Health for life

Prenatal folic acid supplements appear to reduce the risk for autistic spectrum disorders, according to a study published today (February 13) in the Journal of the American Medical Association (JAMA).

The Centers for Disease Control and Prevention estimate that about 1 in 88 children in the U.S. have been identified with an Autism Spectrum Disorder (ASD). ASDs are amongst the most heritable of mental disorders, but little is known about how the disorder develops. Consequently, methods for diagnosis, prevention, and treatment are limited.

Folic acid (Vitamin B9) is required for DNA synthesis and repair in the human body, and its naturally occurring form—folate—is found in leafy vegetables, peas, lentils, beans, eggs, yeast, and liver. Taking folic acid supplements during early pregnancy is known to protect against spina bifida and other neural tube defects in children. In the United States, Canada, and Chile, folic acid is added to flour, so as to automatically provide these supplements to consumers. Norway does not enrich its flour, and since 1998, the Norwegian Directorate of Health has recommended that all women planning to become pregnant take a daily supplement of folic acid from one month before the start of pregnancy through the first trimester.

Despite this policy, studies from North America and Europe have shown that many pregnant women have a lower dietary intake of folate than what is necessary to prevent neural tube defects.

The report in JAMA emerged from the Norwegian Mother and Child Cohort Study (MoBa) and its sub-study of autism, the Autism Birth Cohort (ABC) Study. This international collaboration (see list of members below) comprises the largest prospective birth cohort devoted to the investigation of gene-environment interactions and biomarker discovery for neuropsychiatric disorders.

A total of 85,176 MoBa babies—born from 2002-2008—and their parents participated in the study. Prenatal dietary habits were recorded, and families were regularly surveyed for 3-10 years to measure the development of autism spectrum disorders. A total of 270 cases of autism spectrum disorders were identified in the study population (114 autistic disorder; 56 Asperger syndrome; 100 atypical or unspecified autism; i.e., pervasive developmental disorder not otherwise specified, PDD-NOS).

Mothers who took folic acid supplements in early pregnancy had a 40% reduced risk of having children with autistic disorder compared with mothers who did not take folic acid. The reduction in risk was observed in those who took folic acid during the time interval from 4 weeks before to 8 weeks after the start of pregnancy. Autistic disorder is the most severe form of autism spectrum disorders in children. No reduction in risk was observed for PDD-NOS. For Asperger syndrome, the number of children was too low to obtain sufficient statistical power in the analyses.

The use of folic acid in early pregnancy increased substantially from 2002 to 2008 among women who participated in MoBa. In 2002, 43% of mothers took folic acid supplements; by 2008, 85% of mothers did. However, many women began taking folic acid later than recommended, and only half started before the beginning of pregnancy.

The timing of a mothers intake of folate appears to be a critical factor. Her childs risk of autism was reduced only when the supplements were taken between 4 weeks before to 8 weeks after the start of pregnancy.

"We examined the rate of autism spectrum disorders in children born to mothers who did or did not take folic acid during pregnancy. There was a dramatic reduction in the risk of autistic disorder in children born to mothers who took folic acid supplements," says Pål Surén, first author and epidemiologist at the Norwegian Institute of Public Health (NIPH).

The researchers also analyzed whether the risk of autistic disorder was influenced by the use of other dietary supplements. They did not find any association between the mothers use of fish oil supplements (cod liver oil and omega-3 fatty acids) in early pregnancy and the risk of autistic disorder, and no association for the mothers use of other vitamins and minerals.

In recent years, researchers have started to investigate whether folic acid has other beneficial effects on the development of the fetus brain and spinal cord. A study of language development from MoBa, published in 2011, showed that children whose mothers took folic acid supplements in early pregnancy had only half the risk of severe language delay at age three years compared with other children. A separate 2011 study from the University of California, Davis, demonstrated a lower risk of autism spectrum disorders in children of mothers who had used prenatal vitamin supplements during pregnancy. Prenatal vitamin supplements contain folic acid in combination with other vitamins and minerals.

Joint senior author Ezra Susser, professor of Epidemiology at Columbia Universitys Mailman School of Public Health and professor of Psychiatry at the College of Physicians and Surgeons, stated, "Our findings extend earlier work on the significance of folate in brain development and raise the possibility of an important and inexpensive public health intervention for reducing the burden of autism spectrum disorders."

"This elegant work illustrates the power of the ABC cohort for not only chipping away at the riddle of what causes autism, but for developing new methods for early recognition, prevention and treatment," says W. Ian Lipkin, John Snow Professor of Epidemiology at the Mailman School of Public Health and principal investigator of the ABC cohort.

People who take certain acid-lux medications might have an increased risk of vitamin B-12 deficiency, according to new research.

Taking proton pump inhibitors (PPIs) to ease the symptoms of excess stomach acid for more than two years was linked to a 65 percent increase in the risk of vitamin B-12 deficiency. Commonly used PPI brands include Prilosec, Nexium and Prevacid.

Researchers also found that using acid-suppressing drugs called histamine-2 receptor antagonists -- also known as H2 blockers -- for two years was associated with a 25 percent increase in the risk of B-12 deficiency. Common brands include Tagamet, Pepcid and Zantac.

"This study raises the question of whether or not people who are on long-term acid suppression need to be tested for vitamin B-12 deficiency," said study author Dr. Douglas Corley, a research scientist and gastroenterologist at Kaiser Permanentes division of research in Oakland, Calif.

Corley said, however, that these findings should be confirmed by another study. "Its hard to make a general clinical recommendation based on one study, even if it is a large study," he said.

Vitamin B-12 is an important nutrient that helps keep blood and nerve cells healthy, according to the U.S. Office of Dietary Supplements (ODS). It can be found naturally in meat, fish, poultry, eggs, milk and other dairy products. According to the ODS, between 1.5 percent and 15 percent of Americans are deficient in B-12.

Although most people get enough B-12 from their diet, some have trouble absorbing the vitamin efficiently. A deficiency of B-12 can cause tiredness, weakness, constipation and a loss of appetite. A more serious deficiency can cause balance problems, memory difficulties and nerve problems, such as numbness and tingling in the hands or feet.

Stomach acid is helpful in the absorption of B-12, Corley said, so it makes sense that taking medications that reduce the amount of stomach acid would decrease vitamin B-12 absorption.

More than 150 million prescriptions were written for PPIs in 2012, according to background information included in the study. Both types of medications also are available in lower doses over the counter.

Corley and his colleagues reviewed data on nearly 26,000 people who had been diagnosed with a vitamin B-12 deficiency and compared them to almost 185,000 people who didnt have a deficiency.

While 12 percent of people with a vitamin B-12 deficiency had taken PPIs for more than two years, 7.2 percent of those without a deficiency had taken the medications long-term.

Of those with a deficiency, 4.2 percent took an H2 blocker for two years or longer, while 3.2 percent of those without a deficiency took the drugs for two years or more.

The risk of developing a vitamin B-12 deficiency was 65 percent higher for the long-term PPI users and 25 percent higher for those taking H2 blockers, according to the study.

People who took higher doses were more likely to develop a vitamin B-12 deficiency. People who took an average of 1.5 PPI pills per day had almost double the risk of developing a deficiency compared to those who averaged 0.75 pills per day, the study found.

Women had a greater risk of deficiency than men, and people younger than 30 taking these medications had a greater risk of developing a deficiency than older people, according to the study.

The risk of vitamin B-12 deficiency decreases when you stop taking the medications, but doesnt disappear completely, Corley said.

The studys findings were published in the Dec. 11 issue of the Journal of the American Medical Association. Although the study found an association between taking acid-lux drugs long-term and having a higher risk of a B-12 deficiency, it didnt establish a cause-and-effect relationship.

If youre taking acid-suppressing medications, Corley said, "our study doesnt recommend stopping those medications, but you should take them at the lowest effective dose." And people shouldnt start taking vitamin B-12 supplements on their own, but should discuss it with their doctor, he said.

One expert had concerns about how frequently acid-suppressing drugs are used.

"This study found an adverse effect associated with taking these drugs," said Victoria Richards, an associate professor of medical sciences at the Frank H. Netter M.D. School of Medicine at Quinnipiac University, in Hamden, Conn. "Its also concerning that these drugs are used at such a high rate. Why do so many people have the need to suppress acid so much?"

The bottom line, Richards said, is that if you are having any symptoms of vitamin B-12 deficiency and youve been taking these medications, talk to your doctor about whether you should be tested for a deficiency. Tell your doctor if youve been taking over-the-counter acid-suppressing medications, so your doctor can properly evaluate your risk.

You may be familiar with vitamins C and E, both for their essential role in maintaining healthy tissues and organs, and for their antioxidant abilities. Maybe you regularly take supplements of these vitamins, with the expectation theyll reduce free-radical damage, a condition more common in people with diabetes. (High blood glucose levels increase free radical production.)

If so, you may want to consider adding another antioxidant to your supplement regimen: alpha-lipoic acid.

Alpha-lipoic acid, known as thioctic acid in Europe, is a naturally occurring compound involved in energy production in our body. Its also a potent antioxidant and has the ability to regenerate vitamins C and E when theyve lost their antioxidant capacities in the process of neutralizing free radicals.

A number of studies in the last decade have investigated alpha-lipoic acids therapeutic value for lessening symptoms of diabetic neuropathy - a condition that can be worsened by the oxidative damage wrought by free radicals:

• ALADIN I Study (1995)¹
  
• ALADIN II Study (1999)²
  
• ALADIN III Study (1999)³
  
• DEKAN Study (1997)⁴
  
• OPRIL Study (1999)⁵
  
• SYDNEY Trial (2003)⁶
  
• NATHAN Study (Ongoing)⁷

Results of the last study listed above, NATHAN, are due shortly.⁸ It should be able to discuss effective daily dosages of alpha-lipoic acid for managing diabetic neuropathy. In the meantime, you may opt to experiment with amounts used in the neuropathy studies; they ranged from 600mg to 1800mg daily. Smaller amounts, from 50mg to 400mg, were used in antioxidant studies.

A note of caution: Alpha-lipoic acid can improve insulin sensitivity.⁹ Although this is a desirable effect, it may necessitate changes to any diabetes medications youre taking to avoid bouts of hypoglycemia. If you use insulin, consult with your doctor before supplementing with alpha-lipoic acid. If you dont use insulin, its still a good idea to monitor your blood glucose while taking the supplement and report changes to your doctor.

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¹ Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study)

² Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter randomized double-blind placebo-controlled trial (ALADIN II)

³ Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study)

⁴ Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial (DEKAN Study)

⁵ Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. The Oral Pilot (OPRIL) Study

⁶ The sensory symptoms of diabetic polyneuropathy are improved with {alpha}-Lipoic Acid: The SYDNEY Trial

⁷ Neurological Assessment of Thioctic Acid in Neuropathy Study (NATHAN)
A long-term multicenter study in North American and Europe. NATHAN I investigates oral therapies. NATHAN II investgates intravenous therapy.

⁸ Thioctic Acid for Patients with Symptomatic Diabetic Polyneuropathy: A Critical Review

⁹ Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial