Impact of Maternal Folic Acid Supplementation on Descendants' Kidney in Adulthood

Fernandes, Thayane Ferreira da Costa; Conde, Poliana dos Santos; Brasil, Flavia de Bittencourt; Oliveira, Marcos Roberto de

doi:10.1055/s-0043-1769001

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Revista Brasileira de Ginecologia e Obstetrícia

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Review Article • Rev Bras Ginecol Obstet. 45 (4) • 2023 • https://doi.org/10.1055/s-0043-1769001 copy

Impact of Maternal Folic Acid Supplementation on Descendants' Kidney in Adulthood

Impacto da suplementação materna com ácido fólico no rim dos descendentes na vida adulta

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Supplementation with folic acid (FA) during gestation has been recommended by medical society all over the world, but some studies have shown that intake of high folic acid diet may unleash damages to the descendants. Objectives: Describing the effects of maternal supplementation with FA during gestation on offspring's kidney at late life stages. Data Source: It is a systematic review by which were consulted the following databases: Medline, through Pubmed, Lilacs, and SciELO. The research was performed using the keywords “Folic acid”, “Gestation” and “Kidney”. Study Selection: Eight studies were regarded for this systematic review. Data Collection: Only studies that evaluated folic acid consumption during gestation and its effects exclusively on descendants' kidney at several phases of life were regarded. Results: Gestational FA intake did not change the renal volume, glomerular filtration rate and the expression of some essential genes in the kidney of puppies whose dams were supplemented with FA. Maternal consumption of double FA plus selenium diet was effective in preserving antioxidant enzymes activity in the kidney of descendants from mothers exposed to alcohol. FA supplementation decreased some gross anomalies in the puppies caused by teratogenic drug despite of had not been effective in preventing some renal architectural damages. Conclusion: FA supplementation did not cause renal toxicity; it exerted an antioxidant protective effect and mitigated some renal disorders caused by severe aggressions.

Keywords
Folic acid; Gestation; Kidney; Descendant; Adulthood

Author/Year	Sample	Intervention	Follow-up	Settings & participants	Objective	Assessment methods	Results
Lisle et al. (2003)³⁹39 Lisle SJ, Lewis RM, Petry CJ, Ozanne SE, Hales CN, Forhead AJ. Effect of maternal iron restriction during pregnancy on renal morphology in the adult rat offspring. Br J Nutr. 2003;90(01):33–39. Doi: 10.1079/bjn2003881 https://doi.org/10.1079/bjn2003881...	Control (153 mg Fe/kg diet, n 7) or low-Fe (3 mg/kg diet, n 6)	Experimental study	18 months	Offspring rats (n = 28)	Investigated the renal morphology of adult rats born to mothers who were Fe-deficient during pregnancy.	Kidney weight; Glomerular number and size; Systolic blood pressure	Maternal Fe restriction causes hypertension in the adult offspring that may be due, in part, to a deficit in nephron number.
Miliku et al. (2017)⁴⁵45 Miliku K, Mesu A, Franco OH, Hofman A, Steegers EAP, Jaddoe VWV. Maternal and fetal folate, vitamin B12, and homocysteine concentrations and childhood kidney outcomes. Am J Kidney Dis. 2017;69(04):521–530. Doi: 10.1053/j.ajkd.2016.11.014 https://doi.org/10.1053/j.ajkd.2016.11.0...	Folic acid supplement (0.4–0.5 mg)	Population-based prospective cohort study from fetal life onwards	From pregnancy to 6 years of the child	Pregnant women and their (n = 4.226)	Examined the associations of folate, vitamin B12, and homocysteine concentrations during pregnancy with kidney outcomes in school-aged children.	Folate, vitamin B12 and homocysteine blood concentrations measured in early pregnancy and at birth (cord blood).	Folate, vitamin B12 and homocysteine concentrations during fetal life are associated with offspring kidney development.
Ly et al. (2016)⁴⁶46 Ly A, Ishiguro L, Kim D, et al. Maternal folic acid supplementation modulates DNA methylation and gene expression in the rat offspring in a gestation period-dependent and organ-specific manner. J Nutr Biochem. 2016;33:103–110. Doi: 10.1016/j.jnutbio.2016.03.018 https://doi.org/10.1016/j.jnutbio.2016.0...	Folic acid supplement (2 mg and 5mg)	Experimental study	8 weeks	Sprague-Dawley Rats (n = 10)	This study evaluated whether maternal folic acid supplementation might change the offspring's.metabolism.	Brain, liver, kidney and colon of puppies were assessed about folate concentrations, global DNA methylation and expression. of Igf2, Er-α, Gr, Ppar-α e Ppar-γ genes.	Folic aid supplementation at late pregnancy or throughout gestation reduced the expression of Er-α, Gr and Ppar-α genes in the liver.
Ojeda et al. (2012)⁴⁷47 Ojeda ML, Nogales F, Murillo ML, Carreras O. Selenium or selenium plus folic acid-supplemented diets ameliorate renal oxidation in ethanol-exposed pups. Alcohol Clin Exp Res. 2012;36(11): 1863–1872. Doi: 10.1111/j.1530-0277.2012.01788.x https://doi.org/10.1111/j.1530-0277.2012...	(Se) (0.5 ppm) or with Se (0.5 ppm) + folic acid (8 ppm) administered to EtOH-exposed (20% v/v	Experimental study	8 weeks	Winstar rats (n = 6) female (n = 6) male	Diet supplemented with selenium or with Se + folic acid administered to EtOH-exposed dams during gestation and lactation prevents the oxidative EtOH-provoked effects in their offspring's kidneys.	Serum, urine and kidney, Se levels, creatinine clearance, antioxidant enzyme activities and lipid and protein peroxidation in the kidney.	Dietary supplementation improve renal development, Se deposits, and protein content while decreasing lipid and protein oxidation and modifying antioxidant enzymes' activity.
Ojeda et al. (2010)⁴⁸48 Ojeda ML, Jotty K, Nogales F, Murillo ML, Carreras O. Selenium or selenium plus folic acid intake improves the detrimental effects of ethanol on pups’ selenium balance. Food Chem Toxicol. 2010;48 (12):3486–3491	Se (0.5 ppm) or with Se (0.5 ppm) plus folic acid (8 ppm) to ethanol-exposed (20% v/v)	Experimental study	8 weeks	Winstar rats (n = 6) female (n = 6) male	Supplemented diet with Se or with Se plus folic acid to ethanol-exposed dams prevents the ethanol-provoked effects in their offspring's Se deposits.	Selenium levels in the liver, kidney and testes.	Results show that ethanol decreases Se deposits in pups' heart, liver, kidney and testes. However Se levels in both pancreas and serum were increased by ethanol; it also compromised the weight and length of the offspring at the end of lactation.
Król et al. (2011)⁴⁹49 Król E, Krejpcio Z, Chmurzynska A. Folic acid and protein content in maternal diet and postnatal high-fat feeding affect the tissue levels of iron, zinc, and copper in the rat. Biol Trace Elem Res. 2011;144(1-3):885–893. Doi: 10.1007/s12011-011-9048-3 https://doi.org/10.1007/s12011-011-9048-...	(1) normal protein, normal folic acid (FA) diet (0.002-g FA); (2) protein-restricted, normal folic acid diet (0.002-g); (3) protein restricted, folic acid-supplemented diet (0.005 g FA); (4) normal protein, folic acid-supplemented diet (0.005 g FA).	Experimental study	6 weeks	Offspring (n = 48)	The aim of the study is investigate the influence of maternal diet during gestation on Fe, Zn, and Cu levels in the liver and kidney of adult rats.	The levels of Fe, Zn, and Cu in the livers and kidneys; Offspring's tissue mineral levels.	The results of this study show that maternal dietary folic acid and protein intake during pregnancy, as well as the type of postweaning diet, affect Fe, Zn and Cu levels in the offspring.
El-Ashmawy and Bayad (2016)⁵⁰50 El-Ashmawy IM, Bayad AE. Folic acid and grape seed extract prevent azathioprine-induced fetal malformations and renal toxicity in rats. Phytother Res. 2016;30(12):2027–2035. Doi: 10.1002/ptr.5709 https://doi.org/10.1002/ptr.5709...	(1) AZA (25 mg/kg) (2) AZA, simultaneously with grape seed extract at the dose of 75 mg/kg (3) AZA, simultaneously with folic acid at the dose of 5 mg/kg;	Experimental study	4 weeks	Adult Wister rats (n = 40)	Investigate the influence of AZA on the fetal development and renal function and its co-administration with either folic acid (FA) or grape seed extract (GSE).	Kidney histology; Glutathione level (GSH); Lipid per oxidation content as malondialdehyde in the kidney tissue.	Maternal administrations of both FA and GSE protect against AZA-induced fetal malformations. Grape seed extract was more active than FA in potentiating the antioxidative defenses for controlling AZA-induced oxidative renal damages.
Hawkesworth et al. (2013)⁶⁴64 Hawkesworth S, Wagatsuma Y, Kahn AI, et al. Combined food and micronutrient supplements during pregnancy have limited impact on child blood pressure and kidney function in rural Bangladesh. J Nutr. 2013;143(05):728–734. Doi: 10.3945/ jn.112.168518 https://doi.org/10.3945/jn.112.168518...	(1) Fe30F: 30 mg iron and 400 µg of folate (2) Fe60F: 60 mg of iron and 400 µg of folate (3) MMS: Multiple micronutrient supplement	A trial follow-up study	Between November 2001 and October 2003 (recruited early in pregnancy) Between May 2007 and February 2009 when the descendants were 4.5 years old (children born)	Women were recruited early in pregnancy (n = 3.560) children (n = 3.267)	Assess the association between prenatal food and micronutrient supplementation and childhood blood pressure and kidney function. Women received either iron and folate or multiple micronutrient tablets daily.	Blood pressure; Kidney function.	Limited evidence for long-lasting impacts of pregnancy supplementation on offspring markers of kidney function.

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