More Teratogens!

We all love Miles Vorkosigan, but we don’t necessarily want to have kids like him. (Except for the wit, charm, and leadership ability, of course.)  Here’s how to avoid poisoning your fetus!

Teratogens are poisons that interfere with the development of the fetus.  They cause about 7% of congenital malformations; the rest are genetic or of unknown cause.  Teratogens are dangerous to a fetal organ during the period when that organ is developing, mostly within the first 10 weeks of pregnancy. These fall into three categories: chemicals, such as medications, alcohol, or environmental pollution; infections; and ionizing radiation.  In this post, I’ll focus on chemical teratogens.

Antifolate drugs.  Don’t get pregnant if you have cancer and are taking chemo. You’re looking at >10% chances of major fetal malformations and spontaneous abortion.[14]  A lot of  chemo drugs (aminopterin, methotrexate, pemetrexed) are folate antagonists, which means neural tube defects, cardiac malformations, and other problems.  Other antifolate drugs which are similarly dangerous in pregnancy include sulfasalazine (a rheumatoid arthritis drug), trimethoprim (an antimicrobial), and pyrimethamine (an anti-toxoplasmosis drug).[12]

High dose vitamin A or isotretinoin. Taking more than 10,000 IU of supplemental vitamin A is associated with 4.8x the risk of birth defects compared to taking less than 5000 IU.  The topical acne medication isotretinoin, which also consists of vitamin A, causes 25x the risk of birth defects.[15] Most pregnancies in women taking isotretinoin end in miscarriage or abortion.[16]

Anti-seizure medications.  As I mentioned before, these are really bad. Valproic acid elevates the risk of a variety of birth defects: 12.7x the risk of spina bifida, 2.5x the risk of heart malformation, etc.[9] Carbamazepine increases the risk of neural tube defects by 5x.[8] Topiramate causes 10x the risk of cleft palate.[10]  Trimethadione causes a “trimethadione syndrome” involving developmental delay.[11]  Folic acid antagonists such as phenytoin and sulfalazine were associated with a 2.8x risk of neural tube defects.[12] So what do you do if you are epileptic?  You probably can’t get your risk down to baseline no matter what, but you can choose your anti-seizure drugs to minimize risk. Valproate is the worst, and lamotrigine is the best; valproate is 5x as likely to cause birth defects as lamotrigine.[13]

Lead. Having lead in your water supply while pregnant (>10 ug/L) gives you a 2.87x risk of having a child with a neural tube defect. [4]  Another study found relative risk of all congenital malformations of 2.39-2.73 for lead-exposed mothers.[5]

Mercury.  Methylmercury poisoning is an established cause of birth defects; pollution from an acetaldehyde plant in Minamata, Japan led to an epidemic of cerebral-palsy-like symptoms among newborns in the 1950’s, which became known as congenital Minamata disease. [7] Above-median levels of mercury were associated with an 8x risk of neural tube defects in a Chinese population exposed to high levels of pollution from coal-burning.[6] Mercury is present in fish, particularly fish high on the food chain such as tuna.  The FDA recommends that pregnant women do not eat swordfish, and eat no more than two meals a week of fish in general.

Most recent studies fail to find an effect of lithium on the rate of birth defects, though it was identified as a teratogen in 1970’s retrospective studies that associated it with Ebstein’s anomaly, a rare cardiac defect.[1][2][3]

References

[1]Cohen, Lee S., et al. “A reevaluation of risk of in utero exposure to lithium.”Jama 271.2 (1994): 146-150.

[2]Jacobson, S. J., et al. “Prospective multicentre study of pregnancy outcome after lithium exposure during first trimester.” The Lancet 339.8792 (1992): 530-533.

[3]Warkany, Josef. “Teratogen update: lithium.” Teratology 38.6 (1988): 593-596.

[4]Bellinger, David C. “Teratogen update: lead and pregnancy.” Birth Defects Research Part A: Clinical and Molecular Teratology 73.6 (2005): 409-420.

[5]Needleman, Herbert L., et al. “The relationship between prenatal exposure to lead and congenital anomalies.” Jama 251.22 (1984): 2956-2959.

[6]Jin, Lei, et al. “Placental concentrations of mercury, lead, cadmium, and arsenic and the risk of neural tube defects in a Chinese population.”Reproductive toxicology 35 (2013): 25-31.

[7]Harada, Masazumi. “Congenital Minamata disease: intrauterine methylmercury poisoning.” Teratology 18.2 (1978): 285-288.

[8]Werler, Martha M., et al. “Use of antiepileptic medications in pregnancy in relation to risks of birth defects.” Annals of epidemiology 21.11 (2011): 842-850.

[9]Jentink, Janneke, et al. “Valproic acid monotherapy in pregnancy and major congenital malformations.” New England Journal of Medicine 362.23 (2010): 2185-2193.

[10]Margulis, Andrea V., et al. “Use of topiramate in pregnancy and risk of oral clefts.” American journal of obstetrics and gynecology 207.5 (2012): 405-e1.

[11]Lietman, Paul S., et al. “The fetal trimethadione syndrome.” The Journal of pediatrics 87.2 (1975): 280-284.

[12]Hernández-Díaz, Sonia, et al. “Neural tube defects in relation to use of folic acid antagonists during pregnancy.” American journal of epidemiology153.10 (2001): 961-968.

[13]Hernandez-Diaz, S., et al. “Comparative safety of antiepileptic drugs during pregnancy.” Neurology 78.21 (2012): 1692-1699.

[14]Zemlickis, Donna, et al. “Fetal outcome after in utero exposure to cancer chemotherapy.” Archives of internal medicine 152.3 (1992): 573-576.

[15]Rothman, Kenneth J., et al. “Teratogenicity of high vitamin A intake.” New England Journal of Medicine 333.21 (1995): 1369-1373.

[16]Leyden JJ, Del Rosso JQ, Baum EW (February 2014). “The use of isotretinoin in the treatment of acne vulgaris: clinical considerations and future directions”. J Clin Aesthet Dermatol 7 (2 Suppl): S3–S21.

 

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