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Dr. Bob is Robert Hsiung, MD,
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Posted by Phillipa on June 10, 2010, at 21:19:59
Valproic acid during first trimester of pregnancy listed as cause of congential abnormalities. Phillipa
Valproic Acid in Pregnancy Linked to Several Congenital Malformations
Megan BrooksAuthors and Disclosures
June 9, 2010 A new study confirms that first-trimester exposure to valproic acid is associated with an increased risk for spina bifida compared with no use of antiepileptic drugs or with use of other antiepileptic drugs.The study also links first-trimester valproic acid exposure to increased risk for 5 other congenital malformations: atrial septal defect, cleft palate, hypospadias, polydactyly, and craniosynostosis.
"It is well known that first trimester exposure to valproic acid is associated with increased risk of spina bifida, confirmed in this study. But data on the risks of other specific birth defects are limited," study investigator Lolkje T.W. de Jong-van den Berg, PhD, from the Department of Pharmacoepidemiology and Pharmacoeconomics, University of Groningen, the Netherlands, noted in an email to Medscape Neurology.
"The reason is that most studies are too small to evaluate the risk of other specific birth defects of which the prevalence is rare."
However, it should be recognized, the authors conclude, that although the relative risks for several malformations were increased in association with valproic acid use in early pregnancy, the absolute rates are low. The majority of children born to mothers who took valproic acid while pregnant do not have malformations, they write.
Their study was published in the June 10 issue of The New England Journal of Medicine.
For this report, Dr. de Jong-van den Berg and colleagues combined data from 8 published cohort studies, including a total of 1565 pregnancies during which women were exposed to valproic acid, among which 118 major malformations were found.
They found 14 malformations that were significantly (P < .05) more common among the offspring of women who had taken valproic acid during the first trimester. The investigators tested these associations by performing a case-control study within the European Surveillance of Congenital Anomalies (EUROCAT) antiepileptic-study database.
Included in the analysis were 37,154 cases, defined as having at least 1 of the following 14 malformations: spina bifida, microcephaly, ventricular septal defect, atrial septal defect, tetralogy of Fallot, pulmonary valve atresia, hypoplastic right heart, cleft palate, diaphragmatic hernia, gastroschisis, hypospadias, clubfoot, polydactyly, and craniosynostosis. Also included were 39,472 control patients without chromosomal abnormalities (control group 1) and 11,763 control patients with chromosomal abnormalities (control group 2).
Exposure to valproic acid monotherapy was documented in 122 patients with malformations, 45 control group 1 participants, and 12 control group 2 patients. The frequency of exposure to valproic acid was 3 times as high among patients with malformations, at 3.3 per 1000 registrations that is, pregnancy outcomes with malformations included in EUROCAT as among control patients in both groups, where the frequency was 1.1 per 1000.
Key Findings
"We found an increased risk with valproic acid exposure for 6 of the 14 malformations," Dr. de Jong-van den Berg said. Risk for spina bifida was 12 to 16 times as high for exposed fetuses, depending on the control group used, and risks for the 5 other conditions were 2 to 7 times as high.
Risk for Malformations Associated With First-Trimester Valproic Acid Monotherapy vs No First Trimester Antiepileptic Drug (Control Group 1)
Condition Adjusted Odds Ratios 95% Confidence Interval
Spina bifida 12.7 7.7 - 20.7
Atrial septal defect 2.5 1.4 - 4.4
Cleft palate 5.2 2.8 - 9.9
Hypospadias 4.8 2.9 - 8.1
Polydactyly 2.2 1.0 - 4.5
Craniosynostosis 6.8 1.8 - 18.8The results were generally similar in analyses comparing case patients with the control participants in group 2. The researchers also found an association between limb defects and exposure to valproic acid monotherapy as compared with no antiepileptic drug exposure a finding that has been seen in previous case-control studies, they note.
The risks for most of these malformations (5/6) remained significantly increased in analyses comparing exposure to valproic acid monotherapy with exposure to other antiepileptic drug monotherapy. This supports a "relationship of these malformations to valproic acid specifically rather than to antiepileptic drugs generally or to underlying epilepsy," the authors say.
Steer Clear When Possible; Planning Ahead Critical
Current guidelines from the American Academy of Neurology recommend avoiding valproic acid in pregnant women, if possible, because of the risk for major congenital malformations as well as poor cognitive outcomes.
"In my group, we steer away from [valproic acid] unless it is the only drug that works," Sandra L. Helmers, MD, MPH, who was not involved in the study, noted in a telephone interview with Medscape Neurology.
Because switching drugs during or just before pregnancy is difficult, a forward-thinking approach is important, she added.
"This new study again emphasizes how important this issue is in not only women who are pregnant but women of childbearing age. That means you have to plan ahead, from day 1 that means teenage women with epilepsy and discuss this with them," added Dr. Helmers, who is an associate professor of neurology and pediatrics at Emory University School of Medicine in Atlanta and a member of the American Academy of Neurology.
Dr. de Jong-van den Berg and coauthors and Dr. Helmers have disclosed no relevant financial relationships.
N Engl J Med. 2010;362:2185-2193.
Posted by SLS on June 11, 2010, at 4:35:17
In reply to Valproic Acid Linked To Congenital Malformations, posted by Phillipa on June 10, 2010, at 21:19:59
I am wondering if this is due to the ability of valproate to impair folate metabolism. Perhaps using Deplin (methylfolate) would help to prevent neural tube defects.
- Scott
Posted by Phillipa on June 11, 2010, at 11:26:08
In reply to Re: Valproic Acid Linked To Congenital Malformations, posted by SLS on June 11, 2010, at 4:35:17
Scott if my memory serves me right wasn't the creation of Deplin for neural defects in babies? Pregnant women took it or do need increased levels of folate. Phillipa
Posted by SLS on June 11, 2010, at 11:48:47
In reply to Re: Valproic Acid Linked To Congenital Malformations » SLS, posted by Phillipa on June 11, 2010, at 11:26:08
> Scott if my memory serves me right wasn't the creation of Deplin for neural defects in babies?
Good guess on my part.
- Scott
Posted by linkadge on June 11, 2010, at 13:32:03
In reply to Re: Valproic Acid Linked To Congenital Malformations, posted by SLS on June 11, 2010, at 11:48:47
From what I read, there is some link between the birth defects and GSK-3b inhibition / HDAC inhibition. Other HDAC inhibitors cause some similar birth defects.
Linkadge
Posted by SLS on June 11, 2010, at 15:11:11
In reply to Re: Valproic Acid Linked To Congenital Malformations, posted by linkadge on June 11, 2010, at 13:32:03
> From what I read, there is some link between the birth defects and GSK-3b inhibition / HDAC inhibition. Other HDAC inhibitors cause some similar birth defects.
Interesting.
What does GSK-3b do other than to tell a cell when to die?
- Scott
Posted by linkadge on June 11, 2010, at 18:20:31
In reply to Re: Valproic Acid Linked To Congenital Malformations » linkadge, posted by SLS on June 11, 2010, at 15:11:11
I know that gsk-3b inhibitors have mood stabilizing effects. Gsk-3b is increased by stress and attenuated by mood stabilizers (and some antidepressants like fluoxetine). It has some effect on circadian rhythms, neuronal inflammation as well as blood glucose regulation. GSK-3b inhibiton also affects the sensitivity of 5-ht1b receptors as well, GSK-3b inhibiton also reduces the developement of beta amyloid.
In terms of development of the fetus, not exactly sure. It has some effect on the outgrowth of nerve cells. Mild GSK-3b inhibition in humans appears to have neurotrophic effecs, while as higher doses are neurotoxic. It is linked somehow with beta catenin and bcl-2, which regulate cell survival, nerve growth etc. I'm not a molecular biologist though.
There is some info here (page 5) with regards to the effects of teratogenic effects of valproate. In this case it is in reference to its HDAC inhibiting effects.
http://www.biochemsoctrans.org/bst/037/1126/0371126.pdf
Linkadge
Posted by SLS on June 12, 2010, at 6:46:28
In reply to Re: Valproic Acid Linked To Congenital Malformations, posted by linkadge on June 11, 2010, at 18:20:31
Hi Linkadge.
Thanks for taking the time to respond. I wish I had your memory. Maybe one day...
- Scott
> I know that gsk-3b inhibitors have mood stabilizing effects. Gsk-3b is increased by stress and attenuated by mood stabilizers (and some antidepressants like fluoxetine). It has some effect on circadian rhythms, neuronal inflammation as well as blood glucose regulation. GSK-3b inhibiton also affects the sensitivity of 5-ht1b receptors as well, GSK-3b inhibiton also reduces the developement of beta amyloid.
>
>
>
> In terms of development of the fetus, not exactly sure. It has some effect on the outgrowth of nerve cells. Mild GSK-3b inhibition in humans appears to have neurotrophic effecs, while as higher doses are neurotoxic. It is linked somehow with beta catenin and bcl-2, which regulate cell survival, nerve growth etc. I'm not a molecular biologist though.
>
> There is some info here (page 5) with regards to the effects of teratogenic effects of valproate. In this case it is in reference to its HDAC inhibiting effects.
>
> http://www.biochemsoctrans.org/bst/037/1126/0371126.pdf
>
> Linkadge
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