Fever in Pregnancy
Professor Marshall J. Edwards at the University of Sydney, Australia, is generally considered to be the individual who pioneered the discovery that maternal hyperthermia during pregnancy can be teratogenic (Birth Defects Res A Clin Mol Teratol. 2005;73:857-64). In animal studies over the course of 40 years, Edwards demonstrated that mechanisms for hyperthermia-induced fetal damage included “cell death, membrane disruption, vascular disruption, and placental infarction…” Modest elevations in temperature prior to implantation and more sustained elevations during early embryogenesis may cause fetal death and abortion. Embryos surviving maternal hyperthermia during early development are at risk for a host of congenital anomalies, including neural tube and central nervous system (CNS), micrencephaly, microphthalmia, cataracts, craniofacial, heart, renal, dental, and abdominal wall defects among others.
The most common cause of hyperthermia during pregnancy is fever related to viral illnesses (and other common causes include bacterial infections associated with pyelonephritis, tonsillitis, and appendicitis). Since we are heading into the cold and flu season, women who are either anticipating or already are in the early stages of pregnancy, should be especially cautious (start taking your folic acid now!). Over the years, several studies have confirmed that temperature elevations in pregnant women accompanying influenza and common cold virus infections are associated with greater risk for congenital anomalies, multiple and isolated, especially, neural tube defects.
A meta-analysis of 15 separate studies by Moretti and colleagues (Epidemiology. 2005;16:216-9) included 1,719 cases and 37,898 controls and found an overall odds ratio for neural tube defects associated with maternal hyperthermia of 1.92 (95% CI = 1.61-2.29). Acs and colleagues (Birth Defects Res A Clin Mol Teratol. 2005;73:989-96) evaluated 22,843 newborns or fetuses with congenital anomalies and 38,151 matched controls and found “there was a higher prevalence of maternal influenza during the second and/or third month of pregnancy for the group of newborns with cleft lip +/- palate (adjusted prevalence odds ratio (POR), 3.2; 95% CI, 2.0-5.3), neural tube defects (adjusted POR, 1.9; 95% CI, 1.1-3.3) and cardiovascular malformations (adjusted POR, 1.7; 95% CI, 1.3-2.3).” They also concluded that “a direct teratogenic effect from influenza viruses appears unlikely” and the higher prevalence of congenital anomalies “can be explained mainly by fever, because this risk was reduced by the use of antifever drugs.” These same congenital defects have been found at a higher prevalence in women with folic acid deficiencies and aberrations of folate metabolism, such as those associated with polymorphisms of methylene tetrahydrofolatereductase (MTHFR), so it was most interesting to see that the authors found that “periconceptional folic acid supplementation also showed some preventive effect…”
One other study worth mentioning, conducted by Suarez and colleagues (Birth Defects Res A Clin Mol Teratol. 2004;70:815-9), is interesting because it looked not only at febrile illnesses, but other causes of maternal hyperthermia as well. They studied a population of high-risk Mexican-American women who lived in 14 Texas counties bordering Mexico. To quote their results, the odds ratio (OR) “associated with maternal fever in the first trimester, compared to no fever, was 2.9 (95% CI, 1.5-5.7). Women taking fever-reducing medications showed a lower risk effect (OR, 2.4; 95% CI, 1.0-5.6) than those who did not (OR, 3.8; 95% CI, 1.4-10.9). First-trimester maternal exposures to heat devices such as hot tubs, saunas, or electric blankets were associated with an OR of 3.6 (95% CI, 1.1-15.9). Small insignificant effects were observed for activities such as cooking in a hot kitchen (OR, 1.6; 95% CI, 1.0-2.6) and working or exercising in the sun (OR, 1.4; 95% CI, 0.9-2.2).”
In closing, I would also like to point out that although the period of early fetal development carries the greatest risk from maternal hyperthermia, severe temperature elevations during the second and third trimesters may still put the baby at jeopardy, particularly for CNS damage, and might be responsible for some cases of behavioral and developmental compromise and even more severe neurological conditions, such as schizophrenia, autism, and cerebral palsy. In my experience as well, high fever associated with both viral and bacterial illnesses in late second and third trimester also dramatically increases the risk for subsequent premature labor and delivery and may precipitate preeclampsia!