Anaemia in chronic kidney disease pregnancy

Abstract

Aim

To review the incidence and management of anaemia and outcomes in pregnancies in a cohort of Australian women with chronic kidney disease.

Methods

A retrospective audit of 63 pregnancies in 52 women with chronic kidney disease.

Results

Sixty-eight percent of chronic kidney disease pregnancies were complicated by haemoglobin less than 100 g/L. Iron stores were measured in only 62% of all pregnancies. Serum ferritin was less than 100 ng/ml in 95% of those tested. Erythropoietin-stimulating agents were used in 24 pregnancies (38%). Intravenous iron was used in only nine non-dialysis pregnancies.

Conclusion

Greater awareness of the importance of regular measurement of iron stores and appropriate levels for repletion in chronic kidney disease pregnancies amongst health professionals involved in obstetric care may result in earlier detection and treatment of iron deficiency, and potentially improve maternal and fetal outcomes.

Keywords

Anaemia chronic kidney disease

Introduction

It is estimated that 1:150 women of childbearing age have stage 3–5 chronic kidney disease (CKD), though reduced fertility and an increased rate of early miscarriage results in lower fertility rates in this group.¹ The World Health Organisation (WHO) defines anaemia in pregnancy as a haemoglobin (Hb) less than 110 g/L in first and third trimesters, though it is recognised that Hb concentrations fall by approximately 5 g/L in second trimester.² The lower limit of normal for Hb concentration however may vary in different populations. The Kidney Health Australia – Caring for Australasians with Renal Impairment and National Institute for Health and Care Excellence guidelines for non-pregnant adults with CKD recommend a target Hb of 100–115 g/L and 100–120 g/L respectively.^3,4 The ideal level for Hb in CKD pregnancy is not known.^3,5 Between 1990 and 2016, the prevalence of anaemia complicating all pregnancies in Australia fell from 29.4% to 20.1%; however, maternal anaemia has been found in up to half of pregnant Aboriginal and Torres Strait Islander women in Far North Queensland and the Remote Northern Territory.^6,7 A recent Australian study reported that 47% of CKD pregnancies were complicated by anaemia, although the level of Hb defining anaemia was not stated.⁸ In non-pregnant CKD individuals, iron replacement is indicated with serum ferritin less than 100 ug/L and/or transferrin saturation less than 20%.⁹ Guidelines regarding the levels of ferritin indicating the need for iron replacement in healthy pregnancy vary widely: less than15 ug/L (WHO), less than 30 ug/L (United Kingdom) and less than 70 ug/L (Denmark).¹⁰ It is recommended that erythropoiesis stimulating agents (ESA) should not be initiated until iron deficiency is corrected.¹¹

Maternal anaemia in pregnancy is associated with increased rates of preterm birth, low birthweight, placental abruption, preeclampsia (PET) and postpartum haemorrhage.^12–18 Hb less than 70 g/L is associated with increased risk of maternal death (aOR: 2.36).¹⁹ Additional maternal effects with anaemia in pregnancy include increased susceptibility to infection, increased likelihood of blood transfusion and greater risk of postpartum depression.¹⁶ Adverse fetal outcomes of maternal anaemia include delayed growth and development, impaired psychomotor and mental development, increased risk of cognitive and behaviour abnormalities and increased perinatal and neonatal mortality.^20,21 Iron deficiency anaemia in late pregnancy is associated with abnormal neonatal auditory maturation.²² Systematic reviews of oral and intravenous iron (FeI) therapy for iron deficiency anaemia demonstrate improvement in haematological parameters though no improvement in clinically relevant outcomes.²³

The objective of this study was to review the incidence and management of anaemia, and outcomes in pregnancies in a cohort of Australian women with CKD.

Methods

This was a retrospective cohort study of women with CKD birthing at the Mater Mother’s Hospital, a tertiary referral obstetric hospital, in Brisbane, Australia between 1 January 2003 and 31 December 2017. Ethical, governance and privacy approvals were obtained from the institution’s human research ethics committee and governance office respectively (HREC/MHS/18/46).

Definitions

CKD was defined as a first trimester serum creatinine (SCr) greater than 89 µmol/L. A recent systematic review described a SCr of greater than 76 µmol/L as being the upper limit of normal for first trimester of pregnancy.²⁴ For the purposes of the audit, anaemia was defined as a Hb less than 100 g/L, and moderate anaemia as Hb less than 80 g/L. Pregnancies complicated by CKD were identified through interrogation of the hospital pathology database. Due to the tertiary referral nature of the service, and the 15-year duration of the audit, it was not possible to obtain preconception values in some cases, thus for uniformity, first trimester values of SCr were used. Estimated glomerular filtration rate was derived using the Modification of Diet in Renal Disease equation, and CKD stage defined using the current KDOQI guidelines.²⁵ Deterioration in renal function was defined by a rise in SCr more than 25% above the first trimester level.¹ Fetal growth restriction (FGR) was defined as birth weight below the 10th percentile for gestational age and abdominal circumference below the 2.5th percentile. The diagnosis of superimposed PET in women with CKD may be difficult, particularly in women with preconception hypertension and/or proteinuria. For the purposes of the audit, superimposed PET was diagnosed in the following scenarios:²⁶

In women who were normotensive and non-proteinuric where new hypertension, proteinuria or maternal organ dysfunction occurred after 20 weeks of gestation.

In normotensive women with proteinuric CKD where new hypertension or maternal organ dysfunction occurred after 20 weeks of gestation.

If maternal organ dysfunction occurred after 20 weeks of gestation in women with chronic hypertension and proteinuria.

Details of pregnancy management were obtained from the paper and electronic patient records. In broad terms, women with CKD underwent obstetrician/midwifery and obstetric physician review every four weeks, and Hb, SCr and urine protein:creatinine ratio were routinely measured at each appointment. All women with anaemia during pregnancy were prescribed oral supplementation with a preparation containing 105 mg of elemental iron and 500 mg of vitamin C. Measurement of iron studies, and prescription of intravenous iron and – ESA did not follow a protocol, but occurred at the discretion of the treating obstetric physician or nephrologist.

Statistical analysis

As this was an audit, there were no pregnancies without CKD with which to compare. There were missing data in four pregnancies leaving 59 for statistical analysis. There were small numbers in CKD stage 4/5. Much of the data were in categorical form usually ordered. The gestation at delivery was not normally distributed. With these limitations, a test for trends in proportions of anaemia with levels of CKD was performed, and since both variables were in ordered categories, Kendall’s rank correlation was also used. Wilcoxon and Kruskal–Wallis rank tests were otherwise employed. Multiple regression involving birthweight and gestation at birth, anaemia severity and CKD levels as explanatory variables was attempted, but the small sample size and the distribution of the residuals made it suspect. In addition, there were only seven pregnancies where Hb was less than 80 g/L.

Results

Sixty-three pregnancies to 52 women with CKD were identified over the 15-year study, during which time there were 64,740 pregnancies in total. The incidence of CKD was 1 in 1000 pregnancies. Hb less than 100 g/L and 80 g/L occurred in 68% and 11% of pregnancies respectively. Thirty-one women (49%) were nulliparous. The mean age of the study cohort was 30 years (range 18–41). The major underlying renal pathologies were post-solid organ transplantation (16), reflux nephropathy (10), diabetes mellitus (7), autosomal dominant polycystic kidney disease (6), lupus nephritis (4), other glomerulonephritis (7), post-nephrectomy (4), IgA nephropathy (3) and focal segmental glomerulosclerosis (2). In 33 pregnancies (52%), proteinuria was present pre-conception, and in 42 pregnancies (67%), antihypertensive medication was required pre-conception. With respect to severity of renal dysfunction, 15 pregnancies (24%) were CKD stage 2, 39 pregnancies (62%) were CKD 3 and 9 were stage 4/5 (14%). In five pregnancies (8%), women were receiving dialysis prior to conception. An additional four pregnancies required the commencement of dialysis during pregnancy. The incidence and severity of anaemia, pregnancy complications and outcomes are summarised in Table 1. There was one elective termination of pregnancy because of deteriorating maternal renal function, and one neonatal death related to prematurity in a woman with chorioamnionitis. Twenty-nine pregnancies (50%) were complicated by a greater than 25% rise in SCr from first trimester. PET was diagnosed in 25% of pregnancies overall. Surprisingly only one of the pregnancies in the stage 4/5 CKD group was complicated by PET. As above, one pregnancy in the CKD stage 4/5 group was terminated, and one neonatal death occurred at 23 of weeks gestation due to chorioamnionitis. Five additional deliveries in the CKD 4/5 group occurred prior to 38 weeks of gestation – three because of antepartum haemorrhage due to placental abruption, and two because of deterioration in renal function. None of these five pregnancies fulfilled clinical criteria for superimposed PET and there were no features of PET on placenta histology. Soluble fms-like tyrosine kinase 1:placental growth factor ratios were not available.

Table 1.

Summary of outcomes.

CKD stage	n	BP	Prepregnancy proteinuria	ESA	Mean gestation delivery (wks)	Mean bthWt (g)	FGR	PET	Rise Cr >25%	DialysisPre/started during pregnancy
All	63	42 (67%)	33 (52%)	24 (38%)	34.6	2236	29 (46%)	15 (25%)	32 (51%)	5/4
Hb <100 g/L	43	30	23		34.9	2248	19	10	21	5/4
Hb <80 g/L	7	4	2		31	1515	2	1	2/4	3/1
No anaemia	20	12	10		34.2	2254	10	5	11
Stage 2	15	11 (73%)	9 (60%)	5 (33%)	33.9	2226	5 (33%)	6 (40%)	9 (60%)	0
Hb <100 g/L	9	7	4		34.4	2605	2	4	5
No anaemia	6	4	5		32.2	1809	3	2	4
Stage 3	39	24 (62%)	20 (51%)	12 (31%)	35.4	2360	19 (49%)	8 (20%)	19 (49%)	0/2
Hb <100 g/L	28	18	17		35.6	2285	14	5	14	0/2
No anaemia	11	6	3		35	2558	5	3	5	0
Stage 4/5	9	7 (78%)	4 (44%)	7 (78%)	32.5	1799	5 (56%)	1 (8%)	4 (100%)^a	5/2
Hb <100 g/L	6	5	2		31.8	1599	3	1	2	5/2
No anaemia	3	2	2		35.6	2134	2	0	2	0

CKD: chronic kidney disease; BP: prepregnancy hypertension; FGR: fetal growth restriction; PET: preeclampsia; ESA: erythropoiesis stimulating agent.

^aNon-dialysis patients.

Results for serum ferritin levels were available for only 39 pregnancies (62%). In 37/39 (95%), the nadir serum ferritin was less than 100 ng/mL. In the absence of FeI, the serum ferritin fell progressively during pregnancy from a mean of 122 ng/ml in first trimester to 35 ng/ml and 29 ng/ml in second and third trimester respectively.

The prescription of oral iron to anaemic women resulted in a Hb greater than 100 g/L in 9 of 30 (30%) pregnancies following a mean of 12 weeks therapy (range 6–22 weeks). FeI was administered in only nine non-dialysis pregnancies, all in third trimester, at a mean gestation of 28 weeks. Six of these were after 2014 when iron carboxymaltose (FCM) became available. FeI without ESA was associated with a mean rise in Hb from 86 g/L to 116 g/L over a mean of five weeks.

ESA were used in 24 pregnancies (38%). Five of the women with stage 2 CKD, and 12 of the women with stage 3 CKD received ESA. ESA were commenced during 15 pregnancies: once in first trimester, on 10 occasions in second trimester and four in third trimester. Thirteen of these women were treated with darbopoietin alfa, and two with erythropoietin alfa. Serum erythropoietin (EPO) was measured in second trimester in three stage 3 CKD pregnancies complicated by anaemia, with a mean value of 11 mIU/ml (range: 8–14; non-pregnant reference range: 4–32). ESA and FeI were commenced/given contemporaneously in five non-dialysis pregnancies. Mean increment in Hb with simultaneous ESA and FeI was from 84 to 109 g/L, and from 81 to 105 g/L with ESA alone. Sixteen of the 18 (89%) non-dialysis pregnancies where FeI and/or ESA were used had resolution of anaemia. There were no complications observed with ESA or FeI.

Maternal Hb less than 100 g/L was associated with earlier gestation at delivery (Kruskal–Wallis rank sum test p-value = 0.03). No association was demonstrated between maternal Hb less than 100 g/L and PET (Fisher test p-value = 0.7) or maternal Hb <100 g/L and FGR (Fisher test p-value = 0.47).

More severe CKD stage was associated with earlier gestation at delivery (Kruskal–Wallis rank sum test p-value = 0.03). There was no evidence of an association or a trend in the PET proportion among the levels of CKD (Fisher test p-value = 0.41; Chi-squared test for trend in proportions p-value = 0.17). No association was demonstrated between CKD stage and Hb < 100 g/L (Chi-squared test for trend in proportions p-value = 0.6), CKD stage and birthweight (Kruskal–Wallis rank sum test p-value = 0.44) or CKD stage and FGR (Fisher test p-value = 0.83; Chi-squared test for trend in proportions p-value = 0.4). As expected, birthweight and gestation at birth were highly correlated (Kendall’s rank correlation tau = 0.54, p-value <0.001).

Discussion

In this study, approximately two-thirds of CKD pregnancies developed maternal Hb of less than100 g/L, and Hb was less than 80 g/L in one in nine women. Maternal Hb less than 100 g/L was associated with pre-term birth and low birthweight. Reasons for the lack of an expected association between CKD stage and anaemia, birthweight, PET and FGR might include absence of non-CKD women in the audit, the small numbers in some of the CKD and anaemia categories, a non-normal data distribution and an overall small number of pregnancies. Iron studies were performed in only 62% of women, almost all of which demonstrated low iron stores. The prescription of oral iron resulted in resolution of anaemia in only 30% of anaemic women. FeI and/or ESA resulted in resolution of anaemia in almost all non-dialysis pregnancies. Our cohort was remarkable for the low rate of prescription of FeI, and its use only late in pregnancy in non-dialysis women, despite the high incidence of anaemia and iron deficiency. One possible explanation for the low rates of assessment of iron stores and use of FeI may have been that the primary medical care of pregnant women with CKD was by midwives and obstetricians, who may not have had an appreciation for the altered targets for iron stores in women with CKD. Second, there may have been some reluctance for the prescription of FeI because of the risk of anaphylaxis with older parenteral iron preparations prior to the availability of FCM in 2014. The number of individuals in Australia prescribed parenteral iron increased from 44,000 in the year prior to FCM availability to 87,000 in the following year.²⁷

A meta-analysis revealed pregnant women with anaemia are 2.7 times more likely to achieve their target Hb with FeI than oral iron, and to do so more rapidly and with less risk of adverse effects.²⁸ Non-adherence rates of prescribed oral supplements in pregnancy have been reported to be 27–46%.²⁰ Systematic reviews of oral and intravenous iron therapy for iron deficiency anaemia in pregnancy demonstrated significant improvement in haematologic parameters though no improvement in clinically relevant outcomes.^23,29 Recent retrospective observational Australian studies reported administration of FeI to healthy women at a mean gestation of 34.6 weeks.^30,31 FeI is usually avoided in first trimester because of absence of data regarding teratogenicity.³² Twenty-five cases of intravenous iron administration in healthy women in first trimester have been described without adverse pregnancy outcomes.^33,34 Several thousand pregnancies have been reported in women receiving chronic haemodialysis, with the fetal malformation rate being the same as in the general population.^35,36

EPO levels rise approximately 2–4 fold in early first trimester in healthy pregnancy in order to increase red cell mass in response to the physiological 40% increase in plasma volume.^37,38 In non-pregnant individuals with normal renal function, EPO production increases exponentially in response to anaemia. The EPO response to anaemia, however, is blunted in CKD. In non-pregnant individuals with CKD, a significant linear inverse correlation between EPO and anaemia was demonstrated above a Cr clearance of 40 mls/min, below which no correlation was seen.³⁹ Another study in healthy non-pregnant individuals demonstrated a strong correlation between severity of anaemia and increase in EPO. Increasing stages of CKD were associated with a gradual attenuation of the EPO response to anaemia, with a complete absence of EPO response to anaemia with CKD 4 and 5.⁴⁰ In this audit, three women with stage 3 CKD failed to increase EPO production in pregnancy in response to anaemia, suggesting ESA may be of benefit in some women with relatively mild CKD and anaemia in pregnancy.

Intravenous iron should be administered with ESA. Deficient iron stores may result in reduced responsive to ESA, and parenteral iron supplementation may result in a reduction in ESA dose.^41,42 ESA therapy results in rapid depletion of iron stores due to increased erythropoiesis. A study of 24 healthy iron replete men treated with three regimens of subcutaneous recombinant human EPO together with 300 mg of oral elemental iron daily found a 74% fall in mean ferritin and 25% fall in transferrin saturation levels over a 16-day period.⁴³ Studies of anaemic iron replete women with malignancy have shown the addition of intravenous iron to EPO results in a greater Hb response and reduced EPO dose compared with women treated with EPO alone.^44,45

In women receiving haemodialysis, doses of ESA may need to be increased by 50–100% during pregnancy.⁴⁶ A requirement for higher doses of EPO in woman receiving dialysis may be the first indicator of pregnancy.⁴⁷ The safe use of ESA in pregnancy was first described in 1991.⁴⁸ Concerns regarding ESA precipitating or aggravating hypertensive disorders of pregnancy including PET have proven unfounded. Only four cases where ESA were suspected to be a factor in hypertensive disorders of pregnancy have been reported, despite women with CKD having a 25–50% risk of developing PET.^49–52 Due to their large molecular size, ESA do not cross the placenta.

Limitations

The study was retrospective and may not have identified all women with CKD, or treatments that were received at other hospitals. There was no control group. In several women, care was transferred from other centres during pregnancy and complete data may not have been collected as a result. The calculation of estimated Glomerular Filtration Rate (eGFR) and CKD stage from first trimester SCr is not valid and may underestimate non-pregnant CKD stage. The small sample size precluded extensive examination of risk factors contributing to adverse outcomes. There were too few women with PET to demonstrate an association or lack thereof with Hb less than 100 g/L, low birthweight or earlier gestation at delivery.

Conclusion

Education of midwives, obstetricians and obstetric physicians regarding the need for regular monitoring of iron stores (e.g. monthly) and appropriate targets for intervention during CKD pregnancy may be useful in enabling earlier identification and treatment of iron deficiency. Examination as to whether earlier intervention may improve pregnancy and neonatal outcomes would be valuable. Studies examining the use of parenteral iron in CKD women in first trimester and fetal outcome may provide evidence regarding the safety of low dose FeI early in pregnancy. ESA may be safely used in pregnancy, and a significant proportion of women with mild renal dysfunction may benefit from ESA during pregnancy.

Footnotes

Contributorship

Adam Morton conceived the study, evaluated the data, performed the literature review and wrote the first draft of the manuscript; Michael Burke revised the article and approved the version to be published; Anthony Morton performed the statistical analysis, revised the article and approved the version to be published; and Sailesh Kumar revised the article and approved the version to be published.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval

Ethical, governance and privacy approvals were obtained from the institution’s human research ethics committee and governance office respectively (HREC/MHS/18/46). Informed consent was waived by the institutional review board.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Guarantor

AM is the guarantor of the present work.

ORCID iD

Adam Morton

References

Williams

Davison

Chronic kidney disease in pregnancy. BMJ 2008; 336: 211–215.

WHO. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System, www.who.int/vmnis/indicators/haemoglobin.pdf (2011, accessed 2 August 2020).

Macginley

Walker

RG.

International treatment guidelines for anaemia in chronic kidney disease – what has changed?

Med J Aust 2013; 199: 84–85.

Ratcliffe

Thomas

Glen

, et al. Diagnosis and management of iron deficiency in CKD: a summary of the NICE guideline recommendations and their rationale. Am J Kidney Dis 2016; 67: 548–558.

Pavord

Daru

Prasannan

, et al. UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol 2020; 188: 819–830.

WHO. Prevalence of anemia among pregnant women, https://data.worldbank.org/indicator/sh.prg.anem (2019, accessed 1 February 2019).

Leonard

Buttner

Thompson

, et al. Anaemia in pregnancy among Aboriginal and Torres Strait Islander women of Far North Queensland: a retrospective cohort study. Nutr Diet 2018; 75: 457–467.

Davidson

Wolski

Callaway

, et al. Chronic kidney disease in pregnancy: maternal and fetal outcomes and progression of kidney disease. Obstet Med 2015; 8: 92–98.

Mikhail

Brown

Williams

, et al. Renal association clinical practice guideline on anaemia of chronic kidney disease. BMC Nephrol 2017; 18: 345.

10.

Demmers

Niens

Van der Haar

, et al. Functional iron deficiency markers are absent during pregnancy despite evidence of low iron stores. Ann Clin Biochem 2019; 56: 450–456.

11.

Besarab

Resolving the paradigm crisis in intravenous iron and erythropoietin management. Kidney Int Suppl 2006; S13–S18.

12.

Scholl

TO.

Iron status during pregnancy: setting the stage for mother and infant. Am J Clin Nutr 2005; 81: 1218S–1222S.

13.

Arnold

Williams

Miller

, et al. Iron deficiency anemia, cigarette smoking and risk of abruptio placentae. J Obstet Gynaecol Res 2009; 35: 446–452.

14.

Villar

Merialdi

Gulmezoglu

, et al. Nutritional interventions during pregnancy for the prevention or treatment of maternal morbidity and preterm delivery: an overview of randomized controlled trials. J Nutr 2003; 133: 1606S–1625S.

15.

Suryanarayana

Chandrappa

Santhuram

, et al. Prospective study on prevalence of anemia of pregnant women and its outcome: a community based study. J Family Med Prim Care 2017; 6: 739–743.

16.

Rahmati

Azami

Badfar

, et al. The relationship between maternal anemia during pregnancy with preterm birth: a systematic review and meta-analysis. J Matern Fetal Neonatal Med 2020; 33: 2679–2689.

17.

Figueiredo

Gomes-Filho

Silva

, et al. Maternal anemia and low birth weight: a systematic review and meta-analysis. Nutrients 2018; 10: 601.

18.

Chen

Grewal

Betran

, et al. Severe anemia, sickle cell disease, and thalassemia as risk factors for hypertensive disorders in pregnancy in developing countries. Pregnancy Hypertens 2018; 13: 141–147.

19.

Daru

Zamora

Fernandez-Felix

, et al. Risk of maternal mortality in women with severe anaemia during pregnancy and post partum: a multilevel analysis. Lancet Glob Health 2018; 6: e548–e554.

20.

Auerbach

James

Nicoletti

, et al. Results of the first American prospective study of intravenous iron in oral iron-intolerant iron-deficient gravidas. Am J Med 2017; 130: 1402–1407.

21.

Rahman

Abe

Rahman

, et al. Maternal anemia and risk of adverse birth and health outcomes in low- and middle-income countries: systematic review and meta-analysis. Am J Clin Nutr 2016; 103: 495–504.

22.

ElAlfy

El-Farrash

Taha

, et al. Auditory brainstem response in full-term neonates born to mothers with iron deficiency anemia: relation to disease severity. J Matern Fetal Neonatal Med 2020; 33: 1881–1888.

23.

Seeho

SKM

Morris

JM.

Intravenous iron use in pregnancy: ironing out the issues and evidence. Aust N Z J Obstet Gynaecol 2018; 58: 145–147.

24.

Wiles

Bramham

Seed

, et al. Serum creatinine in pregnancy: a systematic review. Kidney Int Rep 2019; 4: 408–419.

25.

KDIGO 2013. Clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int 2013; 3: 1–150.

26.

Wiles

Chappell

Clark

, et al. Clinical practice guideline on pregnancy and renal disease. BMC Nephrol 2019; 20: 401–411.

27.

Scheme Dus-cPB. Ferric carboxymaltose: 24 month predicted versus actual analysis, http://ferric-carboxymaltose-dusc-prd-2017-02(1).docx (2017, accessed 2 November 2019).

28.

Govindappagari

Burwick

RM.

Treatment of iron deficiency anemia in pregnancy with intravenous versus oral iron: systematic review and meta-analysis. Am J Perinatol 2019; 36: 366–376.

29.

Qassim

Gergis

Jeffries

, et al. Use of intravenous iron polymaltose in the management of iron deficiency in pregnancy: a retrospective cohort study. Aust N Z J Obstet Gynaecol 2018; 58: 163–169.

30.

Froessler

Gajic

Dekker

, et al. Treatment of iron deficiency and iron deficiency anemia with intravenous ferric carboxymaltose in pregnancy. Arch Gynecol Obstet 2018; 298: 75–82.

31.

Qassim

Mol

Grivell

, et al. Safety and efficacy of intravenous iron polymaltose, iron sucrose and ferric carboxymaltose in pregnancy: a systematic review. Aust N Z J Obstet Gynaecol 2018; 58: 22–39.

32.

Weinberg

ED.

Can iron be teratogenic?

Biometals 2010; 23: 181–184.

33.

Rodriguez

Montero

Alporta

JPL

, et al. Retrospective case reports of anemic pregnant women receiving intravenous ferric carboxymaltose: experience from a tertiary hospital in Spain. Obstet Gynecol Int 2016; 2016: 1–5.

34.

Devasenapathy

Singh

Moodbidri

, et al. An observational study on the use of IV iron sucrose among anaemic pregnant women in government healthcare facilities from two states of India. J Obstet Gynaecol India 2015; 65: 230–235.

35.

Shah

Christianson

Meganathan

, et al. Racial differences and factors associated with pregnancy in end stage kidney disease patients on dialysis in the United States. J Am Soc Nephrol 2019; 30: 2437–2448.

36.

Rivera

JCH

Lopez

MJP

Bermudez

CHC

, et al. Delayed initiation of hemodialysis in pregnant women with chronic kidney disease: logistical problems impact clinical outcomes. An experience from an emerging country. J Clin Med 2019; 8: 475.

37.

Sienas

Wong

Collins

, et al. Contemporary uses of erythropoietin in pregnancy: a literature review. Obstet Gynecol Surv 2013; 68: 594–602.

38.

Beguin

Lipscei

Oris

, et al. Serum immunoreactive erythropoietin during pregnancy and in the early postpartum. Br J Haematol 1990; 76: 545–549.

39.

Fehr

Ammann

Garzoni

, et al. Interpretation of erythropoietin levels in patients with various degrees of renal insufficiency and anemia. Kidney Int 2004; 66: 1206–1211.

40.

Artunc

Risler

Serum erythropoietin concentrations and responses to anaemia in patients with or without chronic kidney disease. Nephrol Dial Transplant 2007; 22: 2900–2908.

41.

Kato

Hamada

Suzuki

, et al. Effect of weekly or successive iron supplementation on erythropoietin doses in patients receiving hemodialysis. Nephron 2001; 89: 110–112.

42.

Kaufman

Reda

Fye

, et al. Diagnostic value of iron indices in hemodialysis patients receiving epoetin. Kidney Int 2001; 60: 300–308.

43.

Rutherford

Schneider

Dempsey

, et al. Efficacy of different dosing regimens for recombinant human erythropoietin in a simulated perisurgical setting: the importance of iron availability in optimizing response. Am J Med 1994; 96: 139–145.

44.

Hedenus

Birgegard

Nasman

, et al. Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study. Leukemia 2007; 21: 627–632.

45.

Pedrazzoli

Farris

Del Prete

, et al. Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alpha. J Clin Oncol 2008; 26: 1619–1625.

46.

Stover

Pregnancy and dialysis: an overview. Nephrol Nurs J 2010; 37: 652–654.

47.

Maruyama

Shimada

Obayashi

, et al. Requiring higher doses of erythropoietin suggests pregnancy in hemodialysis patients. Nephron 1998; 79: 413–419.

48.

McGregor

Stewart

Junor

, et al. Successful use of recombinant human erythropoietin in pregnancy. Nephrol Dial Transplant 1991; 6: 292–293.

49.

Szurkowski

Wiecek

Kokot

, et al. Safety and efficiency of recombinant human erythropoietin treatment in anemic pregnant women with a kidney transplant. Nephron 1994; 67: 242–243.

50.

Goshorn

Youell

TD.

Darbepoetin alfa treatment for post-renal transplantation anemia during pregnancy. Am J Kidney Dis 2005; 46: e81–e86.

51.

Cyganek

Pietrzak

Kociszewska-Najman

, et al. Anemia treatment with erythropoietin in pregnant renal recipients. Transplant Proc 2011; 43: 2970–2972.

52.

Kashiwagi

Breymann

Huch

, et al. Hypertension in a pregnancy with renal anemia after recombinant human erythropoietin (rhEPO) therapy. Arch Gynecol Obstet 2002; 267: 54–56.