ROLE OF FOLIC ACID IN OBSTETRICS

AND GYNAECOLOGY

Dr. NOREEN BILAL

ASST. PROF. OBSTETRICS & GYNAECOLOGY
ALLIED HOSPITAL, FAISALABAD
 FOLATE
 FOLATE WATER SOLUBLE VITAMINE B9 AND FOLIC ACID
DERIVE THEIR NAMES FROM THE LATIN WORD FOLIUM,
WHICH MEANS "LEAF“
 HUMANS CANNOT SYNTHESIZE FOLATES DE NOVO;
THEREFORE, FOLIC ACID HAS TO BE SUPPLIED THROUGH THE
DIET TO MEET THEIR DAILY REQUIREMENTS
 HUMAN BODY NEEDS FOLATE TO SYNTHESIZE DNA, REPAIR
DNA, AND METHYLATE DNA AS WELL AS TO ACT AS A
COFACTOR IN CERTAIN BIOLOGICAL REACTIONS
 IMPORTANT IN AIDING RAPID CELL DIVISIONAND GROWTH,
SUCH AS IN INFANCY AND PREGNANCY.
•
 L-METHYLFOLATE
 Neither folate nor folic acid is metabolically active
 Both must be reduced to participate in cellular metabolism.
 l-5-methyltetrahydrofolate
– the predominant micronutrient form of folate that
circulates in plasma and that is involved in biologic
processes
FOLATE METABOLISM
MAJOR ROLE TO PLAY
 To provide l-methylfolate for the one-carbon transfer
reactions (methyl donations) needed for
purine/pyrimidine synthesis during DNA and RNA
assembly, for DNA methylation, and to regulate
homocysteine metabolism

 MTHFR is the critical enzyme for almost all biologic

processes that involve the metabolism of folate and
methionine.
GENETIC POLYMORPHISMS AND FOLIC ACID METABOLISM

• Genetic variations (polymorphisms) are common within the

human genome and, in some cases, can result in the
production of proteins with altered biologic activity
• such polymorphisms have been identified in the genes
encoding proteins involved in folate metabolism
• metabolic processes requiring methyl group donations are
regulated by the enzyme MTHFR
• In the United States,
– 60% of the population are intermediate metabolizers of folate or
heterozygous for genetic polymorphism of the MTHFR enzyme
– 25% of certain populations are homozygous for these genetic
variations.
 These polymorphisms impair the conversion of
folate to its active form, L-methylfolate.
 Supplementation with L-methylfolate rather
than folic acid as a means of preventing folate-
related pathology.
 SERUM FOLATE

• A combination of serum or erythrocyte

concentration used to assess folate status
• Total body content of folate is estimated to
be 10 to 30 mg
• Serum folate concentration value above 3
nanograms (ng)/mL indicating adequacy 
 ERYTHROCYTE FOLATE CONCENTRATION

• provides a longer-term measure of folate

intakes
• concentration above 140 ng/mL indicates
adequate folate status
PLASMA HOMOCYSTEINE CONCENTRATION

functional indicator of folate status .

• Highly specific indicator of folate status
because they can be influenced by other
factors, including kidney dysfunction and
deficiencies of vitamin B12 and other
micronutrients
• Cutoff value 16 micromoles/L, although slightly
lower values of 12 to 14 micromoles/L have
also been used
SOURCES
• Naturally , including vegetables
(especially dark green leafy
vegetables)
• Fruits and fruit juices, nuts,
beans, peas, dairy products,
poultry and meat, eggs,
seafood, and grains
• Spinach, liver, yeast, asparagus,
and Brussels sprouts are among
the foods with the highest levels
of folate.
FOLATE AND PREGNANCY OUTCOME
 PHYSIOLOGICAL CHANGES IN PREGNANCY

• Blood volume expansion resulting from an increase in both

plasma and erythrocytes is a normal physiologic change of
pregnancy.
• More plasma than erythrocytes is usually added to the
maternal circulation, the increase in erythrocyte volume is
considerable, averaging about 450 mL.
• Hemoglobin concentration and hematocrit normally
decrease slightly during pregnancy.
• Hemoglobin concentrations at term average 12.5 g/dL,
approximately 5% of women are anemic, with hemoglobin
concentrations below 11.0 g/dL
 Cont….
• for active erythropoiesis need adequate supplies
of three key nutrients: folate, cobalamin (vitamin
B12), and iron
•   normal erythropoieses involving both folate and
vitamin B12 is the transfer of a methyl group from L-
methylfolate to homocysteine via methylcobalamin
for the regeneration of methionine
• low folate and/or vitamin B12, anemia will likely
ensue.
FOLATE DEFICIENCY AND HYPERHOMOCYSTEINEMIA IN
FEMALE REPRODUCTION
 FOLATE-DEPENDENT PROCESSES

 AN INCREASE IN RED CELL MASS

 ENLARGEMENT OF THE UTERUS
 GROWTH OF THE PLACENTA AND FETUS.
 FOR FETAL DEVELOPMENT

• required for cell division because of its role in

DNA synthesis
• Central feature of fetal development is
widespread and sustained cell division. As a
result of its role in nucleic acid synthesis, the
need for folate increases during times of rapid
tissue growth
 Folate deficiency
in Pakistan
is
39.7%*
Journal of the College of Physicians and Surgeons Pakistan 2009, Vol. 19 (5): 308-312
 Causes of Folate Deficiency

• Dietary deficiency (Alcoholism, dietary fads)

• Poor intake
• Old age
• Poor social conditions
• Malnutrition
• Alcohol excess (also causes impaired utilization)
• Poor intake due to anorexia
• Food fads
• The body's reserves of folate, unlike vitamin
B12, are low and only sufficient for around
four months
• Folate is usually absorbed through the upper
part of the small intestine
 CONT….

absolute and relative folate deficiencies during pregnancy.

– Absolute folate deficiency stemmed from too little folate in the
diet—a supply and demand problem.
– A relative folate deficiency was said to arise from a metabolic
defect in the utilization of dietary folate that was manifested
early in gestation under the stress of pregnancy

Hibbard went on to suggest that most fetal misfortunes occurred

in women with early disturbances in folate metabolism 
 What are the
consequences
of
Folate Deficiency?
 Folic Acid
Deficiency

Mother Child

Neural Tube
Anemia
Defects

Peripheral
Neuropathy
MEGALOBLASTIC ANEMIA
 MEGALOBLASTIC ANEMIA

Interference with DNA synthesis gives rise to

abnormal cell division
Rapidly dividing cells, such as those in the
hematopoetic system, are the most susceptible
to irregularities in DNA production.
 Hypersegmentation of the neutrophils, followed
later by the production of megablastic marrow
cells, macrocytic red cells, and ultimately
macrocytic anemia
NEURAL TUBE DEFECTS - NTDs
 NTDs in Pakistan
“46 out 3310 (1.4%) babies were affected
by Neural Tube Defects”

Gomal Journal of Medical Sciences January–June 2008, Vol. 6, No. 1

“Of 46 women with affected
babies,
ALL had not taken folic acid
supplements in their first
trimester”

Gomal Journal of Medical Sciences January–June 2008, Vol. 6, No. 1

“Studies have demonstrated
that periconceptional
folic acid supplementation
can prevent 50% or more of
NTDs”
http://pediatrics.aappublications.org/content/104/2/325.full
 NEURAL TUBE DEFECT

 Congenital malformations that result from failure of

the neural tube to close during embryogenesis
 The primordial central nervous system begins as a
plate of cells early in embryonic life, which folds on
itself to form a tube. Closure of the tube occurs in the
interval of days 21–28 postconception.
 Failure of closure results in NTDs
 Cranial defect is anencephaly, caudal defect is spina
bifida including meningocele and meningomyelocelei
 NEURAL TUBE DEFECTS

The cell's ability to methylate important compounds such

as proteins, lipids and myelin will be compromised by
deficiency of folate or vitamin B12, resulting in impaired
cellular function.
Interruption of DNA biosynthesis or methylation reactions
could prevent the proper closure of the neural tube.
Neural tube defect
SPONTANEOUS ABIRTION
 SPONTANEOUS ABORTION

• Frequency of NTDs among spontaneously aborted

fetuses is 10-fold higher than is the rate of NTDs at birth

• A rat model of folate deficiency suggests that severe

gestational folate deficiency increases the risk of fetal
demise
 HOMOCYSTEINE A CULPRIT

 About one-half of the pregnancies occurring

in women with hereditary homocystinuria
terminate in fetal demise
Although circulating concentrations of folate
bear little relation to risk of spontaneous
abortion
PLACENTAL ABRUPTION
 PLACENTAL ABRUPTION

Hibbard described an increased risk of placental abruption in

gravidas DUE TO defect in folate metabolism.
• Genetic polymorphism affecting folate metabolism—the heat-
labile C677T mutation—was associated with a >2-fold increase in
the risk of preeclampsia among Japanese gravidas who were
homozygous for the mutation .
• Hyperhomocysteinemia, a marker for folate deficiency or
metabolic abnormality, has been associated with serious
complications such as pregnancy-induced hypertension,
preeclampsia
• All are risk factors for intrauterine growth restriction and
preterm delivery
 CONT..

• 207 patients with a history of preeclampsia or fetal

growth restriction for hyperhomocystenemia
• patients testing positive (17%) were supplemented
with folic acid and vitamin B-6.
• infant birth weight increased by nearly 1800 g and
gestation duration increased by 7.2 wk when first
and subsequent pregnancies were compared.
PRETERM BIRTH AND WEIGHT TO FOLATE
 PRETERM BIRTH AND WEIGHT TO FOLATE

  Risk of spontaneous PTB was inversely related to the

duration of folic acid supplementation, and was lowest
in women who reported using folic acid
supplementation for more than 1 year prior to
conception.
 Role of folate in DNA synthesis and cell replication
suggests that folate can influence fetal growth and
gestation duration
 CONT…

Low folate intake (<240 ng folate/d) was associated

with a >3-fold increase in risk of infant low birth
weight and of preterm delivery
• Circulating folate at week 28 was also associated with
risk; the adjusted odds ratio for low birth weight
increased by 1.5% and the odds ratio for preterm
delivery increased by 1.6% per unit (nmol/L) for each
unit decrease in serum folate at week 28

Bukowski R, Malone FD, Porter FT, et al. Preconceptional folate supplementation and the
risk of spontaneous preterm birth: a cohort study. PLoS Med. 2009;6:e1000061.
FOLATE AND GYNAECOLOGICAL
PROBLEMS
INFERTILITY
 INFERTILITY

• Folate is necessary for the men and women

contributes  to spermatogenesis Therefore, it
is necessary to receive sufficient amounts
through the diet to avoid subfertility.
• Polymorphisms in genes of enzymes involved
in folate metabolism could be one reason for
fertility complications in some women
with unexplained infertility.
FOLATE, HOMOCYSTEINE, AND FOLLICULOGENESIS

• Recently, the impact of folate-mediated OCM has also been investigated

concerning earlier stages of female reproductive physiology
• Hcy concentration in follicular fluid was found to be positively correlated
to follicle diameter

• Elevated Hcy levels in pooled follicular fluid samples were negatively

associated with oocyte maturity87 and in vitro embryo quality on culture at
day 3

• Similar results were reported in a very recent study of IVF patients with
polycystic ovary syndrome. In this study, negative correlations were found
between follicular Hcy concentration and fertilization rate as well as
oocyte and embryo quality, confirming further that Hcy in follicular fluid
may play an important role in the maturation of oocytes and fertilization
GYNAECOLOGICAL CANCEROUS CONDITION
GYNAECOLOGICAL CANCEROUS CONDTIONS

• Methotrexate is an antifolate drug which inhibits cell

division by interfering with DNA replication
• It is used clinically in medicine to treat a range of
cancerous and noncancerous conditions.
• Methotrexate is currently used in gynaecology to
treat disorders arising from trophoblastic tissue,
namely, ectopic pregnancy and gestational
trophoblastic disease.
• ADMNISTRATION OF FOLINIC ACID PRVENT OTHER RAPIDLY
DIVIDING CELLL EPETHELIUM
RECURRENT PREGNANCY LOSS
 RECURRENT PREGNANCY LOSS

• Both inherited and combined inherited/acquired

thrombophilias are common, with more than 15% of
the white population carrying an inherited
thrombophilic mutation

– factor V Leiden mutation,

– mutation in the promoter region of the prothrombin
gene
– mutations in the gene encoding methylene
tetrahydrofolate reductase (MTHFR).
 CONT..

• heritable thrombophilias most often linked to

RPL include hyperhomocysteinemia resulting
from MTHFR mutations
• Acquired thrombophilias associated with RPL
include hyperhomocysteinemia and activated
protein C resistance.
 CONT..

 Impaired placental development and function

secondary to venous and/or arterial thrombosis
could lead to miscarriage
 The transfer of nutrition from the maternal blood
to the fetal tissues depends on uterine blood flow,
and thus may be affected by thrombotic events
occurring there, suggests a role for
thrombophilias in pregnancy losses regardless of
gestational age.
THERAPY IS DISORDER SPECIFIC
 THERAPY IS DISORDER SPECIFIC

• Supplemental folic acid for those patients with

hyperhomocysteinemia
• Prophylactic anticoagulation in cases of isolated defects
with no personal or family history of thrombotic
complications
• Therapeutic anticoagulation in cases of combined
thrombophilic defects
• Homocysteine levels should be retested after initial
treatment, and prophylactic anticoagulation considered
when hyperhomocysteinemia is refractory to dietary
intervention
chematic overview of factors affecting one-carbon metabolism, the genomic and cellular
responses evoked by altered folate status, and subsequent phenotypic outcomes that may affect
female fertility and fetal viability. Modified with permission from Beaudin and Stover (2007).123
 COMMON SUPPLEMENTATION

• L-5-MTHF (folate)
• Methylcobalamin (B12)
• Probiotics
• Vitamin D3
• Vitamin C
• Glutathione
• Baby Aspirin (81 mg)
 CURRENT RECOMMENDATION

• WOMEN AT HIGH RISK of having a child with a

NTD (such as those with a personal or family
history of NTD, a prior child with a NTD, or those
on anticonvulsant medications)
– dietary supplementation with 5 mg folic acid daily prior
to conception
• FOR ALL OTHER REPRODUCTIVE-AGED WOMEN
– 0 .4 to 1 mg folic acid daily for at least 2 to 3 months
prior to conception, throughout pregnancy, and during
the postpartum period
 Prevention

Folate
Supplementation
Genetic Polymorphism Stats

40% to 60%
of the population has
genetic polymorphisms
that
impair the conversion
of supplemental
folic acid
to its
active form
L-Methylfolate
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250974/
“The final stage is done with the enzyme
methyltetrahydrofolate
reductase
(MTHFR)
Those with certain polymorphisms have
inadequate MTHFR activity”
Chronology of Folate
Quatrefolic Advantages
Thank you