Iron Salts, High Levels of Hemoglobin and Ferritin in Pregnancy, and Development of Gestational Diabetes: A Systematic Review

Miranda, Vanessa Iribarrem Avena; Pizzol, Tatiane da Silva Dal; Jesus, Patricia Romualdo de; Silveira, Marysabel Pinto Telis; Bertoldi, Andréa Dâmaso

doi:10.1055/s-0042-1755460

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Revista Brasileira de Ginecologia e Obstetrícia

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Review Article • Rev Bras Ginecol Obstet 44 (11) • 2022 • https://doi.org/10.1055/s-0042-1755460 copy

Iron Salts, High Levels of Hemoglobin and Ferritin in Pregnancy, and Development of Gestational Diabetes: A Systematic Review

Sais de ferro, níveis elevados de hemoglobina e ferritina na gravidez e o desenvolvimento de diabetes gestacional: Uma revisão sistemática

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Objective

The aim of this study was to systematically review literature on the use of iron supplements (not including iron derived from diet), increased levels of hemoglobin and/or ferritin, and the risk of developing gestational diabetes mellitus (GDM).

Data source

The following databases were searched, from the study's inception to April 2021: PUBMED, Cochrane, Web of Science, Scopus, Embase, Cinahl and Lilacs.

Selection of studies

A total of 6,956 titles and abstracts were reviewed, 9 of which met the final inclusion criteria, with 7,560 women in total.

Data collection

Data extraction was performed by two independent reviewers and disagreements were resolved by a third researcher.

Data synthesis

Methodological quality in controlled trials were assessed according to the Cochrane Collaboration tools (ROB-2 and ROBINS-1) and for the observational studies, the National Institutes of Health's (NIH) quality assessment tool was used. Among the 5 observational studies, women with a higher hemoglobin or ferritin level were more likely to develop GDM when compared with those with lower levels of these parameters. Among the 3 randomized clinical trials, none found a significant difference in the incidence of GDM among women in the intervention and control groups. However, we identified many risks of bias and great methodological differences among them.

Conclusion

Based on the studies included in this review, and due to the important methodological problems pointed out, more studies of good methodological quality are needed to better establish the association between iron supplementation and GDM.

Keywords
ferritin; gestational diabetes; hemoglobin; iron supplement; pregnancy

First author (year) Country	Study design	Health service	GDM diagnosis: method/gestational week	Control group			Experimental group
First author (year) Country	Study design	Health service	GDM diagnosis: method/gestational week	N	Age	Iron dose (frequency, duration, trimester)	n	Age	Iron dose (frequency, duration, trimester)
Asadi (2019)²⁸28 Asadi N, Vafaei H, Kasraeian M, Yoosefi S, Faraji A, Abbasi L. Effects of prophylactic iron supplementation on outcome of nonanemic pregnant women: A non-randomized clinical trial. J Chin Med Assoc. 2019;82(11):840–844. Doi: 10.1097/JCMA.0000000000000184 https://doi.org/10.1097/JCMA.00000000000... ^* * This study had three groups of comparison: women with normal serum ferritin levels (= 30 μg/dL) who received standard prophylactic iron supplementation during the pregnancy (designed as the experimental group); those who had minor thalassemia and El-evated serum ferritin levels (= 30 μg/dL) who did not receive prophylactic iron supplementation, or those with normal ferritin levels (≥ 30 μg/dL) who refused to take iron supplementation due to gastrointestinal upset (designed as control group 1); and those with iron deficiency anemia with low serum ferritin levels (< 30 μg/dL) who received standard iron supplementation during pregnancy (designed as control group 2). Iran	NRCT	Hospital	NR	30 30	29.6 ± 12.3 27.5 ± 8.3	NR	30	29.6 ± 16.1	NR
Chan (2009)¹³13 Chan KK, Chan BC, Lam KF, Tam S, Lao TT. Iron supplement in pregnancy and development of gestational diabetes–arandomised placebo-controlled trial. BJOG. 2009;116(06):789–797, discussion 797–798. Doi: 10.1111/j.1471-0528.2008.02014.x https://doi.org/10.1111/j.1471-0528.2008... China	RCT	Hospital	OGTT/ 28–30 and 36 weeks	599	31.3 ± 0.18	Placebo at minimum of 12 weeks (from 16–28), 1^st trimester	565	31.3 ± 0.19	60 mg EI daily, minimum of 12 weeks (16–28 weeks), 1^st trimester
Kinnunen (2016)²⁹29 Kinnunen TI, Luoto R, Helin A, Hemminki E. Supplemental iron intake and the risk of glucose intolerance in pregnancy: reanalysis of a randomised controlled trial in Finland. Matern Child Nutr. 2016;12(01):74–84. Doi: 10.1111/mcn.12139 https://doi.org/10.1111/mcn.12139... Finland	RCT	Primary health care	NR (diagnosis obtained through medical records)^a a The authors stated that GDM “was not assessed systematically among all participants, but was abstracted from patient records as recognized in the usual care.”	1,358	27.8 ± 5.6	50 mg EI twice a day, only if Hb fell below 100 g/L, 2 months or until their Hb increased to 110 g/L, 2^nd trimester	1,336	27.7 ± 4.9	100 mg EI daily^b b The participants received 100 mg elemental iron throughout the pregnancy regardless of Hb level. until delivery, all trimesters
Ouladsahebmadarek (2011)³⁰30 Ouladsahebmadarek E, Sayyah-Melli M, Abbasalizadeh S, Seyedhejazie M. The effect of supplemental iron elimination on pregnancy outcome. Pak J Med Sci. 2011;27(03):641–645 Arab Emirates	RCT	Hospital	NR	372	25.48 ± 4.96	Placebo, 13 weeks, 1^st trimester	410	26.28 ± 5.25	30 mg EI daily, 13 weeks, 1^st trimester

First author (year) Country	Study design	Health service	GDM diagnosis: method/ gestational week	Sample size					Age	Iron dose (frequency, duration)
First author (year) Country	Study design	Health service	GDM diagnosis: method/ gestational week	N	Control group	Exposed group	Case group	Control group		Iron dose (frequency, duration)
Özyiğit (2008)²⁶26 Özyiğit EA, Uğur M, Ünlü S, Özakşiï TG, Avşar F. The effect of oral iron supplementation on the glucose metabolism in non-anemic pregnant women: a prospective case-control study. UHOD. 2008; 18(03):155–162 Turkey	Case-control	Polyclinic	OGTT/24–28 weeks	58	23	35	−	−	26	40 mg IS daily for at least 2 months
Rawal (2016)²⁷27 Rawal S, Hinkle SN, BaoW, et al. A longitudinal study of iron status during pregnancy and the risk of gestational diabetes: findings from a prospective, multiracial cohort. Diabetologia. 2017;60 (02):249–257. Doi: 10.1007/s00125-016-4149-3 https://doi.org/10.1007/s00125-016-4149-... United States	Case-control	Clinical centers	NR (diagnosis obtained through medical records)/ 10–14 and 15–26 weeks	321	−	−	107	214	Control group: 30.4 ± 5.4 Case group: 30.5 ± 5.7	Dose: NR 83% at weeks 10–14; 87% in the 2^nd trimester during 15–26 gestational weeks reported using IS
Liu and Pang (2018)²³23 Liu XN, Pang J. A retrospective study of supplemental iron intake in singleton pregnancy women with risk of developing gestational diabetes mellitus. Medicine (Baltimore). 2018;97(26):e10819. Doi: 10.1097/MD.0000000000010819 https://doi.org/10.1097/MD.0000000000010... China	Cohort	Hospital	NR/at delivery	259	124	135	−	−	Control group 31.1 ± 1.5 Exposed group 30.9 ± 1.3	300 mg of IS daily, 7 days weekly until the baby delivery
Zhu (2019)²⁵25 Zhu B, Liang C, Xia X, et al. Iron-Related Factors in Early Pregnancy and Subsequent Risk of Gestational Diabetes Mellitus: the Ma'anshan Birth Cohort (MABC) Study. Biol Trace Elem Res. 2019;191 (01):45–53. Doi: 10.1007/s12011-018-1595-4 https://doi.org/10.1007/s12011-018-1595-... China	Cohort	NR	OGTT 24–28	3,289^a a The 3,289 pregnant women were evaluated in the 1st and 2nd trimesters of pregnancy, with 4 missing in the 1st and 51 missing in the 2nd trimester;	1^st 2,508 2^nd 2,805	1^st 777 2^nd 433	−	−	26.4 ± 3.7	NR
Si (2020)²⁴24 Si S, Shen Y, Xin X, et al. Hemoglobin concentration and iron supplement during pregnancy were associated with an increased risk of gestational diabetes mellitus. J Diabetes. 2021;13(03): 211–221. Doi: 10.1111/1753-0407.13101 https://doi.org/10.1111/1753-0407.13101... China	Cohort	Hospital	OGTT/ 24–28	1,128^b b The 1,128 pregnant women were evaluated in the 1st and 2nd trimesters of pregnancy.	1^st 831 2^nd 639	1^st 297 2^nd 489	−	−	GDM group 28.60 ± 3.33 No GDM group 27.91 ± 3.25	NR

First author (year)	Biomarker of iron		Trimester collected	Outcomes (incidence of GDM)		Statistically significant difference
First author (year)	Hemoglobin (g/dL)	Ferritin (pmol/L)	Trimester collected	Control group	Experimental group	Statistically significant difference
Asadi (2019)²⁸28 Asadi N, Vafaei H, Kasraeian M, Yoosefi S, Faraji A, Abbasi L. Effects of prophylactic iron supplementation on outcome of nonanemic pregnant women: A non-randomized clinical trial. J Chin Med Assoc. 2019;82(11):840–844. Doi: 10.1097/JCMA.0000000000000184 https://doi.org/10.1097/JCMA.00000000000...	Control group 1: 1^st 12.24 ± 1.5 2^nd 11.88 ± 1.4 3^rd 12.39 ± 2.29 Control group 2: 1^st 12.54 ± 1.23 2^nd 12.02 ± 1.06 3^rd 12.46 ± 1.12 Experimental group: 1^st 14.75 ± 1.42; p = 0.452 2^nd 12.32 ± 1.27; p = 0.387 3^rd 12.79 ± 1.18; p = 0.59	NR	1^st, 2^nd, and 3^rd	0 (0%) 0 (0%)	5 (16.7%)	Yes p = 0.038
Chan (2009)¹³13 Chan KK, Chan BC, Lam KF, Tam S, Lao TT. Iron supplement in pregnancy and development of gestational diabetes–arandomised placebo-controlled trial. BJOG. 2009;116(06):789–797, discussion 797–798. Doi: 10.1111/j.1471-0528.2008.02014.x https://doi.org/10.1111/j.1471-0528.2008...	Control group (n = 531) 11.4 ± 0.04 Experimental group (n = 511) 11.4 ± 0.04 p < 0.001	Control group (n = 490) 49.14 ± 2.17 Experimental group (n = 469) 60.4 ± 2.22 p < 0.001	3^rd	−	OR = 1.04 CI = 0.7–1.53	No
Kinnunen (2016)²⁹29 Kinnunen TI, Luoto R, Helin A, Hemminki E. Supplemental iron intake and the risk of glucose intolerance in pregnancy: reanalysis of a randomised controlled trial in Finland. Matern Child Nutr. 2016;12(01):74–84. Doi: 10.1111/mcn.12139 https://doi.org/10.1111/mcn.12139...	Control group: 20 weeks 126.4 ± 8.9 28 weeks 123.9 ± 9.5 36 weeks 124.8 ± 9.6 Experimental group: 20 weeks 127.0 ± 8.6; p = 0.11 28 weeks 127.0 ± 8.6; p < 0.001 36 weeks 131.2 ± 9.3; p < 0.001	NR	2^nd and 3^rd	11.0%	13.0%	No p = 0.12
Ouladsahebmadarek(2011)³⁰30 Ouladsahebmadarek E, Sayyah-Melli M, Abbasalizadeh S, Seyedhejazie M. The effect of supplemental iron elimination on pregnancy outcome. Pak J Med Sci. 2011;27(03):641–645	Control group: 12.48 ± 0.91 Experimental group: 13.46 ± 0.75; p = 0.03	Control group (μg/dl): 9.26 ± 0.62 Experimental group (μg/dl): 26.91 ± 2.11; p = 0.048	At delivery	0.8%	0.5%	No p = 0.67

First author, year	Biomarker of iron		Trimester collected	OR crude (95% CI or p-value)	OR adjusted (95% CI)	Control for confounding
First author, year	Hemoglobin (g/dL)	Ferritin (pmol/L)	Trimester collected	OR crude (95% CI or p-value)	OR adjusted (95% CI)	Control for confounding
Özyiğit (2008)²⁶26 Özyiğit EA, Uğur M, Ünlü S, Özakşiï TG, Avşar F. The effect of oral iron supplementation on the glucose metabolism in non-anemic pregnant women: a prospective case-control study. UHOD. 2008; 18(03):155–162	Iron group 12.3 ± 1.3 Control group 12.1 ± 1.04	Iron group 16.5 ± 6.09 Control group 12.5 ± 9.7 (ng/mL) (p = 0.018)	1^st	−	−	BMI, age, parity.
Rawal (2016)²⁷27 Rawal S, Hinkle SN, BaoW, et al. A longitudinal study of iron status during pregnancy and the risk of gestational diabetes: findings from a prospective, multiracial cohort. Diabetologia. 2017;60 (02):249–257. Doi: 10.1007/s00125-016-4149-3 https://doi.org/10.1007/s00125-016-4149-...	NR	GDM group 94.5 (67.9–133.5) No GDM group 78.1 (49.7–119.4)	2^nd	3.06 (CI = 1.27–7.34) 15–26 weeks; highest vs. lowest quartiles	3.95 (CI= 1.38–11.3) 15–26 weeks; highest vs. lowest quartiles	BMI, parity, education, family history of diabetes.
Liu and Pang (2018)²³23 Liu XN, Pang J. A retrospective study of supplemental iron intake in singleton pregnancy women with risk of developing gestational diabetes mellitus. Medicine (Baltimore). 2018;97(26):e10819. Doi: 10.1097/MD.0000000000010819 https://doi.org/10.1097/MD.0000000000010...	Iron group 12.1 ± 0.06 Control group 11.7 ± 0.08 p <0.01	Iron group 65.8 ± 3.1 Control group 53.7 ± 2.9 p <0.01	At delivery	1.02 (p = 0.96)	−	NR
Zhu (2019)²⁵25 Zhu B, Liang C, Xia X, et al. Iron-Related Factors in Early Pregnancy and Subsequent Risk of Gestational Diabetes Mellitus: the Ma'anshan Birth Cohort (MABC) Study. Biol Trace Elem Res. 2019;191 (01):45–53. Doi: 10.1007/s12011-018-1595-4 https://doi.org/10.1007/s12011-018-1595-...	GDM group 1^st 128.8 ± 9.2 2^nd 115.4 ± 9.6 No GDM group 1^st 127.2 ± 9.3 2^nd 114.6 ± 9.9 (g/L)	NR	1^st and 2^nd	1^st = 1.1 (1.04–1.16) 2^nd = 1.04 (0.99–1.1)	1^st (n = 113) Crude model = 1.19 (0.94–1.49) Model 1 = 1.12 (0.88–1.43) 2^nd (n = 63) Crude model = 1.13 (0.85–1.52) Model 1 = 1.06 (0.78–1.44)	Age, prepregnancy BMI, family history of diabetes, parity, smoking, drinking, diastolic blood pressure, systolic blood pressure, gestational week at visit, income, and education.
Si (2020)²⁴24 Si S, Shen Y, Xin X, et al. Hemoglobin concentration and iron supplement during pregnancy were associated with an increased risk of gestational diabetes mellitus. J Diabetes. 2021;13(03): 211–221. Doi: 10.1111/1753-0407.13101 https://doi.org/10.1111/1753-0407.13101...	GDM group 1^st 12.68 ± 0.91 2^nd 11.57 ± 0.83 No GDM group 1^st 12.54 ± 0.88 2^nd 11.43 ± 0.83	NR	1^st and 2^nd	−	IS in 1^st / Hb in 2^nd trimester Hb <11 (n = 80) 1.32 (0.67–2.51) Hb >11 (n = 217)1.53 (1.05–2.24) IS in 2^nd / Hb in 2^nd trimester Hb <11 (n = 184) 1.23 (0.68–2.28) Hb >11 (n = 305)1.92 (1.13–3.35) IS in 2^nd / Hb in 1^st trimester Hb < 11 (n = 54) 1.04 (0.13–2.21) Hb > 11 (n = 435)2.15 (1.07–4.34)	Maternal age, education, pre-pregnancy BMI, parity, weight gain during pregnancy, dietary iron intake, family history of diseases, isolated hypothyroxinemia in 1^st trimester, participation in physical exercise during pregnancy, gestational week of Hb measurement and OGTT measurement.

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[1] Address for correspondence Patricia Romualdo de Jesus, Master's degree, Ramiro Barcelos Street, 2400, Porto Alegre, RS, Brazil (e-mail: patriciardejesus@gmail.com).