Higher Topiramate dose in early pregnancy linked to increased risk of oral cleft

Use of Topiramate in early pregnancy for treating epilepsy is associated with nearly 8 times higher risk of oral clefts in newborn reports the results of a large population based cohort study published December 27, 2017 in journal Neurology.

The observed association was not very strong for lower doses of topiramate used for treating migraines and bipolar disorder.

A diagnosis of oral cleft includes cleft lip and cleft palate.

Previous studies have demonstrated a 5-fold increased risk of oral cleft in women taking around 200 mg of topiramate daily for epilepsy, but the association was unclear about consumption of lower dose.

To assess the risk of oral dose, the investigators analyzed a large cohort of 1,360,101 pregnant women with a live-born infant enrolled in Medicaid from 3 months before conception through 1 month after delivery over a period of 10 years. 

The prescription information was obtained from nationwide Medicaid Analytic eXtract (MAX) which keeps a record of all diagnoses and procedures and prescription filled outside hospitals.

The analyses of data identified 2425 women who were exposed to topiramate in early pregnancy as shown by atleast one filled prescription of the drug in first trimester.

The neonatal outcome for this cohort was compared to a reference group of 1,322,955 pregnant women who did not fill prescription for topiramate or other anticonvulsant drugs.

The multivariate analysis included many potential confounders like maternal age, race, topiramate indication (epilepsy, migraine, bipolar disorder, pain condition), obesity, smoking, comorbidities, concomitant medications, and overall health status.

Regression analysis showed that women with topiramate consumption in early pregnancy are 3 times increased risk of giving birth to a baby with oral cleft, as compared to women who have never taken the drug for any indication.

Risk was also assessed for consumption of another anticonvulsant medication, lamotrigine in first trimester. The risk with lamotrigine was only slightly more as compared to non-exposed population and the patients using topiramate were nearly 2.5 times at increased risk of oral clefts as compared to lamotrigine.

Women with epilepsy were nearly 8 times increased risk of oral cleft as compared to non-exposed.

Lead author, Dr Hernandez-Diaz, MD, professor of epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts said, "Our best estimate is that women with epilepsy using 200 mg or more of topiramate have around an 8-fold increased risk, and those using lower doses had a twofold or lower risk. The results suggest that the risk with lower doses, if it is there, is much less than for higher doses."

The researchers carried out multiple sensitivity analyses, with different doses of topiramate and window of exposure, but the association between topiramate and oral clefts remained the same.

The study confirms the results of earlier studies and stress upon the fact that “dose does matter.” The risk ratio for oral clefts for > 100 mg of topiramate was nearly 5 times more than that of < 100 mg.

In addition, topiramate does interfere with oral contraceptives and may be responsible for many unplanned pregnancies because of contraceptive failures. Hence, women who are on topiramate and do not want to conceive should additionally use a barrier method of contraception.

The study limitations include poor socioeconomic status of women (which itself is a risk for oral clefts), and not controlling for folic acid use.

Women with anti-epileptic medication should take folic acid which reduces the chances of oral clefts. 

But sometimes it is prescribed off-label to treat obesity and control weight gain.  In 2012, the United States Food and Drug Administration (FDA) approved topiramate in combination with phentermine (Qsymia) to treat weigh gain issues. 

Abstract

FDA press release

ACOG updates its guidance on Neural Tube Defects

ACOG has recently released its updated guidance on Neural Tube Defects (NTDs) and includes guidelines about prevention, screening, antenatal management and delivery in pregnancies with  such defects. The practice bulletin No.187 is published in December issue of Journal Obstetrics and Gynecology.

NTDs is the second most common group of congenital malformation after cardiac anomalies. The prevalence differs according to race, region and environmental influences.

In contrast to other malformations, NTDs are preventable by supplementation of folic acid.  

The recommendations:

ACOG along with other professional organizations like CDC, AAFP, AAP, ACMG and AAN: Women in the reproductive age group, having the capacity to become pregnant should take at least 0.4 mg (400 µg) of folic acid daily.

USPSTF: all women who are planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400-800 µg) of folic acid.

ACOG, CDC other organization suggests a higher dose of 4 mg (4000 μg) of folic acid for women who are at high risk of having a baby with NTD. These factors are:

Previous history of pregnancy with NTD

Having a partner with NTDs or a partner who previously has had a child with NTD

Patients with a second or third degree relative with NTD

Patient herself was born with NTD

History of taking anti-epileptic medication Valproic acid

Type 1 Diabetes Mellitus

Obesity.

ACOG has also made additional recommendations in the recent 2017 updates.

With Advancements in Ultrasound techniques, Maternal Serum Alpha Feto Protein (MSAFP) has become less important in diagnosing NTDs, when high quality, second trimester ultrasound is routinely used.

MSAFP is more important for screening for other anomalies and placental complications in such cases.

If MSAFP value is ≥ 2.5 MoMs, the detection rate for anencephaly is 95% and 65-80% for other open NTDs.

2D ultrasound has a detection rate of 96% and if structural abnormalities are seen on Ultrasound, they can be considered diagnostic.

3D ultrasound is not superior to 2D in diagnosing NTDs; however, it may be more helpful in delineating the upper limit of spinal defects.

The rates of diagnosing NTDs in first trimester are lower than that of 2^nd trimester sonography.

MRI is not mandatory if NTD has already been identified in sonography.

Pregnancy and delivery management:

After a pregnancy with NTD is diagnosed options should be individualized according to each pregnancy:

Pregnancy termination

In Utero fetal surgery for repair

Expectant management with neonatal surgical repair.

Studies on In-Utero repairs have demonstrated that such neonates have functional level two or more times better than expected, and reduce the neonatal mortality and morbidity.

Delivery:

Regarding the timing of delivery, term delivery is preferred. Elective late preterm or early term cesarean is only considered if fetal repair has been done or other obstetric indication for surgery exists.

Retrospective studies with not very long-term follow-up have demonstrated no increased risk of vaginal delivery, but each case needs to be individualized.

Practice Bulletin Abstract

USPSTF recommendations

CDC recommendations

ACOG committee opinion on Fetal Myelomeningocele Repair

ACMG policy statements

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Media: Univision.com

Multivitamin supplements ‘Is a waste of money’ for most women during pregnancy.

Multivitamins Courtesy Pixabay 

The drug market is flooded with myriad combinations of prenatal multivitamins and nearly all women are routinely prescribed these at prenatal visit to healthcare provider. It has long been claimed that taking a daily multi translate into better health for women and her unborn child.

Maternal deficiency of certain nutrients is linked with congenital malformations and poor pregnancy outcomes like preeclampsia, IUGR, skeletal deformities and neural tube defects.

This has given rise to billion-dollar pharma industry manufacturing and marketing products targeted at antenatal women and her baby. Globally the retail value sales of Prenatal Vitamin grew by 34% between 2008 and 2013 to reach its current market value of US$ 4.7 billion worldwide and is expected to rise continuously.[1]

According to the researchers, a typical prenatal Multi(MV) contains at least 20 different vitamins and minerals and sometimes the dose exceeds 100% RDS value. The average cost of daily prenatal MV is $20 per month.

A recent review[2]  published in British Medical Journal's Drug and Therapeutics Bulletin have refuted the need of Multivitamin supplements in pregnancy, the authors say “For most women who are planning to become pregnant or who are pregnant, complex multivitamin and mineral preparations promoted for use during pregnancy are unlikely to be needed and are an unnecessary expense.”

“The marketing of such products does not appear to be supported by evidence of improvement in child or maternal outcomes. Pregnant women may be vulnerable to messages about giving their baby the best start in life, regardless of cost,” the review further adds.

We found no evidence to recommend that all pregnant women should take prenatal multi-nutrient supplements beyond the nationally advised folic acid and vitamin D supplements, generic versions of which can be purchased relatively inexpensively," they say.

"Pregnancy multivitamins are a waste of money because most mothers-to-be do not need them, according to researchers," BBC News reports[3]

The researchers also looked at individual vitamins and supplements taken during pregnancy like Vitamin A, C, D and E, iron and folic acid. Strong evidence was only found in favor of supplementing Vitamin D and folic acid.

They have also cautioned against the excessive intake of Vitamin A which may be teratogenic to the fetus.

The researchers in this review have further confirmed the NICE guidelines:

• Folic acid (400 micrograms) should be taken when trying to conceive and for the first 12 weeks of pregnancy to protect against neural tube defects (NTD), such as spina bifida, in babies. 
• Folic acid dose is increased to 5 milligrams of folic acid a day where there is a family history of neural tube defects or where they have diabetes or have had a previous baby with a neural tube defect.
• 10 micrograms of vitamin D which equals 400 I.U each day throughout pregnancy that has to be continued while breastfeeding.

ACOG currently advises a pregnant woman to eat a well-balanced diet that includes foods from five groups: grains, fruits, vegetables, protein foods and dairy. Women who are pregnant requires extra folic acid and iron, which can be sourced from taking a prenatal Multivitamin but "a well-rounded diet should supply all of the other vitamins and minerals."[4]

Janet Fyle, from the Royal College of Midwives also dispelled the myth for eating for ‘two’ in pregnancy.

"We would also stress that there is no need for pregnant women to 'eat for two'."This is a myth, and all that is required is a normal balanced amount of food."

This news has angered the pharmaceutical industry, who are arguing that the prenatal vitamins are prescribed to fill in the gaps in the diet and not to cure any specific disease.

Two earlier studies and an expert editorial published in Annals of Internal Medicine have dispelled that myth too.  "The message is simple: Most supplements do not prevent chronic disease or death, their use is not justified, and they should be avoided," says the editorial, signed by two researchers from Johns Hopkins University in Baltimore, one British researcher and one of the journal's senior editors.[5]

The review may not be systematic, but it provides data supporting the current recommendation of NHS. The researchers also argue that most studies favoring Multivitamin supplementation in pregnancy are from developing countries, where women are deficient in many key nutrients. Hence, the same recommendation does not hold true for developed countries.

However, according to current evidence, eating a good balanced diet, along with folic acid and Vitamin D supplementation ensures the best possible outcome for pregnant woman and her unborn child.

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[1] http://blog.euromonitor.com/2014/05/optimizing-development-the-growing-paediatric-and-prenatal-supplements-market.html

[2] http://dtb.bmj.com/content/early/2016/07/11/dtb.2016.7.0414

[3] http://www.bbc.com/news/health-36765161

[4] http://www.acog.org/Patients/FAQs/Nutrition-During-Pregnancy#extra

[5] http://annals.org/article.aspx?articleid=1789253