Summary of findings
Most women in the CLIP India trial had some form of anemia at the time of antenatal care booking, most commonly moderate and rarely, severe. Almost all women received iron supplementation by the time of delivery, regardless of baseline anemia, and in line with Indian guidelines for routine supplementation. In addition, just under 5% received blood transfusion, which was a greater number than those who experienced antepartum or postpartum bleeding,
Compared with a normal hemoglobin level, each of mild, moderate, and severe anemia more frequently prompted receipt of maternal blood transfusion. Women with mild-moderate anemia had no excess of adverse pregnancy outcomes, including bleeding and sepsis, although women with severe anemia was associated with an increased risk of PPH. The findings were unlikely to be related to unmeasured confounders, particularly for severe anemia. However, we observed a ‘U-shaped’ relationship between anemia severity and pregnancy hypertension, and pre-eclampsia specifically, with women with mild- or moderate anemia having significantly lower rates.
Given the near 100% reported rate of iron supplementation in delivered women in this cohort, these data represent the estimated effect of early pregnancy anemia on outcomes in a population where public health efforts for supplementation in pregnancy have been successful.
Comparison with the literature
The prevalence of anemia in pregnancy in India is amongst the highest in the world. Estimates have varied from a substantial proportion to most women in pregnancy, as in our study. In South India, Vindhya et al. estimated the prevalence of anemia in pregnant women to be 33.9%, with 48.4% of cases being mild, 49.5% moderate, and 2.1% severe(5). Other studies have reported even higher rates of maternal anemia in India, up to 88%, similar to our study(2,5) that demonstrate higher than previously published data from Belgaum and Bagalkote (31).
Major factors contributing to the prevalence of anemia in India are low dietary intake of both iron and folic acid, poor bioavailability of iron (3-4% only) in phytate, and chronic blood loss from infections, such as malaria and hookworm(32). Of note, <1% of our study population had malaria. We did not have data to explore possible dietary mechanisms.
Many studies in India and elsewhere have examined the impact of maternal anemia on perinatal outcomes, such as stillbirth, low birth weight, small for gestational age, and preterm birth (8,9,33–36). Far fewer studies have examined the impact of maternal anemia on maternal outcomes, even by systematic review of LMIC data (6,15). One recent review found a 190% increase in the odds of blood transfusion in anemic women (37), but they did not stratify by severity of anemia, as in our study.
The relationship between anemia and anemia severity on gestational hypertension and pre-eclampsia has been mixed. A large cohort study from India and Pakistan (110,033 anemic women) found a U-shaped relationship in Indian women (RRs = 1.89 95% CI = 1.12 to 3.18) for severe anemia, but ~1.0 for mild/moderate) but not in Pakistani women (RR = 1.18, 95% CI = 0.81 to 1.73 for severe anemia) (15). Another smaller study case-control from Sudan (606 anemic women) found increases in pre-eclampsia severe anemia (OR = 3.6, 95% CI = 1.4 to 9.1) , as well as possible increases with mild or moderate (OR = 1.60, 95% CI = 0.80 to 3.40) (38). In contrast, Jung et al’s review of nine studies found little difference in pre-eclampsia among anemic women (OR = 1.15 95% CI = 0.80 to 1.64); however, they did observe a U-shaped dose-response relationship (37) similar to ours and to the Indian cohort referenced above (15). Mechanisms for the relationship between higher hemoglobin values and pregnancy hypertension may include poor nutrient supply to the placenta due to increased blood thixotropy, and production of reactive oxygen species, together with increased iron (39).
It is clear that iron supplementation can increase hemoglobin values in pregnancy, but effectiveness is challenged by poor adherence, continuous access to iron tablets, use of doses lower than necessary, and oral (vs. parenteral) route of administration (32,40,41). However, even when effective, the impact of anemia treatment on adverse maternal and perinatal outcomes remains uncertain. The most recent Cochrane review found that few studies have assessed the impact of iron supplementation on APH, blood transfusion, sepsis, or pre-eclampsia, and most did not focus on anemia in early pregnancy (18). Our findings suggest that current management strategies for mild and moderate anemia are largely effective in reducing risk to that comparable to women with normal hemoglobin. However, more research is needed to understand the increased risk of hypertensive pregnancy in those with normal hemoglobin, and whether iron supplementation is related.
Strengths and limitations
Our study has several strengths, including our large prospective cohort, standardized collection of blood pressure data using a device validated for use in pregnancy and pre-eclampsia, and detailed documentation of other pregnancy outcomes and possible confounders of the anemia-outcome relationship in a high-quality cluster randomized trial. Also, we report findings in the context of successful public health efforts to provide iron supplementation to all pregnant women in India, where malaria is not endemic.
Our study has some limitations. First, our sample size of severely anemic women was small, and therefore despite the large effect sizes, caution should be taken in the extrapolation of findings related to this group, as they may be subject to sparse data bias. Conversely, just over 11% of women had normal hemoglobin, and few had a hemoglobin above 15g/dL to fully evaluate the U-shaped relationship between anemia and pregnancy hypertension. Second, we lacked data on the exact timing of initiation of iron supplementation and associated adherence; stratification by such information may have provided further nuance to our findings. We found low rates of supplementation in miscarried or MTP pregnancies, which occur (by definition) before 20 weeks. Therefore, it is possible that most women began supplementation after this point. Third, we had no information on the reasons for transfusion, but in all groups, the number of women transfused exceeded those with clinical bleeding. Fourth, this is a secondary analysis of data from a clinical trial with different primary objectives, so we did not measure hemoglobin levels throughout pregnancy, or collect information about potential dietary mechanisms. Although we did adjust for vegetarian diet, there are risks of residual confounding due to unmeasured differences (such as diet and nutrition) between anemic and non-anemic women. Our E-values indicate that such variables would need to have strong effect above and beyond our adjustment to explain away the increased risk for severe anemia. For moderate and mild anemia's relationship with hypertension, E-values were more moderate (1.5-2.0), but still unlikely to explain away the U-shape. Finally, as all participants were prescribed iron supplementation, so we cannot comment on the relative benefits and risks of iron supplementation vs. no supplementation.