Rajendran H. S. R, Balaji T, Kumar J. A, Kumar S, Gnanasundaram V. Folic Acid Supplementation on Fetal Growth at Different Gestational Ages. Biomed Pharmacol J 2021;14(4).

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Manuscript received on :10-11-2020
Manuscript accepted on :12-10-2021
Published online on: 17-11-2021

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Hannah Sugirthabai Rajila Rajendran¹, Thotakura Balaji¹, Jyothi Ashok Kumar², Santhosh Kumar³ and Vaithianathan Gnanasundaram¹

¹Department of Anatomy, Chettinad Hospital and research Institute, Chettinad Academy of Research and Education, Chennai, Tamil Nadu, India

²Department of Anatomy, Basaveshwara Medical College, Chitradurga, Karnataka, India

³CRRI, Chettinad Hospital and research Institute, Chettinad Academy of Research and Education, Chennai, Tamil Nadu, India

Corresponding Author E-mail: balajianat@gmail.com

DOI : https://dx.doi.org/10.13005/bpj/2275

Abstract

Introduction: Folate, Vitamin B9, is found naturally in our day to day foods. It is vital for synthesis of DNA and normal cell division in humans. Studies have revealed constantly that maternal folic acid[FA] intake prior to and in early conception decreases neural tube defects. Aim: The aim of the current study is to evaluate the relationship between FA intake by the mother during conception and fetal growth at different gestational ages and also if, periconceptional and preconceptional FA intake has a positive effect on  fetal growth, hence reducing the risk of low birth weight babies or small for gestational age (SGA) babies. Materials and methods: 180 pregnant women were classified based on their period of FA intake as preconception, periconception FA intake and nil FA intake. Standard fetal biometric parameters were measured using ultrasonogram during the 1^st , 2^nd and 3^rd  trimester of their pregnancy. Results: Preconception FA intake had a positive effect on fetal growth as compared to those who abstained from FA supplementation. Intake during preconception and peri-conception i.e. immediately after confirmation of pregnancy was found to have a reduced risk of low fetal weight as against those who did not consume FA. Fetal biometry showed significant difference between preconception and periconception groups. Conclusion: In conclusion, preconceptional and periconceptional FA supplementation of 0.4-0.5 mg/day was positively affecting fetal growth and caused an optimal birth weight by decreasing the incidence of low birth weight.

Keywords

FA; Pregnancy; Supplementation; Weight for Gestational Age

Introduction

Pregnancy usually necessitates a higher consumption of all nutrients. Insufficient nutritional intake peri- conceptionally can result in fetal weight discrepancies and other congenital anomalies^1,2. Fetal growth depends on many factors, which can be classified into maternal, placental, and fetal factors. In this connection, maternal nutritional status has been shown to play a vital role ^3,4,5.

Folic acid  [FA] is vitamin B9,   rich in whole grains, kale, leafy vegetables, and orange.  During fetal growth, cells proliferate enormously and require a high quantity of folate to synthesize DNA and RNA⁶. Therefore, FA demand is increased during pregnancy because of placental and fetal growth⁷.  Insufficient folate ingestion results in reduced serum and RBC’s folate concentrations, elevated homocysteine (Hcy) level, and megaloblastic alterations in the hemopoitic cells and also other fast cleaving cells⁸. Thus folate deficiency elevates the risk for several developmental anomalies, like defects in the neural tube and congenital birth defects^5,7. Administration of 400 µg daily before conception and also during pregnancy can decrease the possibility of the fetus having neural tube defects. Earlier studies have established that periconceptional FA intake can avoid 60 to 70% of  defects of neural tube, including anencephaly, rachichisis and spina bifida.

According to recommendations of updated guidelines of American College of Obstetrics and Gynecology [AAFP] periconceptional FA administration (0.4 mg) as a multi-vitamin for all the female planning for conception. For an individual who plans to conceive and who has no family history of a child with any spinal or neural anomalies, the AAFP intensely advised to take FA around 0.4 to 0.8 mg/d; it also suggests 0.4 mg of folate administration to all female in their reproductive age even though they are not prepared to conceive. AAFP and various other institutions recommends 4 mg/day FA intake by a female having a previous record of a child with neural tube developmental anomalies⁹.  

Various investigations have revealed a positive correlation between FA consumption and fetus development^{10, 11}. Most studies paid attention to the association between fetal growth and FA supplementation during mid and/or late pregnancy. Very little data is available with regard to the effect of FA administration during early fetal development¹². The early weeks of conception are the crucial period for forming the placenta, development of the embryo, and programming of the fetus. There is little knowledge regarding the importance of FA intake at earlier development of the fetus^5,13 and is still in hypothetical phase¹⁴. Therefore the present study investigates whether periconceptional maternal FA intake aids in the growth of a fetus.

Materials and Methods

Study Design

This study was carried out at  Chettinad hospital and research institute, Chennai, between 2016-2018 after obtaining approval from the institutional human ethical committee (Ref: IHEC/04/18Dec2015/Desp.No.155/18.01.2016). Informed consent was acquired from all conceived women who participated in the study.  Self-reported FA intake was collected from the information given in the questionnaire, and the subjects (between 21 to 45 years old) were classified into three groups: Group 1- Preconceptional group (n-60): defined as women taking FA supplementation any time prior to conception; Group 2- periconceptional or post-conception group (n-60): defined as mothers started taking FA from the day conception was confirmed or after that but prior to the eighth week of pregnancy;  Group 3 – No FA intake (n-60): regarded as no intake of FA supplementation ever. The female who begins to take FA following the eighth week of conception and diseases like diabetes mellitus and hypertension were excluded from the study. The range of FA consumed by the subjects was in the range of 0·4–0·5 mg/d, usually in the form of multivitamins.

Fetal ultrasound was performed on all subjects recruited for the study during the 1st, 2^nd, and 3rd trimester of gestation. Fetal biometric measurement is crown-rump length (CRL), Nuchal translucency (NT), head circumference (HC), biparietal diameter (BPD), abdominal circumference (AC), femur length (FL), and estimated fetal weight (EFW) were measured Trans abdominally during each ultrasound examination.

All the data were computed as mean ± standard error. The data analysis was done by  employing one way ANOVA. To determine the difference between the individual groups, an independent t test was performed using SPSS software (IBM, USA, ver. 21) and significance was taken when P value was less than 0.05

Results

During the period between 2016 and 2018, 180 pregnant women took part in this study. Table 1 lists the features of  women enrolled in the study. Among group 1 31.66 % (19) were Nulliparous, and 68.33 % (41) were multiparous. In group 2, 35% (21) were Nulliparous, and  65% (39) were multiparous. Among group 3, 56.66% (34) were Nulliparous and 43.33% (26) were multiparous.

Table 1: Characteristics of participants in the study stratified by category of folic acid use

The association between FA use and fetal development features in the first, second and third trimester of conception are represented in Tables 2,3 and 4, respectively. As observed during the 1^st trimester and 2^nd trimester, there was a significant variation between the groups (Table 2 & 3). In the third trimester . Group 1 showed higher BPD (F-51.10667, P < 0.05), HC (F-687.97895, P- < 0.05), AC (F-55.82911, P- < 0.05),FL (F-222.27436, P- < 0.05),  and EFW (F-138.05683, P- < 0.05s) (Table 4). The fetal biometry of group 3 was significantly less compared to group 1 and 2. The third-trimester results indicate that women of group 1 EFW were optimal even though in group 2, EFW higher than group 3 (Table 4).

Table 2: First trimester fetal biometry.

**Associated fetal growth measurements by ultrasound in first trimester among women of preconception folic acid use, periconception folic acid use and  no use of  folic acid.

Values represented as mean ± SD, significance: p-value < 0.05

Table 3: Second trimester fetal biometry.

** Associated fetal growth measurements by ultrasound in second trimester among women of periconceprion folic acid use, periconception folic acid use and  no use of  folic acid.

Values represented mean ± SD, significance: p-value <0.05

Table 4: Third trimester fetal biometry.

**Associated fetal growth measurements by ultrasound in third trimester among women of  periconceprion folic acid use, periconception folic acid use and  no use of  folic acid.

Values represented mean ± SD, significance: p-value < 0.05

Discussion

Folate is  a type of vitamin-B, that is usually found in most of the day to day foods consumed by us¹⁵ and plays an important role in the synthesis of DNA and in division of cell¹⁶. Folate plays a vital role in homocysteine metabolism and helps retain adequate levels in the body¹⁷. The unavailability of FA is implicated in the causation of many diseases, namely anemia (megaloblastic variety)¹⁸, neurological problems¹⁹, and elevated homocysteine levels ²⁰. Folate as FA is utilized in dietary supplementations and fortified foodstuffs.

In this study, we reveal that preconceptional and periconceptional FA intake in the recommended dose of 0.4-0.5 mg/d is related to increased fetus growth ( Tables 2, 3, 4)compared to women who not used FA equivalence considerably changes the impact. Preconceptional and periconceptional FA intake are also correlated with decreased incidence of having infants with lower body weight at birth or being small for gestational age at birth.

Folate is vitamin B9; takes important role in cell division, programmed cell death, intracellular signaling, and programming. All these processes are essential to have a complete and wholesome fetal development⁷. Therefore, supplementation of FA during gestation influences fetal growth along with placental growth as well^{21,22, 23, 24, 25}.

Our study support earlier findings that demonstrated an optimistic association between elevated FA administration, with an increase in birth weight of the babies^{23, 26, 27, 28, 29}. The feal growth and development are maximum in 2^nd half of gestation. This contradicts many studies, where only the periconceptional and pre-conceptional periods are taken into account. An adequate FA intake throughout this crucial period might directly influence synthesis and division processes in the fetus. Few researches have estimated the association between folate supplementation versus an earlier period of conception and fetal growth¹². Many studies report a raise in incidence of  infants with higher birth weight in those women who begun to consume FA even before pregnancy.

Fascinatingly, decreased occurrence of  SGA was also reported in infants of women who preconceptionally began intake. Though, similar to many other studies that compared FA  and growth of the fetus, a higher dose of FA, i.e.up to 2·5 mg) was administered^30-34. This study stresses the importance of the periconceptional and preconceptional normal range of FA intake to be enough to ensure the increase in fetus growth.

The value of nuchal translucency thickness increased from group 1 to group 3 steadily in the first-trimester fetal biometry (Table 2). Group 1 and 2 had values nearer to the normal value of 1.30 ± 0.54³⁵. The same study also cites that the NT values in the 95^th percentile falling between 1.8 and 2.35 were associated with chromosomal anomalies in the fetus. Though nuchal translucency has been associated with fetal anomalies, the intake of FA and its relationship has been significantly proven in this study. The usual range of NT^36,37,38 has been found only in the first two groups (Table 2), and hence the preconceptional and periconceptional intake of FA has a direct relation with NT and has to study in further detail.

FA serves an essential role in the synthesis of homocysteine. An increase in homocysteine is correlated with a decrease in folate level, and increased homocysteine has been correlated to a reduction in placental vasculopathy and fetal growth^39-42. In the majority of the conditions of hyperhomocysteinemia, the treatment protocol consists of supplementing a low dose of FA⁴². Moreover, the endothelial function can be much improved by folate, irrespective of the homocysteine status.

Earlier studies demonstrated that FA intake of 5mg in the 2nd  or 3rd trimester could significantly increase the size of the placenta ^23,26,28. As the neural tube defects in India is as high as 4.5 per 1000 total births^43,44, the importance of folic acid consumption (0.4mg/d, as  recommended by WHO) can’t be stressed more. In this study, mothers who began consuming FA supplements preconceptionally have significantly higher fetal biometry than the female who started taking FA during the 1^st to 8^th week of gestation.

Conclusion

Preconceptional and periconceptional FA intake favors the growth of the fetus, decreases the risk of low birth weight babies. Intake of FA prior to conception is more beneficial to the growth of the fetus than periconceptional use.

Conflict of Interest

The authors report no conflict of interest.

Funding Sources

There is no funding source.

References

1. De Onis M, Villar J, Gulmezoglu M. Nutritional interventions to prevent intrauterine growth retardation: evidence from randomized controlled trials. Eur J Clin Nutr.,1998;52(Suppl 1):S83-93.
2. Abu-Saad K, Fraser D. Maternal Nutrition and Birth Outcomes. Epidemiol Rev 2010;32:5-25
   CrossRef
3. Barker DJ & Clark PM Foetal undernutrition and disease in later life. Rev Reprod 2.,1997; 105–112.
   CrossRef
4. Wu G, Bazer FW, Cudd TA, et al. Maternal nutrition and foetal development. J Nutr., 2004;134: 2169–2172
   CrossRef
5. Steegers-Theunissen RP & Steegers EA. Nutrient–gene interactions in early pregnancy: a vascular hypothesis.Eur J Obstet Gynecol Reprod Biol., 2003;106: 115–117
   CrossRef
6. V.E. Witthoft. C.M.Human Folate Bioavailability. Nutrients., 2011; 3:475-490.
   CrossRef
7. Tamura T & Picciano MF.Folate and human reproduction. Am J Clin Nutr., 2006; 83:993–1016.
   CrossRef
8. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. Institute of Medicine.,1998; https://doi.org/10.17226/6015.
   CrossRef
9. Centers for Disease Control .Economic burden of Spina bifida –United States, Morbidity and Mortality Weekly report. ,2004;Volume 35: Issue 8, page no. 64-70.
10. Baumslag N, Edelstein T & Metz J. Reduction of incidence of prematurity by FA supplementation in pregnancy.,1970;Br Med J 1: 16–17.
    CrossRef
11. Fawzi WW, Msamanga GI, Urassa W, et al. Vitamins and perinatal outcomes among HIV-negative women in N Engl J Med.,2007;356: 1423–1431.
    CrossRef
12. Rolschau J, Kristoffersen K, Ulrich M, et al. The influence of FA supplement on the outcome of pregnancies in the county of Funen in Denmark. Part I. Eur J Obstet Gynecol Reprod Biol., 1999; 87(2) :105–110
    CrossRef
13. Rolschau J, Date J & Kristoffersen K.FA supplement and intrauterine growth. Acta Obstet Gynecol Scand., 1979; 58: 343–346
    CrossRef
14. Rosenquist TH & Finnell RH. Genes, folate and homocysteine in embryonic development. Proc Nutr Soc., 2001; 60: 53–61.
    CrossRef
15. Combs GF. The Vitamins: fundamental aspects in nutrition and health. Burlington: Elsevier Academic Press.,2008; Pg 58
16. Kamen B. Folate and antifolate pharmacology. Semin Oncol.,1997; 24:S18-30- S18-39
17. Carmel R, Jacobsen DW. Homocysteine in Health and Disease. J R Soc Med., 2002s; 95(3): 159
    CrossRef
18. Wickramasinghe SN. Diagnosis of megaloblastic anaemias. Blood Rev., 2006; 20:299-318
    CrossRef
19. Hutto BR. Folate and cobalamin in psychiatric illness. Compr Psychiatry. 1997; 38:305-14
    CrossRef
20. Green R, Miller JW. Folate deficiency beyond megaloblastic anemia: hyperhomocysteinemia and other manifestations of dysfunctional
    folate status. Semin Hematol. 1999; 36:47-64
21. Rosemary A. Stamm and Lisa A. Houghton. Nutrient Intake Values for Folate during Pregnancy and Lactation Vary Widely around the World, Nutrients., 2013; 5(10): 3920–3947. doi: 10.3390/nu5103920
    CrossRef
22. Steegers-Theunissen RP, Boers GH, Blom HJ, et al.Hyperhomocysteinaemia and recurrent spontaneous abortion or abruptio placentae. Lancet., 1992; 339: 1122–1123
    CrossRef
23. Iyengar L & Rajalakshmi K.Effect of FA supplement on birth weights of infants. Am J Obstet Gynecol., 1975; 122: 332–336
    CrossRef
24. Timmermans S, Jaddoe VW, Hofman A, Steegers-Theunissen RP, Steegers EA. Periconception FA supplementation, fetal growth and the risks of low birth weight and preterm birth: the Generation R Study. British Journal of Nutrition. ,2009;102(5):777-85.
    CrossRef
25. Bleker OP, Buimer M, van der Post JA, van der Veen F. Ted (G.J.) Kloosterman. On intrauterine growth. The significance of prenatal care. Studies on birth weight, placental        weight and placental index. Placenta.,2006;27(11-12):1052–1054.  doi:10.1016/j. placenta.2006.01.001
    CrossRef
26. Goldenberg RL, Tamura T, Cliver SP, et al. Serum folate and foetal growth retardation: a matter of compliance? Obstet Gynecol., 1992; 79: 719–722
27. Scholl TO, Hediger ML, Schall JI, et al. Dietary and serum folate: their influence on the outcome of pregnancy. Am J Clin Nutr., 1996; 63: 520–525
    CrossRef
28. Tamura T, Goldenberg RL, Freeberg LE, et al. Maternal serum folate and zinc concentrations and their relationships to pregnancy outcome. Am J Clin Nut .,1992;56:365–370
    CrossRef
29. Neggers YH, Goldenberg RL, Tamura T, et al.The relationship between maternal dietary intake and infant birthweight. Acta Obstet Gynecol Scand., 1997;165: Suppl., 71–75.
30. Bailey LB & Gregory JF III .Folate metabolism and ,J Nutr 1999; 129: 779–782
    CrossRef
31. Maternal anthropometry and pregnancy outcomes. A WHO Collaborative Study: Introduction. Bull World Health Organ 1995.,73;(Suppl):1-6.
32. http//www.recog.org.UK/women-health/clinical.
33. Waterland RA & Jirtle RL. Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition., 2004;20: 63–68
    CrossRef
34. Steegers-TheunissenRPM. Maternal nutrition and obstetric outcome. In Clinical Obstetrics and Gynaecology. Preventive Care in Obstetrics.,1995;9: 431–445
    CrossRef
35. Sharifzadeh M, Adibi A, Kazemi K, Hovsepian S. Normal reference range of fetal nuchal translucency thickness in pregnant women in the first trimester, one center study. J Res Med Sci., 2015;20(10):969-973. doi:10.4103/1735-1995.172786
    CrossRef
36. Sun Q, Xu J, Hu SQ, Chen M, Ma RM, Lau TK, Zhang L, Xiao X, Qian Y, Guo Z. Distribution and normal reference range of fetal nuchal translucency thickness in Kunming pregnant women in the first trimester. Zhonghua Fu Chan Ke Za Zhi. 2012 ;47(7):514-7. Chinese. PMID: 23141162.
37. Karki S, Joshi KS, Tamrakar SR, Regmi S, Khanal K. Nuchal translucency in normal fetus and its variation with increasing crown rump length (CRL) and gestational age. Kathmandu Univ Med J., 2013;11(44):282-6. doi: 10.3126/kumj.v11i4.12522. PMID: 24899320.
    CrossRef
38. Hasegawa J, Nakamura M, Hamada S, Matsuoka R, Ichizuka K, Sekizawa A, Okai T. Distribution of nuchal translucency thickness in Japanese fetuses. J Obstet Gynaecol Res., 2013;39(4):766-9. doi: 10.1111/j.1447-0756.2012.02037.
    CrossRef
39. van der Molen EF, Verbruggen B, Novakova I, et al.Hyperhomocysteinemia and other thrombotic risk factors in women with placental vasculopathy. BJOG., 2000; 107: 785–791.
    CrossRef
40. DeVilbiss E.A., Mumford S.L., Sjaarda L.A., Connell M.T., Kim K., Mills J.L., Silver R.M. Schisterman E.F. Preconception folate status and reproductive outcomes among a prospective cohort of folate-replete women, American Journal of Obstetrics and Gynecology., 2019, 221(1):51.e1-51.e10
    CrossRef
41. Gaiday A.N., Tussupkaliyev A.B., Bermagambetova S.K., Zhumagulova S.S., Sarsembayeva L.K., Dossimbetova M.B., Daribay Z.Z.Effect of homocysteine on pregnancy: A systematic review, Chem Biol Interact 2018; 293: 70-6
    CrossRef
42. Modaghegh MH, Ravari H, Haghighi MZ, Rajabnejad A. Effect of FA therapy on Homocysteine Level in patients with Atherosclerosis or Buerger’s Disease and in Healthy individuals: A clinical trial. Electron Physician.,2016;25:8(10):3138-3143. doi: 10.19082/3138. PMID: 27957316
    CrossRef
43. Allagh KP, Shamanna BR, Murthy GV, et al. Birth prevalence of neural tube defects and orofacial clefts in India: a systematic review and meta-analysis. PLoS One. 2015;10(3):e0118961. doi:10.1371/journal.pone.0118961
    CrossRef
44. Paayal C, Ganesh U, Shaantanu D. Indian perspective on clinical aspects, usage, and guidelines of folic Acid. J Obstet Gynaecol India. 2014;64(5):328-331. doi:10.1007/s13224-014-0526-3
    CrossRef