{"id":41681,"date":"2021-12-30T11:58:17","date_gmt":"2021-12-30T11:58:17","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=41681"},"modified":"2022-01-04T06:54:14","modified_gmt":"2022-01-04T06:54:14","slug":"folic-acid-supplementation-on-fetal-growth-at-different-gestational-ages","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol14no4\/folic-acid-supplementation-on-fetal-growth-at-different-gestational-ages\/","title":{"rendered":"Folic Acid Supplementation on Fetal Growth at Different Gestational Ages"},"content":{"rendered":"

Introduction<\/strong><\/p>\n

Pregnancy usually necessitates a higher consumption of all nutrients. Insufficient nutritional intake peri- conceptionally can result in fetal weight discrepancies and other congenital anomalies1,2<\/sup>. 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<\/sup>.<\/p>\n

Folic acid \u00a0[FA] is vitamin B9,\u00a0\u00a0 <\/sub>rich in whole grains, kale, leafy vegetables, and orange.\u00a0 During fetal growth, cells proliferate enormously and require a high quantity of folate to synthesize DNA and RNA6<\/sup>. Therefore, FA demand is increased during pregnancy because of placental and fetal growth7<\/sup>.\u00a0 Insufficient folate ingestion results in reduced serum and RBC\u2019s folate\u00a0concentrations, elevated homocysteine (Hcy) level, and megaloblastic alterations in the hemopoitic cells and also other fast cleaving cells8<\/sup>. Thus folate deficiency elevates the risk for several developmental anomalies, like defects in the neural tube and congenital birth defects5,7<\/sup>. Administration of 400 \u00b5g daily before conception and also during pregnancy can decrease the\u00a0possibility of the fetus having neural tube defects. Earlier studies have established that periconceptional FA intake can avoid 60 to 70% of \u00a0defects of neural tube, including anencephaly, rachichisis and spina bifida.<\/p>\n

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\u00a0around 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<\/sup>. \u00a0<\/sup><\/p>\n

Various investigations have revealed a positive correlation between FA consumption and fetus development10, 11<\/sup>. 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\u00a0effect of FA administration during early fetal development12<\/sup>. 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\u00a0the fetus5,13<\/sup> and is still in hypothetical phase14<\/sup>. Therefore the present study investigates whether periconceptional maternal FA intake aids in the growth of a fetus.<\/p>\n

Materials and Methods<\/strong><\/p>\n

Study Design<\/strong><\/p>\n

This study was carried out at\u00a0 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.\u00a0 Self-reported FA intake was collected from the\u00a0information 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\u00a0(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;\u00a0 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\u00a0conception 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\u00b74\u20130\u00b75 mg\/d, usually in the form of multivitamins.<\/p>\n

Fetal ultrasound was performed on all subjects recruited for the study during the 1st, 2nd,<\/sup> 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.<\/p>\n

All the data were computed as mean \u00b1 standard error. The data analysis was done by \u00a0employing 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<\/p>\n

Results<\/strong><\/p>\n

During the period between 2016 and 2018, 180 pregnant women took part in this study. Table 1 lists the features of \u00a0women 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\u00a0 65% (39) were multiparous. Among group 3, 56.66% (34) were Nulliparous and 43.33% (26) were multiparous.<\/p>\n

Table 1: Characteristics of participants in the study stratified by category of folic acid use<\/strong><\/p>\n\n\n\n\n\n\n\n\n
<\/td>\nGroup 1<\/strong><\/td>\nGroup 2<\/strong><\/td>\nGroup 3<\/strong><\/td>\n<\/tr>\n
Mean age (years) Mean \u00b1 SD<\/strong><\/td>\n26.66 \u00b1 5.37<\/td>\n26.62\u00a0 \u00b1 5.01<\/td>\n26.9 \u00b1 4.13<\/td>\n<\/tr>\n
Height (cm) Mean \u00b1 SD<\/strong><\/td>\n155.4\u00a0 \u00b1\u00a0 4.81<\/td>\n156.35 \u00b1 6.01<\/td>\n155.6 \u00b1 5.87<\/td>\n<\/tr>\n
Weight (kg) Mean \u00b1 SD<\/strong><\/td>\n62.69\u00a0 \u00b1 3.77<\/td>\n62.67 \u00b1 3.93<\/td>\n62.4 \u00b1 5.87<\/td>\n<\/tr>\n
Nulliparous\u00a0 [n (%)]<\/strong><\/td>\n19 (31.66)<\/td>\n21 (35)<\/td>\n34 (56.66)<\/td>\n<\/tr>\n
Multiparous [n (%)]<\/strong><\/td>\n41 (68.33)<\/td>\n39 (65)<\/td>\n26 (43.33)<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

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 1st<\/sup> trimester and 2nd<\/sup> 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-\u00a0< 0.05), AC (F-55.82911, P- < 0.05),FL (F-222.27436, P- < 0.05),\u00a0 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).<\/p>\n

Table 2: First trimester fetal biometry.<\/strong><\/p>\n\n\n\n\n\n\n\n
First trimester**<\/strong><\/td>\n<\/tr>\n
Parameters<\/strong><\/td>\nGroup 1 (Mean \u00b1\u00a0 SD)<\/strong><\/td>\nGroup 2<\/strong><\/p>\n

\u00a0(Mean \u00b1\u00a0 SD)<\/strong><\/td>\n

Group 3 (Mean \u00b1\u00a0 SD)<\/strong><\/td>\nf-ratio value<\/strong><\/td>\nP-value<\/strong><\/td>\n<\/tr>\n
Crown-rump length (mm)<\/strong><\/td>\n70.45 \u00b1 1.0<\/td>\n67.64 \u00b1 0.68<\/td>\n65.01 \u00b1 0.54<\/td>\n69.00654<\/td>\n<0 .00001<\/td>\n<\/tr>\n
Biparietal diameter (mm)<\/strong><\/td>\n21.38 \u00b1 0.74<\/td>\n19.95 \u00b1 0.55<\/td>\n18.86 \u00b1 0.38<\/td>\n28.5897<\/td>\n< 0.00001<\/td>\n<\/tr>\n
Nuchal translucency (mm)<\/strong><\/td>\n1.68 \u00b1 0.05<\/td>\n1.74 \u00b1 0.01<\/td>\n1.93 \u00b1 0.03<\/td>\n62.9278<\/td>\n< 0.00001<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

**Associated fetal growth measurements by ultrasound in first trimester among women of preconception folic acid use, periconception folic acid use and\u00a0 no use of\u00a0 folic acid.<\/p>\n

Values represented as mean \u00b1 SD, significance: p-value < 0.05<\/p>\n

Table 3: Second trimester fetal biometry.<\/strong><\/p>\n\n\n\n\n\n\n\n\n
\u00a0Second trimester\u00a0**<\/strong><\/td>\n<\/tr>\n
Parameters<\/strong><\/td>\nGroup 1<\/strong><\/p>\n

\u00a0(Mean \u00b1\u00a0 SD)<\/strong><\/td>\n

Group 2<\/strong><\/p>\n

\u00a0(Mean \u00b1\u00a0 SD)<\/strong><\/td>\n

Group 3<\/strong><\/p>\n

(Mean \u00b1\u00a0 SD)<\/strong><\/td>\n

\u00a0f-ratio value<\/strong><\/td>\nP-value<\/strong><\/td>\n<\/tr>\n
Head circumference (mm)<\/strong><\/td>\n179.38\u00a0 \u00b1 0.69<\/td>\n180.16\u00a0 \u00b1 0.35<\/td>\n181.8\u00a0 \u00b1 0.52<\/td>\n30.94421<\/td>\n< .00001<\/td>\n<\/tr>\n
Abdominal circumference (mm)<\/strong><\/td>\n169.26\u00a0 \u00b1 3.39<\/td>\n159.26\u00a0 \u00b1\u00a0 2.81<\/td>\n154.88\u00a0 \u00b1 2.40<\/td>\n38.74229<\/td>\n\u00a0< .00001<\/td>\n<\/tr>\n
Femur length (mm)<\/strong><\/td>\n35.26\u00a0 \u00b1 1.38<\/td>\n34.43\u00a0 \u00b1 0.97<\/td>\n33.38\u00a0 \u00b1 0.52<\/td>\n5.10725<\/td>\n0.020338<\/td>\n<\/tr>\n
Biparietal Diameter (mm)<\/strong><\/td>\n50.85\u00a0 \u00b1 1.66<\/td>\n49.71\u00a0 \u00b1 1.09<\/td>\n47.91\u00a0 \u00b1 1.22<\/td>\n7.20532<\/td>\n\u00a00.006411.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

** Associated fetal growth measurements by ultrasound in second trimester among women of periconceprion folic acid use, periconception folic acid use and\u00a0 no use of\u00a0 folic acid.<\/p>\n

Values represented mean \u00b1 SD, significance: p-value <0.05<\/p>\n

Table 4: Third trimester fetal biometry.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n
\n

Third Trimester**<\/strong><\/p>\n<\/td>\n<\/tr>\n

Parameters<\/strong><\/td>\nGroup 1<\/strong><\/p>\n

\u00a0(Mean \u00b1\u00a0 SD)<\/strong><\/td>\n

Group 2<\/strong><\/p>\n

\u00a0(Mean \u00b1\u00a0 SD)<\/strong><\/td>\n

Group 3<\/strong><\/p>\n

(Mean \u00b1\u00a0 SD)<\/strong><\/td>\n

\u00a0f-ratio value<\/strong><\/td>\nP-value<\/strong><\/td>\n<\/tr>\n
Biparietal Diameter (mm)<\/strong><\/td>\n84.03\u00a0 \u00b1 0.90<\/td>\n82.5\u00a0 \u00b1 0.86<\/td>\n78.53\u00a0 \u00b1 1.12<\/td>\n51.10667<\/td>\n< .00001<\/td>\n<\/tr>\n
Head circumference (mm)<\/strong><\/td>\n300.51\u00a0 \u00b1 1.53<\/td>\n294.10\u00a0 \u00b1 1.31<\/td>\n269.56\u00a0 \u00b1 1.70<\/td>\n687.97895<\/td>\n< .00001<\/td>\n<\/tr>\n
Abdominal circumference (mm)<\/strong><\/td>\n296.76\u00a0 \u00b1 6.98<\/td>\n286.25\u00a0 \u00b1 4.58<\/td>\n264.16\u00a0 \u00b1 4.41<\/td>\n55.82911<\/td>\n< .00001<\/td>\n<\/tr>\n
Femur length (mm)<\/strong><\/td>\n62.21\u00a0 \u00b1 0.54<\/td>\n60.2\u00a0 \u00b1 0.25<\/td>\n55.31\u00a0 \u00b1 0.80<\/td>\n222.27436<\/td>\n< .00001<\/td>\n<\/tr>\n
EFW (grms)<\/strong><\/td>\n2409.18\u00a0 \u00b1 82.37<\/td>\n2007.26\u00a0 \u00b1 49.76<\/td>\n1776.71\u00a0 \u00b1 63.99<\/td>\n138.05683<\/td>\n\u00a0< .00001<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

**Associated fetal growth measurements by ultrasound in third trimester among women of\u00a0 periconceprion folic acid use, periconception folic acid use and\u00a0 no use of\u00a0 folic acid.<\/p>\n

Values represented mean \u00b1 SD, significance: p-value < 0.05<\/p>\n

Discussion<\/strong><\/p>\n

Folate is \u00a0a type of vitamin-B, that is usually found in most of the day to day foods consumed by us15<\/sup> and plays an important role in the synthesis of DNA and in division of cell16<\/sup>. Folate plays a vital role in homocysteine metabolism and helps retain adequate levels in the body17<\/sup>. The unavailability of FA is implicated in the causation of many diseases, namely anemia\u00a0(megaloblastic variety)18<\/sup>, neurological problems19<\/sup>, and elevated homocysteine levels 20<\/sup>. Folate as FA is utilized in dietary supplementations and fortified foodstuffs.<\/p>\n

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\u00a0lower body weight at birth or being small for gestational age at birth.<\/p>\n

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<\/sup>. Therefore, supplementation of FA during gestation influences fetal growth along with placental growth as well21,22, 23, 24, 25<\/sup>.<\/p>\n

Our study support earlier findings that demonstrated an optimistic association between elevated FA administration, with an increase in birth weight of the babies23, 26, 27, 28, 29<\/sup>. The feal growth and development are maximum in 2nd<\/sup> half of gestation. This contradicts many studies, where only the periconceptional and pre-conceptional periods are taken into account. An adequate\u00a0FA 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<\/sup>. Many studies report a raise in incidence of\u00a0 infants with higher birth weight in those women who begun to consume FA even before pregnancy.<\/p>\n

Fascinatingly, decreased occurrence of\u00a0 SGA was also reported in infants of women who preconceptionally began intake. Though, similar to many other studies that compared FA \u00a0and growth of the fetus, a higher dose of FA, i.e.up to 2\u00b75 mg) was administered30-34<\/sup>. This study stresses\u00a0the importance of the periconceptional and preconceptional normal range of FA intake to be enough to ensure the increase in fetus growth.<\/p>\n

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 \u00b1 0.5435<\/sup>. The same study also cites that the NT values in the 95th<\/sup> percentile falling between 1.8 and 2.35 were associated with chromosomal anomalies in the fetus. Though nuchal\u00a0translucency has been associated with fetal anomalies, the intake of FA and its relationship has been significantly proven in this study. The usual range of NT36,37,38<\/sup> 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.<\/p>\n

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 growth39-42<\/sup>. In the majority of the conditions of hyperhomocysteinemia, the treatment protocol consists of supplementing a low dose of FA42<\/sup>.\u00a0Moreover, the endothelial function can be much improved by folate, irrespective of the homocysteine status.<\/p>\n

Earlier studies demonstrated that FA intake of 5mg in the 2nd \u00a0or 3rd trimester could significantly increase the size of the placenta 23,26,28<\/sup>. As the neural tube defects in India is as high as 4.5 per 1000 total births43,44<\/sup>, the importance of folic acid consumption (0.4mg\/d, as\u00a0 recommended by WHO) can\u2019t 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 1st<\/sup> to 8th<\/sup> week of gestation.<\/p>\n

Conclusion<\/strong><\/p>\n

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.<\/p>\n

Conflict of Interest<\/strong><\/p>\n

The authors report no conflict of interest.<\/p>\n

Funding Sources
\n<\/strong><\/p>\n

There is no funding source.<\/p>\n

References<\/strong><\/p>\n

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