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

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

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Revista Brasileira de Ginecologia e Obstetrícia

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Sumário

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

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

Autoria SCIMAGO INSTITUTIONS RANKINGS

Resumo

Objetivo

O objetivo deste estudo foi revisar sistematicamente a literatura sobre o uso de suplementos de ferro (não incluindo o ferro derivado da dieta), aumento dos níveis de hemoglobina e/ou ferritina e o risco de desenvolver diabetes mellitus gestacional (DMG).

Fontes dos dados

as bases de dados PUBMED, Cochrane, Web of Science, Scopus, Embase, Cinahl e Lilacs foram pesquisadas até abril de 2021.

Seleção dos estudos

Foram revisados 6.956 títulos e resumos, dos quais 9 preencheram os critérios finais de inclusão, totalizando 7.560 mulheres.

Coleta de dados

A extração de dados foi realizada por dois revisores independentes e as divergências foram resolvidas por um terceiro revisor.

Síntese dos dados

A qualidade metodológica dos ensaios controlados foi avaliada de acordo com as ferramentas da Colaboração Cochrane (ROB-2 e ROBINS-1) e para os estudos observacionais, foi utilizada a ferramenta de avaliação de qualidade do National Institutes of Health (NIH). Entre os 5 estudos observacionais, as mulheres com maiores níveis de hemoglobina ou ferritina apresentaram maior probabilidade de desenvolver DMG quando comparadas àquelas com níveis mais baixos nesses parâmetros. Entre os 3 ensaios clínicos randomizados, nenhum deles encontrou diferença significativa na incidência de DMG entre as mulheres dos grupos de intervenção e controle. No entanto, identificamos muitos riscos de viés e enormes diferenças metodológicas entre eles.

Conclusão

Com base nos estudos incluídos nesta revisão e devido aos importantes problemas metodológicos apontados, são necessários mais estudos de boa qualidade metodológica para melhor estabelecer a associação entre suplementação de ferro e DMG.

Palavras-chave
ferritina; diabetes gestacional; hemoglobina; suplemento de ferro; gravidez

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).