Mechanism of Hyperthermia-Induced Orofacial Clefts in Early Pregnancy
Maternal hyperthermia during the first trimester of pregnancy, particularly during weeks 4-10 of gestation when facial structures are forming, increases the risk of cleft lip and cleft palate through multiple biological mechanisms including cell death, membrane disruption, vascular disruption, and placental infarction. 1
Critical Timing and Developmental Window
The first few weeks of pregnancy represent the period of organogenesis when the facial structures are actively forming. Hyperthermia exposure during this critical developmental window—specifically the first trimester—directly interferes with normal craniofacial development. 2, 1 The type of defect produced depends precisely on the timing of the hyperthermic insult, as different facial structures form at different gestational ages. 1
Biological Mechanisms of Teratogenesis
Maternal fever causes birth defects through several established pathophysiological pathways:
Cell death (apoptosis): Elevated temperatures trigger programmed cell death in developing facial tissues, disrupting normal fusion of the lip and palate structures 1
Membrane disruption: Hyperthermia damages cellular membranes in rapidly dividing embryonic cells, interfering with normal cellular function and tissue formation 1
Vascular disruption: Fever causes disruption of the developing blood supply to facial structures, leading to ischemic damage during critical developmental periods 1
Placental infarction: Maternal hyperthermia can cause placental damage, reducing oxygen and nutrient delivery to the developing embryo 1
Epidemiological Evidence
Recent epidemiologic studies from 2005-2020 have confirmed strong associations between first-trimester maternal fever and increased risk for oral clefts. 1 A large case-control study found that 24-33% of mothers of children with orofacial clefts reported febrile illness during the critical developmental period. 2
The National Birth Defects Prevention Study demonstrated a modestly increased risk for cleft lip with or without cleft palate (OR 1.28,95% CI 1.01-1.63) among mothers reporting febrile illness in early pregnancy. 3 A 2023 study identified high temperatures exceeding 39°C as one of the top 5 most significant risk factors for cleft lip and palate. 4
Temperature Threshold and Severity
The magnitude and duration of elevated maternal body temperature directly correlates with increased risk. 1 While stratification by fever grade (<101.5°F vs ≥101.5°F) did not yield significant differences in some studies 3, the consistency of findings across multiple study designs supports the causal relationship between maternal hyperthermia and orofacial clefts. 1
Role of Antipyretic Use
Risk estimates were significantly higher among women who reported fever but did not take antipyretics to control their temperature, particularly for non-isolated compared with isolated oral clefts. 3 This finding suggests that adequate fever control may diminish the deleterious effects of hyperthermia on facial development. 3
Clinical Implications
The evidence supports that maternal febrile illnesses during early pregnancy—including influenza (OR 2.4), acute bronchitis (OR 4.5), and urinary tract infections (OR 3.5)—are associated with elevated risk of cleft lip and palate. 5 Aggressive treatment of maternal fever during the first trimester, particularly with antipyretic medications, should be prioritized to reduce teratogenic risk. 3
Confounding Medication Exposures
While addressing hyperthermia, clinicians must be aware that certain medications used during pregnancy carry independent risks for orofacial clefts:
Glucocorticosteroids increase oral cleft incidence when used before 10 weeks of gestation (when palate formation occurs), though more recent studies have not consistently confirmed this association 6, 7
Diphenhydramine has been associated with cleft palate in some case-control studies, though recent studies have not detected increased risk 6
Ondansetron shows a marginal relative increase in cleft palate (0.03% absolute increase) when used in early pregnancy 6