Extra folic acid taken during pregnancy doesn't prevent pre-eclampsia, trial shows

Taking high-dose folic acid during pregnancy does not prevent pre-eclampsia in women at elevated risk for the potentially deadly condition, a Canadian-led international study has found.

The finding, which refutes a long-held belief about folic acid's preventive role in pre-eclampsia, is expected to alter the practice of prescribing extra doses of the B vitamin to high-risk pregnant women worldwide.

Principal investigator Dr. Mark Walker said the study's finding doesn't mean foregoing low-dose folic acid, which is taken to prevent fetal neural-tube defects, which can cause such conditions as spina bifida.

"All women should take folic acid for at least three months prior to conception," said Walker, chief of obstetrics and gynecology at the Ottawa Hospital. "I think it's safe and efficacious to take .4 to 1 milligram of folic acid in a multivitamin throughout the pregnancy.

"However, those women who are at risk for pre-eclampsia, there is no benefit to being on a high dose of folic acid."

Pre-eclampsia is a condition caused by elevated blood pressure as a result of pregnancy. It is the second-leading cause of maternal death in Canada after venous blood clots that go to the lungs. Each year, about 78,000 women around the world die from the condition. 

 After pre-term birth, pre-eclampsia is also the second-leading cause of perinatal mortality in Canada, "so it's a big contributor to still birth as well as neonatal death," said Walker.

"In the majority of cases, we need to deliver the baby to save the mother's life," he said. "If that's at 37 weeks, it's not such a problem. But if it's at 26 or 28 weeks, it is a huge issue."

Findings could change practice worldwide

Walker said previous observational studies, by his team and other research groups around the globe, had led to the conclusion that having high-risk women take an extra four mg of folic acid daily during pregnancy would cut the incidence of pre-eclampsia by about 30 per cent.

But the Ottawa scientists wanted to put that notion to the acid test with a large randomized controlled trial, the type of study considered the gold standard of medical research.

The 2011-2016 study recruited about 2,300 pregnant women at risk for pre-eclampsia, who were enrolled at 70 centres in five countries — Canada, the U.K., Australia, Jamaica and Argentina. 

Half the women were randomly assigned to take four extra milligrams of folic acid daily, while the other half received a placebo pill.

"What we had hypothesized and anticipated was that the high-dose folic acid would reduce the incidence of pre-eclampsia by 30 per cent," said Walker.

"However, what we found was there was absolutely no difference between the group treated with high-dose folic acid and the placebo. Both groups had a pre-eclampsia rate around 14 per cent."

Walker believes findings from the study, published Wednesday in the BMJ, will "absolutely" change standard practice around the world.

Disappointment in search for prevention

Dr. Linda Szymanski, a maternal-fetal medicine specialist at the Mayo Clinic, said she was not surprised by the finding and that high-dose folic acid is not something she or her colleagues would have prescribed to prevent pre-eclampsia.

"I would hope if that people were prescribing it for pre-eclampsia prevention that this study would change their practice because it is a well-done randomized controlled trial, with a lot of subjects," Szymanski, who was not involved in the research, said Wednesday from Rochester, Minn.

Doctors often have pregnant women at risk of pre-eclampsia take low-dose Aspirin. But that regimen isn't foolproof either — studies have shown the drug reduces the incidence of the condition by only about 10 to 20 per cent.

In an editorial, British specialists say the Canadian-led findings "are another disappointment in the long search for a more effective measure to prevent pre-eclampsia."

"All pregnant women and their families hope for a healthy pregnancy and a happy outcome; until we find additional ways to prevent pre-eclampsia, thousands of women each year will not achieve this goal," write Jenny Myers of the University of Manchester; Marcus Green, chief executive of the group Action on Pre-eclampsia; and obstetrics research professor Lucy Chappell of King's College London.

The next step for Walker's team is to follow the children born to mothers in the study up to the age of six to assess their neurological and behavioural development, to see if they derived any benefit or harm from maternal exposure to extra folic acid.

But longer term, the researchers hope to determine what intervention could prevent pre-eclampsia, which even without severe complications can lead to hospitalization during pregnancy and pre-term delivery through induction or caesarean section.

"We plan a couple of more trials and we're not going to rest until we've answered this question," Walker said.