The Effect of High Dose Folic Acid Versus Placebo on the Rate of Gestational Diabetes or Gestational Hypertension in Pregnant Women

Subjects (DoD beneficiaries) will be recruited from all non-diabetic female subjects whom
are at least 18 years of age and are empanelled for care at Nellis Air Force Base. Upon
arrival at the mandatory New Obstetrics (OB) Orientation, potential subjects will be offered
an opportunity to participate in this study. A total of 650 subjects will be recruited.
After consent and HIPAA Authorization is obtained, the subjects will have Baseline blood
pressure, fasting glucose, folic acid, vitamin B12, homocysteine, vitamin D measurements,
and weight, height, race, ethnicity, parity, vegetarian status recorded. Subjects will be
written a prescription and sent to the Clinical Pharmacy where they will be randomized via
block randomization. After randomization, they will receive either placebo or 4 milligrams
of folic acid (in addition to the standard of care pre-natal vitamins) from the
pharmacy--thus investigators and subjects will be blinded as to their treatment.

Group 1: Placebo plus standard of care pre-natal vitamins (which include 1 milligram of
folic acid) a day for the duration of pregnancy Group 2: Will take an additional
4-milligrams of folic acid a day for the duration of pregnancy plus standard of care
pre-natal vitamins (which include 1 milligram of folic acid)

The Placebo will be a gelatin capsule filled with starch which does not increase the risks
to subjects.

The pre-natal vitamins dispensed at the MOFH Clinical Pharmacy include 1 milligram of folic
acid. The folic acid is manufactured by West Ward Pharmaceutical Corp.

Those subjects in Group 2 will be taking a total of 5 milligrams of folic acid (1 milligram
of folic acid is contained in their standard of care pre-natal vitamins and they will be
given an additional 4 milligrams of folic acid as part of this research study).

The placebo is manufactured by Green Valley Medical Supply Company.

Subjects will continue to receive routine obstetrics care and take their prescription for
the duration of their pregnancy. Per the American College of Obstetrics and Gynecology
(ACOG), patients will be tested for gestational diabetes either at 2nd trimester for those
with risk factors of prior GDM, age >34 or body mass index >25 or at 28 weeks for standard
risk women. There will be an unblinded person to monitor any adverse effects that may occur.

At 28 weeks gestation, weight, height, diagnosis of GDM, gestational hypertension,
pre-eclampsia, post-partum hemorrhage, maternal death will be recorded, and will be asked if
they took the study medications as prescribed (studies have shown that patient recall is as
accurate as pill counts).

At delivery, folic acid, B12, homocysteine, vitamin D will be measured and weight, height,
diagnosis of GDM, gestational hypertension, pre-eclampsia, post-partum hemorrhage, maternal
death, birth weight, shoulder dystocia, neonatal/fetal mortality will be recorded, and will
be asked if they took the study medications as prescribed (studies have shown that patient
recall is as accurate as pill counts).

After completion of the first 200 subjects, an interim power analysis to identify whether
the trial can be stopped early. At this point and at the conclusion of the study, the data
will be de-identified and analyzed. A paper will be written and submitted to a scientific
journal at the conclusion of the study.

When subjects have completed the study, the Pharmacy will then de-randomize the information
and send to the Principal Investigator for analysis.

If at any time during the study, the subject decides to withdraw from the study, they will
be referred to their Primary Care Manager to initiate standard of care treatment.

If any subjects experience fetal demise or maternal death, the Principal Investigator will
consult with Obstetrics to initiate proper clinical care.

Folic acid is a common supplement in pregnancy.

"In accordance with 21 CFR 312.2(b)(i-v), an IND exemption is requested based on the
following provisions: (i) The investigation is not intended to be reported to FDA as a
well-controlled study in support of a new indication for use nor intended to be used to
support any other significant change in the labeling for the drug; (ii) If the drug that is
undergoing investigation is lawfully marketed as a prescription drug product, the
investigation is not intended to support a significant change in the advertising for the
product; (iii) The investigation does not involve a route of administration or dosage level
or use in a patient population or other factor that significantly increases the risks (or
decreases the acceptability of the risks) associated with the use of the drug product; (iv)
The investigation is conducted in compliance with the requirements for institutional review
set forth in part 56 and with the requirements for informed consent set forth in part 50;
and (v) The investigation is conducted in compliance with the requirements of §312.7."

Inclusion Criteria:

- Tricare Insurance Beneficiary (military insurance) receiving care at Nellis AFB

- Pregnant females (DoD beneficiaries) at least 18 years of age

Exclusion Criteria:

- Diagnosed as being diabetic

- Diagnosed with chronic hypertension prior to pregnancy

- Personal or family history of neural tube defects or personal history of birth
defects

- Unable to communicate

- Non-English speaking

- Patients who know they will move prior to delivery

- Patients who have had Gastric Bypass surgery

- Patients with known seizure disorder or on anti-seizure medication

- Patients taking a folic acid antagonist

- Patients who are hypohomocysteine

- Previously diagnosed with Methylenetetrahydrofolate reductase (MTHFR) mutation