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Effect of high dose folic acid supplementation in pregnancy

on pre-eclampsia (FACT): double blind, phase III,
randomised controlled, international, multicentre trial
1,2,3 1 1 1,2,3
Shi Wu Wen, Ruth Rennicks White, Natalie Rybak, Laura M Gaudet, Stephen
4 5,6 7 8 9
Robson, William Hague, Donnette Simms-Stewart, Guillermo Carroli, Graeme Smith,
10,11,12 2,13,14,15 16,17,18 19
William D Fraser, George Wells, Sandra T Davidge, John Kingdom,
2 15,20 1 15 15
Doug Coyle, Dean Fergusson, Daniel J Corsi, Josee Champagne, Elham Sabri, Tim
15,20 5,21 22,23 1,23
Ramsay, Ben Willem J Mol, Martijn A Oudijk, Mark C Walker
For numbered affiliations ABSTRACT gestation with major proteinuria or HELLP syndrome
see end of article. OBJECTIVE (haemolysis, elevated liver enzymes, low platelets).
Correspondence to: MC Walker, To determine the efficacy of high dose folic acid RESULTS
Ottawa Hospital Research
supplementation for prevention of pre-eclampsia Pre-eclampsia occurred in 169/1144 (14.8%) women
Institute, Ottawa, ON, K1H 8L6,
Canada [email protected] in women with at least one risk factor: pre-existing in the folic acid group and 156/1157 (13.5%) in the
Additional material is hypertension, prepregnancy diabetes (type 1 or placebo group (relative risk 1.10, 95% confidence
published online only. To view 2), twin pregnancy, pre-eclampsia in a previous interval 0.90 to 1.34; P=0.37). There was no
please visit the journal online. pregnancy, or body mass index ≥35.
Cite this as: BMJ 2018;362:k3478 evidence of differences between the groups for any
DESIGN other adverse maternal or neonatal outcomes.
http://dx.doi.org/10.1136/bmj.k3478
Randomised, phase III, double blinded international, CONCLUSION
Accepted: 11 July 2018
multicentre clinical trial. Supplementation with 4.0 mg/day folic acid beyond
SETTING the first trimester does not prevent pre-eclampsia in
70 obstetrical centres in five countries (Argentina, women at high risk for this condition.
Australia, Canada, Jamaica, and UK). TRIAL REGISTRATION
PARTICIPANTS Current Controlled Trials ISRCTN23781770
2464 pregnant women with at least one high risk and ClinicalTrials.gov NCT01355159.
factor for pre-eclampsia were randomised
between 2011 and 2015 (1144 to the folic acid
Introduction
group and 1157 to the placebo group); 2301 were
Pre-eclampsia is a serious medical condition, affecting
included in the intention to treat analyses. 1 2
about 3-5% of pregnancies, accounting for more than
INTERVENTION 35 000 maternal deaths annually worldwide and an
Eligible women were randomised to receive either 13 4
important factor in maternal morbidity. Pre-eclampsia
daily high dose folic acid (four 1.0 mg oral tablets) affects multiple organ systems and leads to an increased
or placebo from eight weeks of gestation to the 5
risk of severe complications in pregnancy. Since delivery
end of week 16 of gestation until delivery. of the placenta is the only known cure, pre-eclampsia is a
Clinicians, participants, adjudicators, and study leading cause of indicated preterm delivery,
1 2
perinatal
staff were masked to study treatment allocation. 6 7
morbidity, mortality, and long term disability.
MAIN OUTCOME MEASURE Epidemiological studies of the association between folic
The primary outcome was pre-eclampsia, defined acid supplementation and the incidence of pre- eclampsia
9
as hypertension presenting after 20 weeks’ have shown a potential protective effect, although findings
8-14
have been inconsistent.
WHAT IS ALREADY KNOWN ON THIS TOPIC In a randomised trial of supplementation with a
multivitamin containing 0.8 mg folic acid and hypertension
Evidence from epidemiological and biological studies has shown a clear dose- in pregnancy in a high risk population of women positive
response relation between increasing folic acid supplementation and decreasing for antibodies to HIV, a 38% reduction was observed in the
risk of pre-eclampsia in women with additional identified risk factors primary composite outcome of gestational hypertension
Until now, a lack of randomised evidence has limited the development of a (including pre -eclampsia or eclampsia) in the intervention
15
comprehensive recommendation for the use of high dose folic acid for group compared with placebo group. Other forms of
prevention of pre-eclampsia in women at high risk of developing pre-eclampsia folate, including 5-methyltetrahydrofolate, have been
16
investigated with similar results, whereas folic acid
WHAT THIS STUDY ADDS antagonists have shown the opposite effect, increasing the
This study suggests that high dose folic acid supplementation in later 17
risk of pre-eclampsia.
pregnancy has no benefit for preventing pre-eclampsia
However, folic acid supplementation remains indicated in preconception 18 19
Based on large randomised trials, supplementation of
and early pregnancy but there is a need to define when to discontinue
folic acid to prevent neural tube defects has been
supplementation as current clinical practice guidelines do not provide clear recommended worldwide during the preconception period
guidance beyond the first trimester and the first trimester of pregnancy. Recommended

the bmj | BMJ 2018;362:k3478 | doi: 10.1136/bmj.k3478 1

RE SE ARCH

doses are 4.0-5.0 mg daily up to 12 weeks’ gestation for Methods

women at high risk of having an affected fetus, and 0.4 -1.0 Trial design and study population
20-22 FACT was a randomised, double blinded, placebo
mg daily for women at low risk. Although the neural
tube closes in the first trimester, pre-eclampsia is a two controlled, phase III, international multicentre trial carried
stage disorder, with the first stage occurring in the late first out at 70 high risk obstetric referral centres covering
trimester (after eight weeks) and the second stage occurring diverse populations in Canada, Argentina, Australia,
in the third trimester. Supplementation of high doses of Jamaica, and the United Kingdom (see supplementary table
folic acid in early gestation may work at both stages of pre- S1).
eclampsia development, and a larger dose in the late first or We considered pregnant women to be eligible for
early second trimester (between eight and 16 week’s participation in the trial if they were between eight and 16
gestation) during the peak period of placental growth and completed weeks of gestation with a confirmed viable fetus
development may be most effective in preventing pre- and at least one of the following risk factors for pre-
eclampsia. Findings from the Ottawa and Kingston (OaK) eclampsia: pre-existing hypertension, prepregnancy
Birth Cohort suggested a 60% reduction in risk of pre- diabetes (type 1 or 2), twin pregnancy, pre-eclampsia in a
eclampsia and a dose-response association between folic 2
previous pregnancy, or body mass index (BMI) ≥35 kg/m .
acid and risk of pre-eclampsia in women with identified
Documentation of BMI measured (height and weight)
9 23
risk factors. A high daily dose (4.0 mg) of folic acid between three months before pregnancy and up to the time
might be needed for these women because they may have of randomisation was required as part of study eligibility.
placental, endothelial, and metabolic defects (including We excluded women if they had a known fetal anomaly or
those of folate metabolism) leading to an increased risk of fetal death, a history of maternal medical complications
developing pre-eclampsia. Previous studies have been (including renal disease with altered renal function),
observational in nature and thus warranted a large epilepsy, cancer, or current use of folic acid antagonists,
randomised controlled trial. The current study, the Folic illicit drug or alcohol misuse (≥2 drinks daily) during
Acid Clinical Trial (FACT), was designed and conducted to
current pregnancy, known hypersensitivity to folic acid,
evaluate the effect of daily supplementation with 4.0 mg
multiple pregnancy, previous participation in this trial, or a
folic acid beyond the first trimester on the risk of
history or presence of any important disease or condition
developing pre-eclampsia among pregnant women at high
that would preclude the use of high dose (up to 5.1 mg
risk for this condition.
daily) folic acid.

Participant recruitment and randomisation

The purpose and requirements of the trial were explained

Visual Abstract Folic acid for pre-eclampsia to eligible women, and after written informed consent, we
Effect of high dose supplementation randomised participants to either folic acid or placebo.
Randomised controlled trial in pregnancy on pre-eclampsia
The Methods Centre at Ottawa Hospital Research
FACT trial (Folic Acid Clinical Trial) Institute implemented randomisation using a web based
randomisation platform that generated a unique
Pregnant women at high risk of randomisation ID. Randomisation used variable permuted
2301
developing pre-eclampsia
blocks of four and six with stratification by centre. Study
obstetrical centres Five countries data were entered into the web based platform at each site.
Mean gestational age at recruitment = weeks Study treatment was centrally prepared, pre-labelled with
unique study IDs and provided to each site.
Randomisation
Double blind trial
Primary outcome The trial intervention consisted of 4.0 mg folic acid or
placebo, taken as four 1.0 mg tablets once daily, from
Proportion of patients
developing pre-eclampsia 1144 1157 randomisation (8-16 completed weeks of gestation) until
after weeks' gestation
High dose folic acid (four Placebo (four delivery. Participants could continue taking prenatal
. mg oral tablets daily) oral tablets daily) vitamins or low dose folic acid supplements containing up
Clinical significance Defined
as a % reduction of pre- to 1.1 mg of folic acid. The folic acid and placebo tab lets
eclampsia in the folic acid arm Difference between arms had no taste and an identical external
appearance, thereby masking participants to
Patients developing pre-eclampsia 14.8% 1.3% higher 13.5%
their treatment group. The data coordinating centre
No benefit found for high dose folic acid supplementation beyond the first trimester for the managed treatment allocation, and all participants, site
prevention of pre-eclampsia or related maternal and neonatal adverse outcomes. investigators, coordinators and other research staff, and
©BMJ Publishing members of the trial coordinating centre were blinded to
Read the full article online http://bit.ly/BMJshoimp
group Ltd. treatment allocation after randomisation. No unmasking
occurred during the trial.
2 doi: 10.1136/bmj.k3478 | BMJ 2018;362:k3478 | the bmj
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Frequency and duration of follow-up Adverse events reporting and safety monitoring
A total of four follow-up visits occurred at 24-26 completed An independent data safety and monitoring board oversaw
weeks of gestation, 34-36 completed weeks of gestation, the safety of the trial. We collected and reviewed all
after delivery, and 42 days post partum. At the initial study adverse events from randomisation to 42 days post partum.
visit, information was collected on personal characteristics An adverse event was defined as an untoward medical
and maternal medical history. At study visits we carried out occurrence in a participant that may or may not have had a
a physical examination (blood pressure, weight, urinalysis causal relation to the study treatment. A serious adverse
(urine dipstick), and fetal wellbeing) and documented event was defined as any untoward medical occurrence that
concomitant drugs. Laboratory values were obtained at resulted in maternal, fetal, or neonatal death; was life
delivery, and maternal and neonatal information were threatening; required prolonged hospital stay; caused
collected from hospital records. At each visit we assessed persistent or major disability, incapacity, or congenital
and documented adverse events. Adherence to the study anomaly; or was deemed an important medical event. No
treatment was determined with the aid of a drug diary and safety issues were detected after the independent data
pill counts. We asked participants to return their study safety and monitoring board’s review.
treatment bottles at each visit. Compliance was measured
as the percentage of pills remaining in the returned bottles,
and participants completed the Dietary Folate Equivalent Statistical analysis
Screener (Block Food Frequency Questionnaire: 24
On the basis of data from high risk pregnant women, we
www.nutritionquest.com) at randomisation and at 24-26 originally estimated that a sample of 3656 pregnant women
completed weeks of gestation. was needed to detect a 30% reduction of pre-eclampsia
from 12.0% to 8.4% (90% power, two sided type I error
0.05) and to allow for up to 30% non-adherence,
withdrawal, loss to follow-up, or other unanticipated
Primary outcome events. However, owing to budget limitations, and because
The primary outcome was pre-eclampsia, defined using the our follow-up rate was better than expected, we
accepted definition at the time the trial commenced: recalculated the sample size to 2464 women, which
diastolic blood pressure ≥90 mm Hg on two occasions four retained a study power of greater than 80% and still
hours or more apart and proteinuria (more than allowed for up to 10% loss to follow-up and withdrawal. In
+ on dipstick, or urinary protein ≥300 mg in 24 hour September 2015 the trial steering committee approved the
urine collection, or random protein:creatinine ratio ≥30 mg sample size adjustment, and we notified the independent
protein/mmol) in women at 20 weeks of gestation or data safety and monitoring board. Based on the recruitment
greater, or diagnosis of HELLP syndrome (haemolysis, rate at the time of these meetings, a total new anticipated
elevated liver enzymes, low platelets) or superimposed pre- recruitment target of 2464 participants would be achieved
eclampsia (history of pre-existing hypertension diagnosed by November, and as a result no interim analysis of
before pregnancy or before 20 weeks’ gestation with new outcomes would be conducted.
2
proteinuria). The primary outcome (the trial protocol
definition of pre-eclampsia) was adjudicated based on the The analysis was carried out on an intention to treat
consensus opinion of three investigators (MW, LG, and basis. We first compared the baseline characteristics,
SWW). Adjudication was conducted before any statistical compliance, folic acid intake from other sources, and
data analysis, masked to treatment group, country, and site. supplementation with aspirin or calcium, or both, between
We excluded women from the primary outcome analysis intervention and placebo groups. The outcomes between
who experienced a miscarriage, experienced early 2
these groups were then compared, using χ tests for the
intrauterine fetal death (20-24 weeks of gestation), or incidence of pre -eclampsia and categorical secondary
withdrew consent. outcomes and t tests for the means of continuously
distributed secondary outcomes. Multiple log binomial
regression was conducted on the primary outcome to adjust
Secondary outcomes for potential confounding by parity, age, cigarette smoking,
Prespecified secondary outcomes included maternal death, and other important prognostic factors identified a priori. A
severe pre-eclampsia (pre -eclampsia with convulsion or generalised estimating equation model was used to account
HELLP or delivery <34 completed weeks of gestation), for the correlation between two fetuses or infants from the
placental abruption, preterm delivery (<37 completed same pregnancy in analyses of neonatal outcomes.
weeks of gestation), premature rupture of membranes, Treatment effects are expressed as relative risk with 95%
antenatal inpatient length of stay, intrauterine growth confidence intervals. No allowance for multiplicity was
restriction (<3rd centile), perinatal mortality, spontaneous made for secondary outcomes. All statistical analyses were
abortion (miscarriage), stillbirth, neonatal mortality, performed using Statistical Analysis System, version 9.1
neonatal morbidity (retinopathy of prematurity, (SAS Institute, Cary, NC).
periventricular leukomalacia, early onset sepsis, necrotising

enterocolitis, intraventricular haemorrhage, ventilation, Patient involvement

need for oxygen at 28 days), and length of stay in neonatal Although we did not actively seek patient engagement in
intensive care unit. the development of this protocol, physicians’ input

the bmj | BMJ 2018;362:k3478 | doi: 10.1136/bmj.k3478 3

RE SE ARCH

outcome ascertainment (n=85), primary outcome data were

Total screened (n= ) available for 2301 women (93.4%) (1144 in the folic acid
Excluded (n=): group and 1157 in the placebo group) (fig 1), representing
Not eligible (n=): a follow-up rate of 96.5%. A total of 485 women across
Taking > . mg of folic acid (n= ) both groups discontinued study treatment but remained in
Delivery elsewhere (n= )
Fetal disease (n= ) the trial and provided data for primary and secondary
Other (n= ) outcomes.
Declined to participate (n=)
The distribution of baseline and pregnancy
Loss to follow-up (n= )
characteristics was similar between the two groups. More
Randomised (n=) than 80% of pregnant women in both groups reported
taking supplemental folic acid or folic acid containing
vitamins. Among the 1941 (78.8%) women who returned
Allocated to receive folic acid mg daily (n=) Allocated to receive placebo (n=)
study treatment bottles, 1465 (75.5%) took at least 75% of
Study treatment withdrawal (n= ) Study treatment withdrawal (n= )
their pills, confirming a high compliance rate (table 1).
Withdrew consent (n= ) Analyses of blood samples from 50 participants (19 in folic
acid group and 31 in placebo group) in Canadian centres
Analysed for baseline characteristics (n=) Analysed for baseline characteristics (n=)
indicated that serum folate was substantially higher in the
Excluded (n= ): Excluded (n= ): folic acid group (mean 260.1 v 77.8 nmol/L, P=0.008) and
Withdrew consent (n= ) Withdrew consent (n= )
red blood cell folate levels were similar (2700 v 2680
No primary outcome data (n= ) No primary outcome data (n= )
nmol/L, P=0.88).
Excluded from primary analysis (n= ): Excluded from primary analysis (n= ):
Spontaneous abortion (< weeks) Spontaneous abortion (< weeks)
(miscarriage) (n= ) (miscarriage) (n= ) No statistically significant differences were observed in
Early intrauterine fetal death Early intrauterine fetal death reported adverse events or severe adverse events between
( - weeks) (n= ) ( - weeks) (n= ) the two groups (see supplementary table S2). The effect did
Participants who completed study and were Participants who completed study and were not differ by country (see supplementary table S4).
analysed for primary outcome (n=) analysed for primary outcome (n=)

Discussion
Fig 1 | Trial flow diagram
The results of our international randomised controlled
multicentre trial did not show evidence that
was provided through a survey, suggesting that their patient
supplementation with high dose folic acid (4.0-5.1 mg)
population would be interested in the trial and we sought
initiated between eight and 16 completed weeks of
their advice on best practices to roll out the trial. A steering
gestation and continued until delivery prevents pre-
committee of international content experts with varied
eclampsia in at risk women. We adjusted analyses for
expertise provided input in the development of the
potential confounders by parity, maternal age, and cigarette
protocol, study outcomes, and trial procedures. The
smoking and confirmed there was no effect of folic acid on
committee also examined how to minimise the impact on
the prevention of pre-eclampsia. When we explored the
trial participants, as such, trial follow-up visits were
effect of high dose folic acid on risk of pre-eclampsia by
coordinated with routine antenatal care visits. Patients were
not involved in setting the research question or the outcome country, no difference in effect was observed.
measures, nor were they involved in developing plans for
recruitment or implementation of the study. Patients were
Comparison with other studies
not asked to advise on interpretation or writing up of the
Supplementation with folic acid during pregnancy is now
results. Participants are acknowledged and thanked for their
common in many countries of the world. In our previous
contribution and participation in this important trial. A cohort study, of 2951 pregnant women recruited between
dissemination strategy has been developed to work closely 2002 and 2005 in Ottawa and Kingston, Canada, 2713
with stakeholders and knowledge users to facilitate transfer 9
(91.9%) took folic acid supplements during pregnancy,
of the findings to relevant users, including patients and
and of women who used folic acid supplementation, only
clinicians.
544 (20.0%) discontinued in the third trimester, whereas
9
447 (16.5%) used more than 2.0 mg/day. Similar patterns
were observed in our trial population, with more than 80%
Results of women taking supplemental folic acid. Supplementation
Characteristics of participants with high dose folic acid (usually 4.0-5.0 mg daily) in
Between April 2011 and November 2015, 6499 pregnant pregnant women has already become widespread beyond
women were screened and 2464 of these women were 9 13 14 25-29
the first trimester. Anecdotal evidence suggests
enrolled into the trial, 1228 of whom were randomised to that supplementation with high dose folic acid is occurring
folic acid and 1236 to placebo. After excluding women who outside the recommendations for use only in early
experienced miscarriage (n=37), experienced early pregnancy for prevention of neural tube defects, even
intrauterine fetal death (20-24 weeks of gestation, n=12), though the most recent Cochrane review of folic acid in
had no primary outcome data available (n=28), or withdrew
consent before

4 doi: 10.1136/bmj.k3478 | BMJ 2018;362:k3478 | the bmj

 RE SE ARCH

Tabel 1 | Perbandingan baseline maternal & karakteristik kehamilan antara kelompok percobaan. Nilai adalah angka (persentase) kecuali dinyatakan
sebaliknya
Karakteristik Kelompok asam folat (n=1227) Kelompok plasebo (n=1236)
Negara:
  Kanada 600 (48.9) 607 (49.1)
  Australia 157 (12.8) 153 (12.4)
  Argentina 61 (5.0) 61 (4.9)
  Jamaica 29 (2.4) 32 (2.6)
  UK 380 (31.0) 383 (31.0)
Riwayat preeklampsia 308 (25.1) 303 (24.5)
Hipertensi kronik 203 (16.5) 241 (19.5)
Diabetes tipe 1 84 (6.8) 72 (5.8)
Diabetes tipe 2 98 (8.0) 84 (6.8)
Kehamilan kembar 233 (19.0) 229 (18.5)
Indeks massa tubuh ≥35 606 (49.4) 656 (53.1)
Paritas:
  0 413 (33.7) 420 (34.0)
  1 498 (40.6) 499 (40.4)
  ≥2 316 (25.7) 317 (25.6)
Usia kehamilan (tahun):
  20 10 (0.8) 10 (0.8)
  20-29 439 (35.8) 447 (36.2)
  30-34 411 (33.5) 441 (35.7)
  ≥35 367 (29.9) 338 (27.3)
Usia rata-rata (SD) (tahun) 31 (5.4) 31 (5.4)
Etnisitas maternal:
  Aborigin 35 (2.85) 24 (1.94)
  Putih 970 (79.0) 987 (79.8)
  Hitam 93 (7.6) 107 (8.7)
  Asia 45 (3.7) 50 (4.05)
  Latin/Hispanik 31 (2.5) 22 (1.8)
  India/Asia Selatan 45 (3.7) 36 (2.9)
  Tidak menjawab 8 (0.65) 10 (0.8)
Indeks massa tubuh pra hamil:
  18.5 15 (1.2) 11 (0.9)
  18.5-25 230 (18.7) 225 (18.2)
  25-30 210 (17.1) 199 (16.1)
  30-35 164 (13.4) 146 (11.8)
  ≥35 607 (49.5) 655 (53.0)
  Rata-rata (SD) Indeks massa tubuh pra hamil 34 (8.6) 34 (13)
Tingkat pendidikan:
  SMA ke bawah 353 (28.8) 348 (28.2)
  Universitas (belum selesai) 198 (16.15) 197 (16.0)
  Universitas (sudah selesai) 675 (55.1) 689 (55.8)
Usia kehamilan (minggu):
  8-12 386 (31.5) 433 (35.0)
  13-16 841 (68.5) 803 (65.0)
  Rata-rata (SD) usia kehamilan (minggu) 14 (1.9) 14 (1.9)
Merokok selama kehamilan:
  Ya 98 (8.0) 95 (7.7)
  Tidak 1046 (85.2) 1035 (83.7)
  Keluar saat kehamilan 83 (6.8) 106 (8.6)
Konsumsi alkohol selama kehamilan:
  Ya 23 (1.9) 27 (2.2)
  Tidak 977 (80.0) 955 (77.3)
  Keluar saat kehamilan 227 (18.5) 254 (20.5)
Suplementasi asam folat* 989 (80.6) 1016 (82.2)
Supplementation asam folat dosis tinggi saat pengacakan 346 (28.2) 335 (27.1)
Supplementation aspirin dosis tinggi saat pengacakan 358 (29.2) 340 (27.5)
Supplementation kalsium dosis tinggi saat pengacakan 97 (7.9) 109 (8.8)
Rata-rata (SD) folat (μg):
  Kunjungan 1 (8-16 completed weeks’ gestation) 494 (209), n=1215 504 (222), n=1225
  Kunjungan 2 (24-26 completed weeks’ gestation) 494 (209), n=1008 500 (213), n=1023
Kepatuhan†:
  ≤50% 108 (11.2) 106 (10.8)
  50-75% 140 (14.5) 122 (12.5)
  ≥75% 716 (74.3) 749 (76.7)
* Termasuk multivitamin yang mengandung asam folat.
† Dihitung pada perawatan studi yang dikembalikan (n = 1941). Peserta yang tersisa tidak mengembalikan pengobatan studi dan kepatuhan tidak dapat dihitung (n = 522).

Di antara peserta dengan data hasil primer yang tersedia (n = 2301), 169 (14,8%) pada kelompok asam folat memiliki diagnosis pre-eklampsia dibandingkan dengan 156 (13,5%) di

kelompok plasebo (risiko relatif 1,10, interval kepercayaan 95% 0,90-1,34, P = 0,37). Perbedaan dalam tingkat HELLP (1.21, 0.37 hingga 3.96, P = 0.75), pre-eklampsia berat (1.52,
0.81 hingga 2.84, P = 0.19; tabel 2), dan semua hasil maternal lainnya tidak signifikan secara statistik (tabel 2) .
the bmj | BMJ 2018;362:k3478 | doi: 10.1136/bmj.k3478 5
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Tabel 2 | Perbandingan outcome maternal antara kelompok percobaan. Nilai adalah angka (persentase)
kecuali dinyatakan sebaliknya
Outcomes Kelompok as. folat Kelompok plasebo Risiko relatif (95% CI) P value
Kematian maternal 0 0 - -
Spontaneous abortion (miscarriage) 27 (2.3), n=1172 21 (1.8), n=1180 1.29 (0.74 - 2.28) 0.37
Abruptio plasenta 12 (1.0), n=1169 19 (1.6), n=1179 0.64 (0.31 - 1.31) 0.21
KPD 215 (18), n=1169 224 (19), n=1180 0.97 (0.82 - 1.15) 0.71
Usia kehamilan <37 minggu 297 (26), n=1150 304 (26), n=1164 0.99 (0.86 - 1.13) 0.87
Sindroma HELLP 6 (0.52), n=1144 5 (0.43), n=1156 1.21 (0.37 - 3.96) 0.75
PEB 24 (2.10), n=1144 16 (1.4), n=1156 1.52 (0.81 - 2.84) 0.19
Lama rawat antenatal (hari) 5.6 (7.7) *, n=221 5.2 (6.2) *, n=232 0.34 (7.0) (−0.96 - 1.63) † 0.61
HELLP=haemolysis, elevated liver enzymes, low platelets.
*Rata-rata (SD).
†Perbedaan rata-rata (SD) difference (95% CI).
Sebanyak 2.738 bayi lahir dari wanita yang direkrut ke dalam trial (1364 pada kelompok asam folat dan 1374 pada kelompok plasebo).
Tingkat kelahiran mati adalah 1,1% pada kelompok asam folat dan 1,9% pada kelompok plasebo (0,60, 0,30-1,19; tabel 3). Tidak ada
perbedaan yang signifikan secara statistik yang diamati dalam terjadinya outcome neonatal yang merugikan antara kedua kelompok.

pregnancy for maternal health outcomes was not able to A clear advantage of our trial is the robust randomised
report on pre -eclampsia owing to lack of data from clinical design, although some limitations are present. Pre-
30
trials. Caution should always be exercised in eclampsia has a complex heterogenous aetiology despite
31
recommending treatments before thorough evaluation has characteristic phenotypic outcomes. In the original trial
been completed, including follow-up of offspring when protocol we clearly laid out the criteria for the definition of
possible. pre-eclampsia and used this for case adjudication. These
criteria have remained consistent with NICE guidelines for
Strengths and limitations of this study the diagnosis of pre-eclampsia, although there have been
FACT has several notable strengths. Firstly, it was designed revisions to the definition of pre- eclampsia in other
to be as conclusive as possible in a rigorous, large, 32
settings, including Canada. As a result, using the revised
randomised, double blinded, placebo controlled, phase III, guidelines, there may be additional women in the study
international and multicentre trial. The trial conduct population who would have a diagnosis of pre-eclampsia;
adhered to strong research and ethical principles, high data however, owing to the randomised design this would be
completeness, and compliance by participants. The follow- balanced across the treatment groups and not anticipated to
up rate was greater than 95% and compliance to the study affect the association between folic acid and pre-eclampsia,
treatment was greater than 75% in most of the study regardless of definition. Finally, power was reduced from
population. Steps were taken to ensure the lowest possible 90% to 80%, but because we found no evidence in favour
risk of bias, although we did not investigate baseline folic of the study intervention, even an increase of power would
acid values, compliance, and levels during pregnancy in have been unlikely to find a treatment effect.
subgroups of high risk factors for pre-eclampsia.

Tabel 3 | Perbandingan outcome janin atau bayi antara kelompok percobaan

Outcomes Kelompok asam folat Kelompok plasebo Risiko relatif (95% CI)* P value*
Outcomes dikotomi:
  Lahir mati 15 (1.1), n=1364 26 (1.9), n=1374 0.60 (0.30 - 1.19) 0.14
  Pertumbuhan janin terhambat 3rd centile 20 (1.4), n=1347 25 (1.9), n=1348 0.76 (0.41 - 1.39) 0.37
  Pertumbuhan janin terhambat10thcentile 151 (11.2), n=1347 144 (11), n=1348 1.03 (0.81 - 1.30) 0.82
  Neonatal death 8 (0.60), n=1343 11 (0.82), n=1347 0.87 (0.31 - 2.44) 0.79
  Mortalitas perinatal 23 (1.7), n=1364 37 (2.7), n=1374 0.63 (0.37 - 1.05) 0.07
  Retinopai prematur 21 (1.6), n=1342 13 (0.97), n=1347 1.20 (0.54 - 2.66) 0.65
  Leukomalacia periventrikel 4 (0.30), n=1343 2 (0.15), n=1347 2.00 (0.37 - 10.92) 0.42
  Sepsis onset dini 3 (0.22), n=1342 9 (0.67), n=1347 0.34 (0.09 - 1.23) 0.10
  Enterokolitis nekrotikans 8 (0.60), n=1343 3 (0.22), n=1347 2.04 (0.49 - 8.57) 0.33
  Perdarahan intraventrikular 18 (1.3), n=1343 19 (1.4), n=1347 0.97 (0.47 - 2.00) 0.94
  Ventilasi 49 (3.6), n=1346 30 (2.2), n=1348 1.61 (0.97 - 2.66) 0.06
  Kebutuhan oksigen pada 28 hari 9 (0.74), n=1220 3 (0.2), n=1227 2.37 (0.61 - 9.14) 0.21
  Perawatan NICU 299 (22), n=1346 267 (20), n=1348 1.08 (0.91 - 1.28) 0.37

Outcome kejadian merugikan janin atau 63 (4.7), n=1349 51 (3.8), n=1348 1.20 (0.80 - 1.80) 0.38
neonatal*
Outcome yang didistribusi terus-menerus:
  Lama rawat inap NICU 16 (27) †, n=299 17 (23) †, n=263 −1.60 (−5.84 - 2.64) 0.46
NICU=neonatal intensive care unit.
* Persamaan estimasi umum digunakan untuk menjelaskan korelasi antara dua janin atau bayi dari kehamilan yang sama. Outcome komposittermasuk
retinopati prematuritas, leukomalasia periventrikular, sepsis onset dini, enterokolitis nekrotikans, perdarahan intraventrikular, ventilasi, kebutuhan oksigen
pada 28 hari, dan masuk NICU
†Rata-rata (SD). ‡Perbedaan rata-rata (95% CI).

6 doi: 10.1136/bmj.k3478 | BMJ 2018;362:k3478 | the bmj

 RE SE ARCH

Conclusion and policy implications Alberta, Canada

19
Future directions for this research include exploration of Maternal-Fetal Medicine Division, Department of
the increased risk of pre -eclampsia in mothers carrying Obstetrics and Gynecology, Mount Sinai Hospital,
University of Toronto, Toronto, Ontario, Canada
twins and using high dose folic acid, and the potential 20
Departments of Medicine, School of Epidemiology, Public
protective effect of folic acid on perinatal death warrants Health and Preventive Medicine, University of Ottawa,
ongoing study. Perhaps most importantly, FACT provides a Ottawa, Ontario, Canada
21
unique opportunity to follow the participants and their Department of Obstetrics and Gynaecology, Monash
offspring to study the effects of high dose folic acid during University, Clayton, Victoria, Australia
22
Department of Obstetrics, University Medical Center,
prenatal development on long term maternal and child
Utrecht, Utrecht, Netherlands
health, given the potential epigenetic effects of folic acid. 23
Department of Obstetrics, Academic Medical Center,
Funding has been obtained to follow these FACT offspring Amsterdam, Netherlands
for mortality and neurocognitive development through to We thank the participants in FACT, site investigators, research staff
six years of age. at the participating sites, and staff at the Ottawa Hospital Research
Institute for their support and hard work. A full list of the FACT
Collaborating Group is available in the supplementary file.
Our well powered trial did not find benefit for high dose Contributors: MCW and SWW designed the trial, planned the
folic acid supplementation beyond the first trimester for the analyses, and wrote the manuscript with assistance from RRW, NR,
prevention of pre-eclampsia or related maternal and LMG, SR, WH, DSS, GC, GS, WDF, GW, STD, JK, DC, DF, DJC, JC,
TR, BJM, and MAO. ES with assistance from DJC carried out the
neonatal adverse outcomes. The trial deals with an
statistical analyses. All authors participated in the review and critical
important public health issue: the lack of demonstrated revisions of the final manuscript. MCW is the guarantor. The
benefit of high dose folic acid supplementation beyond the corresponding author attests that all listed authors meet authorship
criteria and that no others meeting the criteria have been omitted.
first trimester for women at high risk of developing pre-
Funding: This study was sponsored by the Ottawa Hospital Research
eclampsia indicates that high dose recommendation should Institute, and funded by the Canadian Institutes of Health Research
now cease, and the search for an effective and acceptable (grants 198801 and 98030). FACT was conceived, designed, and
strategy to prevent pre-eclampsia must continue. coordinated independently of the funding source. The funder did not
act as sponsor for the trial and had no role in analysis, interpretation
of the data, writing of the report, or decision to submit for publication.
Competing interests: All authors have completed the ICMJE uniform
AUTHOR AFFILIATIONS disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no
On behalf of: the FACT Collaborating Group support from any organisations for the submitted work; no financial
1 relationships with any organisations that might have an interest in the
OMNI Research Group, Clinical Epidemiology Program, Ottawa
Hospital Research Institute, Ottawa, Ontario, Canada submitted work in the previous three years; no other relationships or
2 activities that could appear to have influenced the submitted work.
School of Epidemiology, Public Health and Preventive
Medicine, University of Ottawa, Ottawa, Ontario, Canada Ethical approval: FACT was approved by the Ottawa Health
3 Sciences research ethics board (2009107), and at all participating
Department of Obstetrics, Gynecology & Newborn Care,
sites. All applicable regulatory agency approvals were also obtained.
University of Ottawa, Ottawa, Ontario, Canada
4 Data sharing: The authors of this trial commit to making data
Institute of Cellular Medicine, The Medical School,
available upon reasonable request. Requests for access to data
Newcastle University, Newcastle upon Tyne, UK
5 from FACT should be addressed to the corresponding author.
Obstetric Medicine, Robinson Research Institute, Transparency: The lead author (MCW) affirms that this manuscript is
University of Adelaide, South Australia, Australia
6
an honest, accurate, and transparent account of the study being
Women’s and Children’s Hospital, Adelaide, South reported; that no important aspects of the study have been omitted;
Australia, Australia and that any discrepancies from the study as planned (and, if relevant,
7
Department of Obstetrics and Gynaecology, Faculty of registered) have been explained.
Medical Sciences, The University of the West Indies, This is an Open Access article distributed in accordance with the Creative
Mona, Kingston, Jamaica Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
8
Centro Rosarino de Estudios Perinatales (CREP), Rosario, permits others to distribute, remix, adapt, build upon this work non-
Santa Fé, Argentina commercially, and license their derivative works on different terms, provided
9 the original work is properly cited and the use is non-commercial. See:
Queen’s Perinatal Research Unit, Kingston General
Hospital, Department of Obstetrics and Gynecology, http://creativecommons.org/licenses/by-nc/4.0/.
Queens University, Kingston, Ontario, Canada
10 1 American College of Obstetricians and Gynecologists, Task
Mother & Child Axis, Centre de recherche du Centre Hospitalier Force on Hypertension in Pregnancy. Hypertension in
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Cardiovascular Research Methods Centre, University of doi:10.1016/S1701-2163(16)32776-1
Ottawa Heart Institute, Ottawa, Ontario, Canada 3 Duley L. Maternal mortality associated with hypertensive disorders of
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Supplementary information: Members of the FACT
2163(15)30230-9. Collaborating Group

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