1) Micronutrient deficiencies during the periconceptional period can lead to adverse pregnancy outcomes such as infertility, fetal abnormalities, miscarriage, and preeclampsia. The periconceptional period involves critical stages of embryonic development. 2) Folate, vitamin B12, and vitamin B6 are especially important as they are involved in DNA replication, cell cycle regulation, and amino acid metabolism including the homocysteine-methionine cycle. 3) Studies have shown that folate status is associated with ovarian response to stimulation and embryo quality, with folate supplementation improving outcomes. Folate and other B vitamins may also help prevent orofacial clefts.

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FEMALE INFERTILITY
NUTRITION DURING PERICONCEPTIONAL AND
IN DIFFERENT STAGES OF PREGNANCY
Anjala Sikri

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PROPHYLACTIC USE OF MICRONUTRIENTS IN PREVENTING ADVERSE
PREGNANCY OUTCOMES
Micronutrient deficiencies have been associated with significantly high reproductive risks,
ranging from infertility to fetal structural defects and long-term diseases. In this leaflet we will
focus on the reproductive risks related to some micronutrients during the periconceptional
period, a critical step in determining fetal development and health due to the potential onset of
several disorders.
 The periconceptional period consists of preconception, conception, implantation, placentation and
embryo- or organogenesis stages and specific cellular events occurs during the distinct stages of
embryogenesis and this period is critical as it may affect fetal development and health and also the
onset of several malformations and pregnancy related disorders i.e. congenital abnormalities, fetal loss,
miscarriage, insufficient fetal growth, premature birth and preeclampsia etc.
 Micronutrients seem to affect pregnancy outcomes through alterations in maternal and fetal metabolism
due to their role/involvement in enzymes, signal transduction and transcription and Table I shows the
main functions of different micronutrients.
Main functions of micronutrients involved in the periconceptional period
Micronutrient Function
Folate Involvement in the DNA replication (cell cycle); methylation cycle (amino acids
cysteine and methionine cycle)
Vitamin B12 Conversion of homocysteine to methionine as cofactor of the methioninsynthase
Vitamin B6 Metabolism of amino acids, lipids, one-carbon units and glycogen as co-enzyme;
pathways of gluconeogenesis, heme and neurotransmitter biosynthesis
Vitamin A Growth and differentiation of a number of cells and tissues
Iron Haematopoiesis; nucleic acid metabolism; carrier of oxygen to the tissues by red
blood cell haemoglobin; transport medium for electrons within cells; integrated
part of important enzyme systems
Antioxidant Defence systems against free radical species
Zinc Structural, regulatory and catalytic functions as cofactor for numerous
metalloenzymes
Copper Neurotransmission, neuroropeptide maturation, oxidative phosphorylation,
defence from free radical damage as cofactor for numerous cuproenzymes and
copper-binding proteins
Table 1
 The nutritional status of women must be a goal for preventing detrimental nutritional unbalances especially
preconceptional nutrition is crucial for an optimal onset and development of pregnancy.
 Diet during the first trimester may be more important to development and differentiation of various organs.
 The prophylactic use of some micronutrients may be useful in preventing several adverse pregnancy
outcomes

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HOMOCYSTEINE METABOLISM
 Homocysteine is a sulfur amino acid whose metabolism stands at the intersection of two pathways:
1.remethylation to methionine, which requires folate and vitamin B12 (or betaine in an alternative
reaction); and 2. transsulfuration to cystathionine, which requires pyridoxal-5'-phosphate. The two
pathways are coordinated by S-adenosylmethionine, which acts as an allosteric inhibitor of the
methylenetetrahydrofolate reductase reaction and as an activator of cystathionine beta-synthase as
shown in figure 1
Figure 1
1. Vitamin B12 deficiency prevents the generation of methionine from homocysteine by trapping folate as
5-methyltetrahydrofolate, and subsequently reduces protein synthesis and lean tissue deposition.
2. Folate functions as a co-enzyme in single-carbon transfers in the metabolism of aminoacids and nucleic
acids. Moreover, folate is the substrate donor in the remethylation of homocysteine into methionine,
catalyzed by methionine synthase and 5,10-methylenetetrahydrofolatereductase (MTHFR)

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FOLIC ACID AND OVARIAN HYPERSTIMULATION
 Folate-deficient women undergoing COH have lower oocyte quality, lower pregnancy rates, and
impaired ovarian function and it was shown in an randomized trial among subfertile women in which 24
and 26 subjects received conventional and mild ovarian stimulation, respectively. Folic acid use was
validated by questionnaire and serum folate levels. Preovulatory follicles were visualized, counted, and
diameters recorded using transvaginal ultrasound. The relation between folic acid use and ovarian
response was assessed thus It was concluded that Folate status is associated with the quality of many
parameters in human reproduction, from gamete and embryo quality to the occurrence of congenital
malformations and folates also attenuate the ovarian response to ovarian stimulation treatment.
IMPORTANCE OF ROS
 Reactive oxygen species (ROS), reactive nitrogen species and reactive chlorine species are produced
in humans and animals under physiological and pathological conditions .Free radicals play a key role in
the origin of life and biological evolution, such as signal transduction and gene transcription, regulating
platelet B aggregation, leukocyte adhesion and angionesis, mediation of the immune response and are
also involved in female reproduction such as folliculogenesis, oocyte maturation, ovulation, corpus
luteum formation, endometrial cycle, luteolysis, implantation, embryogenesis and pregnancy. Thus,
imbalance in homeostatic control of ROS exposure causes OS, which can affect fertilization and induce
apoptosis, resulting in embryo fragmentation, implantation failure or abortion or impair metabolic activity
within embryos for fetal and post-natal development.
ROLE OF FOLIC ACID AND PYRIDOXINE IN PREVENTION OF OROFACIAL CLEFT
 Periconceptional intake of thiamine, niacin and pyridoxine seems to contribute to the prevention of OFC
(orofacial clefts) and it was studied in two hundred and six mothers of a child with nonsyndromic OFC
and 203 control mothers who filled out a general questionnaire and a food frequency questionnaire. The
periconceptional intake of thiamine, niacin and pyridoxine was significantly found to be lower in mothers
of an OFC child.

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ABBREVATIONS:
 MTHFR-5,10-METHYLENETETRAHYDROFOLATEREDUCTASE
 OFC- OROFACIAL CLEFT
 OS-OVARIAN STIMULATION
 ROS-REACTIVE OXYGEN SPECIES
REFERENCES:
 Krapels IP, van Rooij IA, Ocké MC, van Cleef BA, Kuijpers-Jagtman AM, Steegers-Theunissen RP.
Maternal dietary B vitamin intake, other than folate, and the association with orofacial cleft in the
offspring. Eur J Nutr. 2004 Feb;43(1):7-14. Epub 2004 Jan 6.
 Cetin I, Berti C, Calabrese S. Role of micronutrients in the periconceptional period. Human
Reproduction Update, Vol.16, No.1 pp. 80–95, 2010
 John M. Twigt, Fatima Hammiche, Kevin D. Sinclair et al. Preconception Folic Acid Use Modulates
Estradiol and Follicular Responses to Ovarian Stimulation J Clin Endocrinol Metab 96: E322–E329,
2011