Building Better Baby Brains: Just Say No To FAS

Fetal Alcohol Syndrome is our most preventable form of disability.

Despite a growing focus on the hazards of prescription painkillers for newborns, drinking during pregnancy remains the nation’s leading preventable cause of birth defects and developmental disorders in children. Fetal Alcohol Spectrum Disorders (FASD) encompass a wide variety of neurobehavioral and central nervous system disabilities related to alcohol use during pregnancy, including, but not limited to, developmental delays, growth retardation speech disabilities, and poor social skills. The classic physical characteristics of FASD, such as small head size, wide-set eyes and a thin upper lip, are not always present.

September 9th is International Fetal Alcohol Spectrum Disorders Awareness Day. Kenneth Warren, acting director of the National Institute on Alcohol Abuse and Alcoholism, said in a prepared statement that “Almost 40 years have passed since we recognized that drinking during pregnancy can result in a wide range of disabilities for children, of which fetal alcohol syndrome (FAS) is the most severe. Yet up to 30 percent of women report drinking alcohol during pregnancy.”

NIAAA, in a brief history of the disorder, calls fetal alcohol syndrome the “most common known cause of mental retardation.” Tragically, the knowledge of alcohol as a teratogen responsible for birth defects was not widely recognized by the medical community in American until the 1970s, when a group of crusading physicians began reporting observations of clustered birth defects among alcoholic mothers. (French doctors were on to FAS in the 1960s). In short order, the Surgeon General issued an FAS advisory, the U.S. Congress passed laws requiring pregnancy warning labels on alcoholic beverages, and doctors began warning their pregnant patients about the hazards of heavy drinking while pregnant. Nonetheless, CDC studies have shown that 0.2 to 1.5 cases of fetal alcohol syndrome (FAS) occur for every 1,000 live births.

Not surprisingly, the NIAAA finds that the risk for teratogenic injury and the severity of injury “appear to increase with greater levels of alcohol consumption.” Facial features associated with FAS are linked to early fetal exposure, so it is possible that “an embryo may escape the injury necessary to develop the characteristic FAS face but receive sufficient injury later in development to exhibit all the FAS-associated CNS and neurobehavioral deficits.”

Organ abnormalities are also characteristic of early exposure, while growth deficits are more likely the result of alcohol exposure later in pregnancy. Binge drinking—high peak dose drinking—is especially troublesome, as it has a great negative impact than low-dose steady drinking. But no period is risk-free. Genetic and environmental factors are plausibly invoked as contributors, but nobody knows what they are at present.

The disabilities caused by FASD often linger throughout adulthood, burdening families with anguish and heavy medical costs. “The message is simple, not just on Sept. 9, but every day,” says Warren. “There is no known safe level of drinking while pregnant. Women who are, who may be, or who are trying to become pregnant, should not drink alcohol.”

Graphics Credit: http://edmontonfetalalcoholnetwork.org/

Drug News in Brief

Short takes on matters various.

Taking Aim at Pot—Researchers have recently made clinical efforts to test three drugs that might help during marijuana withdrawal to keep pot abstainers on the straight and narrow. Researchers at Columbia University, led by Margaret Haney, have been testing a synthetic THC compound called nabilone. The drug is designed to address sleep and appetite problems during withdrawal.  Whether it is any better tolerated by users than Marinol, Uncle Sam’s widely unpopular version of synthetic THC, remains to be seen. This approach can be viewed rather like methadone or buprenorphine substitution therapy. Meanwhile, work goes on with lofexidine, a drug sometimes used in combination with naltrexone for opiate detoxification. A 2008 study in Psychopharmacology showed a modest improvement over placebo when lofexidine was used for marijuana abstinence, but it worked much better when combined with, yes, synthetic THC. Finally, velafaxine, better known as the antidepressant Effexor, was used in a randomized, double-blind, placebo controlled trial of marijuana-dependent outpatients recently published in Addiction. Not only did velafaxine fail to help the patients with their cannabis dependence, but in fact “may lead to an increase in cannabis use.”

Smoking is Bad to the Bone—The Journal of Adolescent Health reports that cigarette smoking dramatically impacts the rate of bone density growth in teenage girls. Young women may be smoking their way toward a future of osteoporosis, the loss of bone density that often plagues older women. “This age group is when you should gain about 50 percent of your bone accrual,” reports study author Lorah Dorn at Cincinnati Children’s Hospital Medical Center, in Science News. A 2001 study of adult smokers found that smoking increased the risk of hip fracture by 31% in women. In addition, at the recent annual meeting of the American Academy of Orthopedic Surgeons, researchers reported on a study of 6,779 patients undergoing treatment for spinal disorders with severe pain. Those who quit smoking during treatment reported greater pain improvement than patients who didn't stop smoking. 

Dr. Google Will See You Now—Researchers are starting to data-mine the Internet to identify unanticipated side effects and interactions between prescription drugs. According to an article in Science by Sean Treacy, one study in 2011 data-mined reports to the FDA from doctors, nurses, and patients, and “uncovered a hidden drug interaction: When taken together the antidepressant paroxetine and the cholesterol suppressant pravastatin can cause hyperglycemia, or high blood sugar.”  Bioinformatics researcher Nigam Shah of Stanford told the magazine that “if a lot of people are concerned about a symptom, that in itself is valuable information.”

Fetal Health—Scientists have traced out a molecular signaling pathway that appears to play a crucial role in the development of fetal alcohol spectrum disorders (FASD). According to the researchers, whose study was published in the Proceedings of the National Academy of Sciences, “ethanol may cause FASD in part by decreasing the adhesion of the developmentally critical L1 cell adhesion molecule through interactions with an alcohol binding pocket on the extracellular domain.” In English, it means that the research points to strong candidate genes, therefore identifying a specific locus of action for future drugs designed to block alcohol neurotoxicity in the womb. A group led by Michael Charness at Harvard Medical School did the work, building on previous studies that identified the alcohol sensitivity of L1 adhesion molecules. “Prenatal alcohol exposure is the leading preventable cause of birth defects and developmental disorders in the United States,” according to perennial Acting NIAAA Director Kenneth Warren, in an NIH news release.

Photo Credit:  http://jimbaker.wordpress.com/

Misdiagnosing Fetal Alcohol Spectrum Disorder

Facial abnormalities not present in most cases.

Back in 1967, when a French pediatrician tried to alert doctors to developmental problems he had recognized in the children of alcoholic mothers, he didn’t make much progress.  A few years later, pediatrician David Smith began seeing the same sorts of trouble as Paul Lemoine had seen in France. Hoping to draw more attention to the problem, Dr. Smith coined the term fetal alcohol syndrome, or FAS. It was a successful gambit. By now, almost everyone has heard of the disorder. And once NIAAA-funded studies had succeeded in proving that the problem did not only affect the children of poor alcoholic women, research on it has been a major theme at the National Institute on Alcohol Abuse and Alcoholism (NIAAA) ever since. Fetal alcohol disorders may in fact be the most common and preventable form of developmental disorder in the world.

Typically, physicians have used three basic features to diagnose full FAS:

--Characteristic facial abnormalities
--Growth deficits
--Nervous system dysfunctions

But there’s a problem: Fetal Alcohol Syndrome is considered a spectrum disorder, meaning that it includes variations on the full pattern of birth defects. Fetal Alcohol Spectrum Disorder (FASD) doesn’t always show all three of these diagnostic features. In the early going, therefore, clinicians missed a lot of children suffering from FASD, catching only full FAS in the diagnostic net. Kenneth Warren, acting director of the NIAAA, said in a press release that “if you didn’t have the distinctive facial features, you weren’t diagnosed with FAS. If you didn’t have a growth deficit, you weren’t diagnosed with FAS.”

All of this means that recognizing the effects of fetal alcohol exposure is trickier than first thought. For example, FASD is often mistaken for attention deficit hyperactivity disorder (ADHD). The distinction certainly matters, because stimulant medications, which work for some kids with ADHD, are of no use to children with fetal alcohol spectrum disorder. Now, a long-term study of heavy drinking during pregnancy by researchers at the University of Chile appears to nail down the fact that most children regularly exposed to alcohol in the womb do not show the distinct facial characteristics of fetal alcohol syndrome (FAS). Rather, said collaborators on the study at the U.S. National Institute of Child Health and Human Development (NICHD), abnormalities of the nervous system and behavioral problems like language delays, hyperactivity, and attention deficits are far more reliable diagnostic clues.

In the study, investigators interviewed a group of 9000 women in Santiago, Chile, and eventually matched 101 pregnant women who drank four or more drinks a day with a control group of pregnant non-drinkers. The study followed the children until the age of 8. The investigators found “functional neurologic impairment” in 44 % of children whose mothers consumed four or more drinks per day. In contrast, only 17 % of the alcohol-exposed children showed any abnormal facial features. 

“Our concern is that in the absence of the distinctive facial features,” said Devon Keuhn of the NICHD in a prepared statement, “health care providers evaluating children with any of these functional neurological impairments might miss their history of fetal alcohol exposure.”

The NICHD University of Chile Alcohol in Pregnancy Study is an ongoing project.

Photo Credit: http://en.wikipedia.org

Choline for Fetal Alcohol Spectrum Disorders?

Common supplement may reduce cell death in pregnancies.

A common dietary supplement markedly decreases defects in the skull and brain formation of  lab mice born to mothers exposed to alcohol, say researchers at the Medical College of Georgia.

Among the grisly list of potential effects caused by alcohol consumption during pregnancy, one involves a relatively obscure lipid called ceramide. Ceramide can markedly increase the rate of programmed cell death—a process known as apoptosis—and may be involved in the characteristic cranial defects seen in fetal alcohol syndrome.

In the study, 25 % of the mouse embryos exposed to alcohol showed characteristic defects in skull development, including diminished growth in the multi-layered membrane—the meninges--covering the brain.  Biochemists Erhard Bieberich and Guanghu Wang, in an article published in Cell Death and Disease, found that the supplement CDP-choline decreased cell death and protected the fetal cranium from damage due to maternal drinking episodes. According to Dr. Bierberich in a press release from the Medical College of Georgia, the result of alcohol on pregnancy is “a snowball effect. The neural crest is damaged, the meninges doesn’t develop properly and tissue like bone and brain that are regulated by the meninges don’t develop properly either.”

Choline is a precursor to the neurotransmitter acetylcholine. In addition, it has been known for decades that alcohol increases choline requirements. Choline is already added to some baby formulas and prenatal vitamins. Choline’s effects on stroke and traumatic brain injury are also being investigated.

A similar discovery twenty years ago concerning folic acid led the U.S. Public Health Service (USPHS) to recommend that all women thinking of becoming pregnant should consume supplemental folic acid daily in order to reduce their risk of having a pregnancy affected by spina bifida or other neural tube defects. The rate of occurrence of this kind of birth defect has been dropping ever since.

The researchers believe that “there is just a little window” four weeks after conception—while neural cells are forming numerous organs--when the alcohol-related cranial damage is likely to occur. Unfortunately, this window of disaster opens before many women have discovered that they are pregnant. 

Since warnings about the dangers of drinking during pregnancy are either not known or are ignored in many cases, researchers are always on the lookout for medications that could be given after exposure to alcohol--or even after birth of a baby to an alcoholic mother.  As early as 2005, researchers at Tripler Army Medical Center in Honolulu demonstrated that adding choline to the pre-natal diet of pregnant alcoholic rats suppressed physiological symptoms of fetal alcohol syndrome in the offspring. In a press release from the American Physiological Society, lead researcher John Claybaugh asserted that the results “are consistent with the hypothesis that supplemental dietary choline fed to the pregnant dam can prevent the alcohol-induced partial diabetes insipidus seen in the young adult offspring.”

The American Psychological Association, in the wake of a 2007 study published in Behavioral Neuroscience, announced that “giving choline to infants who were exposed in the womb to alcohol may mitigate some of the resulting problems” related to learning, attention, and motor skills. The researchers gave choline to rat pups exposed to alcohol during the third trimester. Alcohol-related hyperactivity and learning deficits decreased, the researchers say. “The data suggest that early dietary interventions may reduce the severity of some fetal alcohol effects, even when administered after birth."

 Despite such optimism, the issue is whether a choline supplement would be capable of rescuing cells after alcohol exposure, or whether choline would need to be taken ahead of time as a supplement.

What is not at issue is that pregnant women should not drink, and should be aware that fetal damage can occur very early in a pregnancy.

Graphics Credit: http://www.cholineinfo.org/

Wang, G., & Bieberich, E. (2010). Prenatal alcohol exposure triggers ceramide-induced apoptosis in neural crest-derived tissues concurrent with defective cranial development Cell Death and Disease, 1 (5) DOI: 10.1038/cddis.2010.22