Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Mar 23;15(7):1553.
doi: 10.3390/nu15071553.

Elevated Maternal Folate Status and Changes in Maternal Prolactin, Placental Lactogen and Placental Growth Hormone Following Folic Acid Food Fortification: Evidence from Two Prospective Pregnancy Cohorts

Tanja Jankovic-Karasoulos  1 , Melanie D Smith  1 , Shalem Leemaqz  1 , Jessica Williamson  1 , Dylan McCullough  1 , Anya L Arthurs  1 , Lauren A Jones  1 , Konstantinos Justin Bogias  1 , Ben W Mol  2 , Julia Dalton  3 , Gustaaf A Dekker  3   4 , Claire T Roberts  1
Affiliations

Elevated Maternal Folate Status and Changes in Maternal Prolactin, Placental Lactogen and Placental Growth Hormone Following Folic Acid Food Fortification: Evidence from Two Prospective Pregnancy Cohorts

Tanja Jankovic-Karasoulos et al. Nutrients. .

Abstract

Folic acid (FA) food fortification in Australia has resulted in a higher-than-expected intake of FA during pregnancy. High FA intake is associated with increased insulin resistance and gestational diabetes. We aimed to establish whether maternal one-carbon metabolism and hormones that regulate glucose homeostasis change in healthy pregnancies post-FA food fortification. Circulating folate, B12, homocysteine, prolactin (PRL), human placental lactogen (hPL) and placental growth hormone (GH2) were measured in early pregnancy maternal blood in women with uncomplicated pregnancies prior to (SCOPE: N = 604) and post (STOP: N = 711)-FA food fortification. FA food fortification resulted in 63% higher maternal folate. STOP women had lower hPL (33%) and GH2 (43%) after 10 weeks of gestation, but they had higher PRL (29%) and hPL (28%) after 16 weeks. FA supplementation during pregnancy increased maternal folate and reduced homocysteine but only in the SCOPE group, and it was associated with 54% higher PRL in SCOPE but 28% lower PRL in STOP. FA food fortification increased maternal folate status, but supplements no longer had an effect, thereby calling into question their utility. An altered secretion of hormones that regulate glucose homeostasis in pregnancy could place women post-fortification at an increased risk of insulin resistance and gestational diabetes, particularly for older women and those with obesity.

Keywords: folic acid; gestational diabetes mellitus; human placental lactogen; obesity; placental growth hormone; pregnancy; prolactin.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
One-carbon metabolism: Overview of one-carbon metabolism. Folic acid (FA) is reduced via dihydrofolate reductase (DHFR) to dihydrofolate (DHF) and tetrahydrofolate (THF). Methylenetetrahydrofolate dehydrogenase (MTHFD1) converts THF to intermediate metabolites 10-formyltetrahydrofolate (10-formylTHF), 5,10-methenyltetrahydrofolate (5,10-methenylTHF) and 5,10-methylenetetrahydrofolate (5,10-methyleneTHF). 5,10-methyleneTHF can be used in the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) via thymidylate synthase (TS) or to 5-methylTHF via methylenetetrahydrofolate reductase (MTHFR). 5-methylTHF is used for homocysteine remethylation to methionine, which is reliant on vitamin B12 (B12)-dependent methionine synthase (MTR). Methionine is converted to S-adenosylmethionine (SAM), a methyl donor in methylation reactions, and sequentially to S-adenosylhomocysteine (SAH), a substrate of homocysteine remethylation. Adapted from Williamson et al., 2022 [34].
Figure 2
Figure 2
Study flow chart: Study exclusion criteria are shown for both SCOPE and STOP, with final totals of N = 604 and N = 711 participants, respectively, who had uncomplicated pregnancies.
Figure 3
Figure 3
Red cell folate concentration in pregnant women prior to and post-FA food fortification: Data in the pre- and post-FA fortification categories are presented as medians (IQ range) and divided into two groups: women who did not take FA supplements (None, in red) and women who took FA supplements in the first trimester of pregnancy (Folic Acid, in green). The RCPA RCF reference range (360–1400 nmol/L) is represented by red dotted lines. The assay’s upper limit of detection is 1790 nmol/L. Measures of red cell folate were compared between STOP (N = 711) and a separate pre-FA fortification cohort (not SCOPE, N = 410) using the Mann–Whitney U test.
Figure 4
Figure 4
Serum hormone concentrations: PRL, hPL and GH2 concentrations across gestation are shown for SCOPE (N = 465) and STOP (N = 684) women with uncomplicated pregnancies. Estimated marginal means (±SEM) for SCOPE and STOP women at 10 weeks and 16 weeks of gestation are presented. Serum hormone (PRL, hPL and GH2) concentrations were analysed using a linear mixed effects model, adjusting for gestational age at sampling. Significance is indicated with asterisks (**** p < 0.0001 and *** p < 0.001).
Figure 5
Figure 5
Serum hormone concentrations stratified by FA supplementation: Estimated marginal means for (A) prolactin (PRL), (B) human placental lactogen (hPL) and (C) placental growth hormone (GH2) in SCOPE (14–16 weeks of gestation) and STOP (6–16 weeks) women are stratified by four different FA supplementation categories (SCOPE N = 465; STOP N = 624).
Figure 6
Figure 6
Prolactin concentrations stratified by maternal age and BMI: PRL in early gestation SCOPE (N = 465) and STOP (N = 684) women was stratified by maternal age and BMI status. Women were stratified as younger than 35y or 35y and older, and non-obese (healthy BMI) and obese.
Figure 7
Figure 7
Human placental lactogen (hPL) concentrations stratified by maternal age and BMI: hPL in early gestation SCOPE (N = 465) and STOP (N = 684) women was stratified by maternal age and BMI status. Women were stratified as younger than 35y or 35y and older, and non-obese (healthy BMI) and obese.
Figure 8
Figure 8
Placental growth hormone (GH2) concentrations stratified by maternal age and BMI: GH2 in early gestation SCOPE (N = 465) and STOP (N = 684) women was stratified by maternal age and BMI status. Women were stratified as younger than 35y or 35y and older and as non-obese (healthy BMI) or obese.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Molloy A.M., Kirke P.N., Brody L.C., Scott J.M., Mills J.L. Effects of folate and vitamin B12 deficiencies during pregnancy on fetal, infant, and child development. Food Nutr. Bull. 2008;29((Suppl. S2)):S101–S111;. doi: 10.1177/15648265080292S114. discussion S112–S105. - DOI - PubMed
    1. Field M.S., Stover P.J. Safety of folic acid. Ann. N. Y. Acad. Sci. 2018;1414:59–71. doi: 10.1111/nyas.13499. - DOI - PMC - PubMed
    1. MRC-Vitamin-Study-Research-Group Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet. 1991;338:131–137. doi: 10.1016/0140-6736(91)90133-A. - DOI - PubMed
    1. Czeizel A.E., Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N. Engl. J. Med. 1992;327:1832–1835. doi: 10.1056/NEJM199212243272602. - DOI - PubMed
    1. Murphy M.E., Westmark C.J. Folic Acid Fortification and Neural Tube Defect Risk: Analysis of the Food Fortification Initiative Dataset. Nutrients. 2020;12:247. doi: 10.3390/nu12010247. - DOI - PMC - PubMed
-