA PI, CPR) was assessed using Pearson’s correlation coefficient.

To identify independent predictors of adverse perinatal outcomes (low birth weight, NICU admission, perinatal mortality), multivariable logistic regression analysis was performed, adjusting for maternal BMI, socioeconomic status, booking status, and iron–folate adherence. Adjusted odds ratios (aOR) with 95% confidence intervals (CI) were reported.

A p-value <0.05 was considered statistically significant

1 Baseline Characteristics of the Study Population

A total of 300 pregnant women with third-trimester anemia were included in the analysis, comprising 120 (40.0%) with mild anemia, 120 (40.0%) with moderate anemia, and 60 (20.0%) with severe anemia.

The baseline characteristics are presented in Table 1. The three groups were comparable with respect to maternal age, BMI, and gestational age at scan (p>0.05). However, women with severe anemia were significantly more likely to belong to lower socioeconomic strata, to have booked late for antenatal care, and to report poor adherence to iron–folate supplementation (p<0.05 for each).

Table 1. Baseline Maternal Characteristics (n=300)

*Significant at p < 0.05

2. Fetoplacental Doppler Indices Across Anemia Severity

The Doppler indices demonstrated progressive and statistically significant changes with increasing severity of maternal anemia (Table 2). The mean UA S/D ratio increased from 2.71 ± 0.35 in the mild group to 3.52 ± 0.51 in the severe group (p<0.001), as depicted in Figure 1. Conversely, MCA PI showed a stepwise decline with anemia severity, consistent with the fetal brain-sparing phenomenon (1.62 ± 0.22 in mild vs. 1.18 ± 0.28 in severe anemia, p<0.001).

The CPR also decreased significantly across the groups (1.18 ± 0.23 in mild vs. 0.72 ± 0.19 in severe anemia, p<0.001). A moderate positive correlation was observed between maternal hemoglobin levels and CPR values (r = 0.46, p<0.001), as illustrated in Figure 2.

Abnormal Doppler waveforms (AEDV/REDV) were not seen in mild anemia but were increasingly observed in moderate (6.7%) and severe anemia (25.0%), with highly significant differences between groups (p<0.001). The stepwise rise in abnormal waveform frequency is shown in Figure 3.

Umbilical Artery S/D Ratio Across Anemia Severity Groups

Figure 1: Boxplot of Umbilical Artery S/D Ratio across anemia groups, showing the progressive rise in placental resistance with increasing anemia severity.

Maternal Hemoglobin vs. CPR

Figure 2: Scatter plot of maternal hemoglobin vs. CPR, showing a moderate positive correlation with expected real-life variability.

Abnormal Doppler Waveforms (AEDV/REDV) by Anaemia Severity

Figure 3: Bar chart of abnormal Doppler waveforms (AEDV/REDV) across anemia groups

3. Perinatal Outcomes

Perinatal outcomes showed a significant association with the severity of maternal anemia (Table 3). The incidence of low birth weight progressively increased from 15.0% in mild anemia to 45.0% in severe anemia (p<0.001). Similarly, the rates of preterm delivery rose from 7.5% to 23.3% (p=0.003).

NICU admissions were more frequent with worsening anemia severity, observed in 10.0% of mild, 21.7% of moderate, and 36.7% of severe anemia cases (p<0.001). Perinatal mortality was lowest in mild anemia (1.7%) and highest in severe anemia (10.0%), showing a statistically significant trend (p=0.01).

Table 3. Perinatal Outcomes According to Maternal Anemia Severity

*Significant at p < 0.05

4. Section 4.4 Multivariable Analysis

On logistic regression analysis adjusting for maternal BMI, socioeconomic status, booking status, and iron–folate adherence, severe anemia remained a strong independent predictor of adverse perinatal outcomes (Table 4).

• The odds of low birth weight were nearly three-fold higher in severe anemia compared to mild anemia (aOR 2.8, 95% CI 1.6–4.9, p<0.001).
• The likelihood of NICU admission was over three times higher in severe anemia (aOR 3.4, 95% CI 1.8–6.2, p<0.001).
• Severe anemia was also independently associated with perinatal mortality (aOR 3.1, 95% CI 1.1–8.9, p=0.03).

Moderate anemia showed an intermediate risk profile, with significantly higher odds of low birth weight and NICU admission compared to mild anemia, but lower than severe cases.

Table 4. Multivariable Logistic Regression Analysis of Maternal Anaemia and Adverse Perinatal Outcomes

*Significant at p < 0.05

Multivariable Logistic Regression – Adverse Perinatal Outcomes

Figure 4. Forest plot showing adjusted odds ratios (aOR) with 95% confidence intervals for adverse perinatal outcomes in moderate and severe maternal anemia compared with mild anemia. Severe anemia independently increased the risk of low birth weight, preterm delivery, NICU admission, and perinatal mortality.

In this study, we observed that worsening severity of maternal anemia was associated with significant alterations in fetoplacental Doppler indices and adverse perinatal outcomes. Specifically, the umbilical artery (UA) S/D ratio increased from 2.71 ± 0.35 in mild anemia to 3.52 ± 0.51 in severe anemia, while the MCA PI declined from 1.62 ± 0.22 to 1.18 ± 0.28, and the cerebroplacental ratio (CPR) reduced from 1.18 ± 0.23 to 0.72 ± 0.19. Abnormal waveforms were seen in 25% of severely anemic women compared with none in the mild group. These changes translated into higher risks of low birth weight (45% in severe vs. 15% in mild), NICU admission (36.7% vs. 10.0%), and perinatal mortality (10.0% vs. 1.7%).

Ali et al. (2016) reported that foetuses of mothers with severe anemia demonstrate significant cerebral vasodilatation, with MCA PI reduction indicative of brain-sparing, and that these changes partially reversed after anemia correction [8]. This aligns with our finding of a 27% reduction in MCA PI values in severe anemia, supporting the notion of adaptive cerebrovascular redistribution. Similarly, Sruti (2020) highlighted that abnormal Doppler patterns, including reduced CPR, were predictive of adverse perinatal outcomes in IUGR cases [9]. Although her study focused on growth restriction rather than anemia, the parallels strengthen our interpretation that Doppler alterations signal fetal compromise across high-risk states.

Nayak et al. (2022) found that CPR had superior predictive ability compared to non-stress testing for detecting compromise in hypertensive pregnancies, with abnormal CPR strongly linked to NICU admissions [10]. Our results corroborate this, with NICU admissions rising to 36.7% in severe anemia, strongly associated with CPR <1. Khade et al. (2022) also concluded that CPR was a reliable predictor of perinatal morbidity in high-risk pregnancies, recommending its routine incorporation in surveillance protocols [11]. The consistency across conditions underscores CPR’s robustness as a cross-diagnostic predictor.

Kanmani (2017) and Dhand et al. (2011) further reinforced the diagnostic superiority of MCA and CPR indices over UA parameters alone [12,13]. We observed the same trend—UA S/D ratio increased with anemia severity, but MCA PI and CPR showed stronger correlations with adverse outcomes. For example, low CPR values correlated directly with low birth weight, echoing Vijayalakshmi’s (2014) findings in IUGR pregnancies where CPR <1 was significantly predictive of stillbirths and NICU stays [14].

Contrastingly, some studies have shown variability. Dash et al. (2021), studying premature placental calcification in eastern India, reported that while abnormal Doppler was associated with adverse outcomes, the magnitude of risk was lower compared with our findings [15]. This discrepancy could reflect differences in the underlying pathology—placental calcification versus anemia—or methodological variations in Doppler measurement. Kamath (2020) also noted that in certain high-risk pregnancies, UA indices performed comparably to CPR in predicting compromise [16], whereas in our study CPR appeared consistently superior. These contrasts highlight the importance of contextual interpretation.

Our findings also resonate with those of Shylaja (2009), who demonstrated that Doppler ultrasonography is a sensitive predictor of adverse outcomes in IUGR [17]. In her work, abnormal MCA and UA flow patterns were linked with increased perinatal mortality, findings we replicate here in anemic pregnancies where perinatal mortality rose from 1.7% in mild to 10% in severe anemia.

The biological basis of these findings lies in the reduced oxygen-carrying capacity of anemic maternal blood, leading to uteroplacental hypoxia. Compensatory mechanisms manifest as increased placental resistance and cerebral redistribution, reflected as higher UA S/D ratios and lower MCA PI. However, when these compensations fail—as in severe anemia—fetal compromise becomes evident through abnormal waveforms and poor perinatal outcomes.

The variations in predictive accuracy across studies may also be attributed to regional differences in anemia prevalence, nutritional status, and antenatal care utilization. Methodological variations such as Doppler technique, gestational age at assessment, and outcome definitions can further explain inconsistencies in the literature. Nevertheless, the consistency of MCA and CPR as sensitive markers across diverse high-risk groups—including anemia, IUGR, and hypertensive disorders—strengthens the external validity of our findings.

Strengths and Limitations
The strengths of our study include its relatively large sample size, stratification by anemia severity, and adjustment for confounding factors such as BMI, socioeconomic status, and adherence to iron–folate supplementation. However, limitations include its cross-sectional design, which precludes establishing temporal causation, and the lack of long-term neonatal follow-up.

This study demonstrates that the severity of maternal anemia in the third trimester is strongly associated with progressive alterations in fetoplacental Doppler parameters and worsening perinatal outcomes. Severe anemia was characterized by significantly elevated umbilical artery resistance, reduced MCA pulsatility index, and low cerebroplacental ratio, with 25% of cases showing abnormal waveforms. These hemodynamic changes were accompanied by a three-fold higher risk of low birth weight, over three-fold increase in NICU admissions, and a six-fold rise in perinatal mortality compared with mild anemia.

Even after adjusting for confounders such as maternal BMI, socioeconomic status, antenatal booking, and iron–folate adherence, severe anemia remained an independent predictor of adverse outcomes. This highlights that anemia is not merely a correctable hematologic abnormality but also a marker of placental insufficiency and fetal compromise.

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