Anemia in Pregnancy With CKD

Chronic kidney disease (CKD), anemia, and iron deficiency are global health issues affecting individuals in both high-income and low-income countries. In pregnancy, both CKD and iron deficiency anemia increase the risk of adverse maternal and neonatal outcomes, including increased maternal morbidity and mortality, stillbirth, perinatal death, preterm birth, and low birthweight. However, it is unknown to which extent iron deficiency anemia contributes to adverse outcomes in CKD pregnancy. Furthermore, little is known regarding the prevalence, pathophysiology, and treatment of iron deficiency and anemia in pregnant women with CKD. Therefore, there are many unanswered questions regarding optimal management with oral or i.v. iron and recombinant human erythropoietin (rhEPO) in these women. In this review, we present a short overview of the (patho)physiology of anemia in healthy pregnancy and in people living with CKD. We present an evaluation of the literature on iron deficiency, anemia, and nutritional deficits in pregnant women with CKD; and we evaluate current knowledge gaps. Finally, we propose research priorities regarding anemia in pregnant women with CKD.

2][43] The iron requirements gradually increase during gestation, from an additional daily  35 van Santen et al., 36 and Whittaker et al. 37 with permission.need of 0.8 mg of iron in the first trimester to >6 mg in the third trimester, attributed equally to increased demands of mother and fetus. 29,32During pregnancy, iron is efficiently mobilized from maternal stores, as reflected by the gradual decrease in serum ferritin over the course of the pregnancy (Figure 1); however, many women enter pregnancy with minimal iron stores.Recycling of maternal red blood cell iron serves as a substantial source of iron for the fetus, particularly in women with depleted body iron stores. 44Soluble transferrin receptors (sTfRs) levels, reflecting the mass of erythroid precursors and their iron status, are increased in the third trimester of pregnancy, particularly in women with iron deficiency anemia. 45 present, we know that coordination between erythropoietic activity and iron homeostasis is mainly regulated by 3 hormones, namely EPO, hepcidin, and erythroferrone (ERFE). 3,30,46,47Major alterations occur in these 3 hormones during pregnancy (Figure 2).First, peak EPO concentration is reached during the third trimester but continues to be elevated postpartum. 48econd, maternal hepcidin is known to be decreased in the second and third trimester of the pregnancy by a yet unknown mechanism, although iron deficiency certainly contributes.Hepcidin coordinates iron homeostasis by directly binding to ferroportin, the sole known iron exporter, leading to blocking of iron absorption from the gut and iron release from stores in the reticuloendothelial system. 3,491][52][53] Mouse models show that low maternal hepcidin levels are critical for establishing normal fetal iron endowment. 51Third, ERFE levels mildly increase during pregnancy and are positively associated with EPO and sTfR levels.ERFE is produced by erythroblasts in response to EPO.ERFE decreases hepatic expression of hepcidin and thereby increases circulating iron concentrations. 46,54However, in animal studies of nonanemic pregnancies, ERFE did  Red color: process that worsens anemia; green color: process that diminishes anemia.Created with Biorender.com.
not appear to play a major role in maternal and fetal iron homeostasis. 55Finally, in case of maternal iron deficiency anemia, the common homeostatic regulatory mechanisms of iron uptake and transfer to the fetus are engaged and possibly regulated more by fetal than by maternal iron demands. 56Maternal and fetal hepcidin both decrease further with iron deficiency anemia to promote iron availability and transfer to the fetus.Interestingly, placenta senses its own iron levels via the iron-regulatory protein 1 and, in conditions of severe iron deficiency, modulates its iron transporters to acquire and retain iron, maintaining its own iron homeostasis. 57,58

Definitions and Treatment of Anemia and Iron Deficiency During Pregnancy
6][67][68] This is further confounded by a considerable interpersonal variation in the degree of plasma volume expansion. 31,59,60,65,66,69n fact, the lack of anemia caused by the absence of hemodilution has been found to be prognosticator of worse outcomes, 65 implying that physiological anemia due to hemodilution should be regarded as beneficial. 70,71However, anemia due to other causes, e.g., iron deficiency, is considered detrimental and warrants treatment.][61] Anemia and iron deficiency during pregnancy are generally managed by oral or i.v.iron.3][74] I.V. iron should be used from the second trimester onward up to postpartum, in case of intolerance or nonresponsiveness to oral iron, or when there is a clinical need for rapid and efficient anemia treatment. 75,76Treatment with rhEPO is mainly used when anemic women during or after pregnancy decline blood transfusion. 77emia in CKD Anemia in CKD has a multifactorial cause, including a relative EPO deficiency, iron deficiency, uremicinduced inhibitors of erythropoiesis, and shortened red blood cell lifespan.3 Iron deficiency can be absolute or functional.Absolute iron deficiency implies a deficit of total body iron, whereas functional implies a deficiency of circulating iron that limits erythropoiesis despite normal or elevated body iron stores.3 The latter is mainly caused by increased levels of hepcidin, inflammatory cytokines, and, if applicable, use of erythropoiesis stimulating agents.3,78 Hepcidin excess, often present in CKD due to the reduced renal clearance and up-regulation of hepcidin by proinflammatory cytokines, leads to impaired iron absorption from the gut and reduced iron mobilization from stores.Anemia and iron deficiency in CKD are generally defined according to the definitions used in Table 3, although these cutoffs have come under scrutiny and discussion.
2][83] Controversy also exists regarding how to manage iron metabolism in CKD and therefore management and guidelines among countries have differences (Table 4). 78Data on clinical benefits of iron administration in CKD beyond stimulating erythropoiesis are limited and rarely assessing hard patient outcomes. 3,78,84Nevertheless, i.v.iron formulations have been found to be superior to oral iron in raising Hb levels, and delaying or reducing the need for other anemia management, including need for erythropoiesis stimulating agent therapy. 85,86egarding these outcomes, the FIND-CKD study has established in the nondialysis CKD population that i.v.iron (ferric carboxymaltose) dosed to a target ferritin of 400 to 600 mg/l was superior to i.v.iron dosed to a target ferritin of 100 to 200 mg/l or oral iron. 84In a dialysis-dependent CKD population, the PIVOTAL study showed that proactive i.v.iron (iron sucrose) administration (unless serum ferritin >700 mg/l or TSAT >40%) was superior to a reactive strategy (triggered only for TSAT <20% and ferritin <200 mg/l) with respect to a lower risk of death or major cardiovascular event, lower dose of erythropoiesis stimulating agents needed, and a lower incidence of blood transfusions; whereas no difference was found for incidence of infections or hospitalizations. 87Finally, in patients with CKD, blood transfusions are generally avoided to minimize the general risks related to its use, especially in patients eligible for organ transplantation due to induction of HLA antibody. 88emia in Pregnancy and CKD Anemia is common in pregnancy and in CKD and, therefore, likely to be prevalent when the 2 conditions coexist.

Definitions of Anemia and Iron Deficiency in Pregnant Women With CKD
Definitions of anemia and iron deficiency for the specific population of pregnant women with CKD are lacking.Definitions for healthy pregnancy or nonpregnant CKD might not be valid because pregnancy in CKD is probably characterized by a different pathophysiology (see also next paragraph).Indeed, to date, no studies have been performed to identify optimal target values of Hb and iron parameters in pregnant women with CKD relating to outcomes, 33 and these are likely to be challenging due to population heterogeneity and prescribing practice.However, guidelines on pregnancy and CKD give advice about target levels for Hb and iron parameters although they report that sensitivity and specificity of these   parameters are unknown in this patient setting (Table 2). 61,620][91][92] Regarding definitions for different CKD stages, the Dutch guideline is the only guideline presenting advice on different definitions across CKD stages 1 to 2, 3 to 5 nondialysis, and dialysis.It is important to note that there is no evidence-based rationale for these treatment target levels because of a lack of research on cutoffs relating to outcomes.For example, in the Dutch guideline on CKD and Pregnancy the target values were based on frequency of anemia in the specific CKD stages compared with the general population. 61To further complicate the field of definitions derived from the general and CKD populations, it can be argued that definitions in pregnant women with CKD should not only differ among CKD stages, but also among trimesters of pregnancy.[95] Pathophysiology of Anemia in Pregnant Women With CKD In Figure 2, we summarize the presumed pathophysiology of anemia in pregnant women with CKD.The pathophysiology of anemia in this specific population of pregnant women with CKD has not been investigated, but it is multifactorial and can at least partly be described as extrapolated from the pathophysiology of anemia in healthy pregnancy and in CKD.For example, apart from representing high iron stores, ferritin is an acute-phase reactant whose levels increase in response to inflammation. 96,97Adjustment of serum ferritin for inflammation has not been validated in pregnant women. 97,98Moreover, pregnancy itself might be associated with a physiological rise in acute-phase proteins (C-reactive protein, alfa-1-antichymotrypsin) and increased iron utilization, both of which influence serum ferritin levels in an opposing manner. 99Finally, iron deficiency during pregnancy could also be identified by increased sTfR concentrations; however, these are not routinely assessed in clinical settings yet.Notably, neither trajectories of routinely tested variables (Hb, ferritin, TSAT, iron concentrations, and inflammatory parameters) nor variables used in research (hepcidin and sTfR) have been investigated in pregnant patients with CKD.Therefore, in Figure 2, we show which regulatory mechanisms are opposite in the pathophysiology of anemia in healthy pregnancy compared with anemia in nonpregnant CKD.2][43] Furthermore, women with CKD are commonly prescribed aspirin in pregnancy for reducing the risk of preeclampsia. 100,101However, the potential impact of aspirin on gastrointestinal blood loss and subsequently worsening of iron deficiency has not been explored in this patient setting.In addition, the functional iron deficiency associated with CKD could contribute to the anemia in pregnant women with CKD.
Of the 3 important regulators of erythropoietic activity and iron homeostasis, it has been shown that pregnant women with CKD are not able to appropriately increase EPO levels, which in healthy pregnancy doubles between the first trimester and the end of the third trimester. 35,77,91,102or example, a case series of 5 pregnant women with CKD demonstrated an absence of EPO response to anemia. 103Until now, ERFE levels have not been investigated in pregnant women with CKD, but most likely will be decreased because ERFE production is stimulated by EPO.Finally, regarding hepcidin, it can be hypothesized that hepcidin may be relatively suppressed in pregnant women with CKD similarly to healthy pregnant women, but also that the inflammation in CKD may prevent adequate suppression of hepcidin, and thereby leads to disturbed iron uptake and mobilization. 51The latter is supported by several animal and human studies.For example, when inflammation was mimicked by administration of a hepcidin agonist in an animal study with pregnant mice, 51 high doses of hepcidin agonist caused severe hypoferremia and anemia in both the mothers and embryo; whereas low doses of hepcidin agonist did not cause maternal anemia, but still adversely affected the embryo, causing anemia and tissue iron deficiency.Interestingly, increased levels of maternal hepcidin also caused adverse effects on embryo outcomes, including decreased placenta weight and birthweight, as seen in pregnant women with higher CKD stages. 10,102,104In a human cohort of pregnant women affected by inflammation and nutrient deficiencies, increased hepcidin levels were associated with a greater odds ratio of intrauterine growth restriction. 1057][108] All together, these findings underscore the necessity to evaluate the effect of CKD on the course of hepcidin levels during pregnancy, maternal iron restriction and also on the offspring outcomes (Table 5).

Nutritional Deficiencies Related to Iron Deficiency and Anemia in Pregnant Women With CKD
Considering that macronutrient and micronutrient requirements are increased during pregnancy, pregnant women are at a high risk of developing (multiple) micronutrient deficiencies such as deficiencies in iron, folic acid (vitamin B9), and vitamin B12, among others; also partly because of suboptimal diet quality, and sometimes even despite use of supplements. 105,109owever, adaptation of diet can help target certain deficiencies. 109For example, folic acid intake can be increased from a minimum of 4 weeks before conception in supplements but also by dietary fortification, also to reduce the risks for neural tube defects. 1102][113][114][115] In particular, pregnancy is a well-known physiological cause of hyperfiltration in which CKD is associated with an increase in proteinuria, but this increase could be diminished by diet. 112,116The Italian Study Group on Kidney and Pregnancy has performed the largest study on a plant-based, moderately protein-restricted diet in pregnant women with CKD to counterbalance this proteinuria. 112These 52 pregnant women with CKD receiving an intervention diet were compared with a propensity-score-matched cohort of CKD pregnancies on unrestricted diets.The goal was to control protein intake to 0.8 g/kg/d, with over 80% coming from plant-derived sources.Women in the control group had a significant increase in proteinuria during pregnancy, while the intervention group did not. 1128][119][120] Some, therefore, do not recommend a low-protein diet. 33[123]

Treatment of Anemia and Iron Deficiency in Pregnant Women With CKD and Research Opportunities
At present, there is a paucity on clinical studies regarding anemia and iron deficiency in pregnant women with CKD.The lack of clinical studies is partly because of the relatively low frequency of pregnancy in women with CKD, particularly in the advanced stages.The heterogeneity of underlying diseases may further complicate the design of clinical studies or analysis of data.In Table 5, we provide research priorities following from the knowledge gaps outlined above and in this paragraph.2,[124][125][126] These treatment approaches are summarized in a proposed flowchart (Figure 3).Table 5. Research priorities for the management of anemia in pregnant women with CKD Etiology and diagnosis of iron deficiency and anemia in pregnant women with CKD 1. Describe the variability in Hb and iron parameters in pregnant women with CKD by levels of eGFR, kidney transplantation, and kidney disease to increase understanding of the range of iron and Hb levels.
2. Increase knowledge on pathophysiology by conducting studies investigating Hb, iron parameters, sTFR, EPO, hepcidin, ERFE and IL-6 levels in pregnant women with and without CKD, and associate these to maternal and fetal outcomes.
3. Investigate cutoff levels for and changes in iron parameters and Hb during pregnancy associated with maternal and fetal outcomes and necessitating treatment.
Treatment of iron deficiency and anemia in pregnant women with CKD 4. Investigate the effectiveness of different dosing schedules with oral and i.v.iron formulations in all stages of CKD.
5. Collect international data regarding the safety and effectiveness of rhEPO in pregnancy.
6. Conduct a longitudinal cohort study of women with a range of CKD severity and pathology including postpartum relating RBC parameters, ERFE and sTfR to treatment with iron and/or rhEPO to maternal and fetal outcomes including anemia at birth in the offspring.
7. Conduct a trial using stable iron isotopes to gain insight in placental transfer of iron in pregnant women with CKD.
8. Investigate how maternal iron treatments impact the iron stores of the offspring at birth and the relation with bone metabolism.

Consider starting iron with mild ID
In second/third trimester, switch to target levels with oral agents.
In case of i.v.iron: prescribe modern, stable iron supplements.
Consider transfusions in women on dialysis if Hb <9.7 g/dl and not expected to correct with iron/rhEPO.
Consider the risk of allosensitization.
German guideline 64 Treat with oral iron up to Hb <10.Review 2020 125 Iron sucrose is considered safe in pregnancy and lactation x ESAs considered safe in pregnancy and lactation x In case of a low Hb, it is suggested to also check and supplement folic acid and vitamin B12 in CKD in general as well as in dialysis. 61,63,90Because a ferritin level <30 mg/l implies absolute iron deficiency also with concomitant CKD, and TSAT <20% has been validated as a good marker for functional iron deficiency in patients with chronic diseases, 3,127 it seems reasonable to assume that pregnant women with CKD and anemia should be treated with iron when the ferritin level is <30 mg/l or when TSAT level is <20%, or even with mild iron deficiency, because of the increased iron need during pregnancy. 61,63No clear evidence exists regarding the optimum maintenance ferritin and TSAT levels with iron therapy, also not within the pregnancy field or the anemia in CKD field.In the latter, only the PIVOTAL study clearly showed that ferritin <700 mg/l or TSAT <40% can be safely used as upper limits for iron therapy.However, the optimal treatment targets of ferritin and TSAT in terms of safety, erythropoiesis stimulating agent dose reduction, and patient outcomes will need to be delineated in detail in the future, also for pregnant women with CKD.2][63][64] When target levels are not reached with oral formulations, it is recommended to start i.v.iron formulations but only in the second and third trimester, although there is no evidence of teratogenicity or fetotoxicity if i.v.3][64]102 Frequent checks of Hb and iron parameters are recommended. 91egarding treatment with EPO, animal studies with monkeys and sheep in late gestation and in ex vivo human placenta perfusion experiments showed that rhEPO did not pass the placenta. 128,1290][131][132][133] However, treatment with rhEPO may lead to (worsening of) maternal hypertension because of indirect vasoconstrictive effects. 134Incidence of hypertension and preeclampsia caused by rhEPO is reported to be low; however, the risk might be increased when blood viscosity or hematocrit increases; e.g., >5% in 4 weeks or becoming higher than 30% to 35%, as extrapolated from hemodialysis patients treated with rhEPO. 48,135Furthermore, all guidelines and reports recommend increasing the rhEPO dose between 50% to maximum 100% compared with preconception, because women with more advanced stages of CKD may have insufficient capacity for the gestational increase in EPO levels, 6,33,63,77,91,102 and that rhEPO should be titrated every 2 to 3 weeks by Hb. 48,92 Finally, regarding the role of blood transfusion in pregnant women with CKD, the goal in all potential candidates for future (kidney) transplantation and all kidney transplant recipients is to avoid blood transfusions because of the risk of allosensitization. 136uidelines recommend delaying blood transfusion perioperatively until Hb <7.3 g/dl, or until 8.0 g/dl if the pregnant woman is cardiopulmonary compromised or has possible occult coronary disease. 61ture Perspectives Many questions on the mechanisms and optimal management of anemia and iron deficiency have not been answered for pregnant women with CKD.Pregnancy in women with CKD is becoming more frequent. 33,126onsequently, unraveling the pathophysiology of anemia in pregnant women with CKD is necessary, and could lead to improved treatment opportunities in these women and enhanced maternal and neonatal outcomes; therefore, we recommend prioritizing research in this topic.
KB has received consultant fees from AstraZeneca, GSK, Vertex, and Bayer.
MFE has declared receiving consultant fees from Vifor Pharma and Cablon Medical; serving on the Advisory Board for Cablon Medical and GlaxoSmithKline; and receiving speaker fees from Vifor Pharma, Pharmacosmos, and Astellas (all to employer).All the authors declared no competing interests.

Figure 1 .
Figure 1.Course of iron and red blood cell parameters during healthy pregnancy.Reproduced from reference McMullin et al., 35 van Santen et al., 36 and Whittaker et al. 37 with permission.

Figure 2 .
Figure 2. Simplified pathophysiology of iron deficiency anemia in healthy pregnancy, in CKD, and in pregnant women with CKD.CKD, chronic kidney disease; EPO, erythropoietin; ERFE, erythroferrone; IDA, iron deficiency anemia; RBC, red blood cell.Red color: process that worsens anemia; green color: process that diminishes anemia.Created with Biorender.com.

Figure 3 .
Figure 3. Proposed flow-chart for work-up and treatment of anemia during Pregnancy in CKD.CKD, chronic kidney disease.

Table 1 .
30on balance in pregnancy Adapted from reference Fisher et al.30with permission.

Table 3 .
Definitions used for anemia and iron deficiency in CKD CHr, reticulocyte hemoglobin content; CKD, chronic kidney disease; DD-CKD: dialysis-dependent chronic kidney disease; ERBP, European Renal Best Practices; ESA, erythropoietin stimulating agent; F, female; Fe, ferritin; Hb, hemoglobin; HRC, hypochromic red blood cells; ID, iron deficiency; KDIGO, Kidney Disease Improving Global Outcomes; M, male; ND-CKD, nondialysis chronic kidney disease; NICE, National Institute for Health and Care Excellence; T, trimester; TSAT, transferrin saturation; UK, United Kingdom; US, United States of America; WHO, World Health Organization.

Table 4 .
Treatment targets of anemia in CKD according to the different current CKD guidelines Hb target during ESA treatment <11.5 g/dl >11.5 g/dl for more QoL.Avoid >13 g/dl 10-12 g/dl 10-12 g/dl Start of iron therapy If Hb increase/ESA dose reduction is desired and ferritin #500 mg/l and TSAT #30% When ID is present as defined in Table 3 Ferritin <100 g/dl and TSAT <20% Ferritin and TSAT targets Does not recommend routine use of iron if ferritin >500 mg/l or TSAT >30% Avoid SF >500 ng/ml and TSAT >30%.Avoid SF >800 mg/l Review iron dose when ferritin >500 mg/l CKD, chronic kidney disease; ERBP, European Renal Best Practice; ESA, erythropoietin stimulating agent; Hb, hemoglobin; ID, iron deficiency; KDIGO, Kidney Disease Improving Global Outcomes; NICE, National Institute for Health and Care Excellence; QoL, quality of life; SF, serum ferritin; TSAT, transferrin saturation.

Table 6 .
Suggested treatment approaches from reviews and guidelines on anemia and iron deficiency in pregnant women with CKD