Heat exposure during pregnancy leads to fetal growth restriction due to placental hypoxia

Shuang Liang^1,2; Van Tu Nguyen³; Wanting Wen^1,3,4; Jiaji Cai³; Nanchao Wang³, Junjie Yao³; Liping Feng¹

1. Duke University School of Medicine, Durham, NC, USA. Department of Obstetrics

and Gynecology, Duke University Medical Center, Durham, NC, USA.

2. Tianjin Central Hospital of Gynecology Obstetrics/ Nankai University Affiliated Maternity Hospital, Tianjin, China.

3. Department of Biomedical Engineering, Duke University, Durham, NC 27708 USA

4. Duke Global Health Institution, Durham, NC, USA.

Abstract Text:

Pregnancy increases vulnerability to extreme heat, including severe weather conditions and sauna use. Growing evidence suggests that heat stress from high temperatures can lead to fetal growth restriction and low birth weight, affecting both short- and long-term outcomes for mothers and children. Fetal growth restriction has significant prenatal and postnatal consequences, including an elevated risk of perinatal death, neurodevelopmental disorders, metabolic syndrome, and cardiovascular disease. Despite growing attention, gaps remain in understanding susceptibility periods, heat thresholds, and biological pathways of heat-related complications. The existing guidelines lack clarity and may lead to misinterpretation. Although fetal growth restriction is considered a placental-origin disease, the role of the placenta in heat stress-induced fetal growth restriction remains underexplored.

This study aims to investigate birth outcomes and reveal the mechanisms linking heat exposure to pregnancy complications. It emphasizes placental hemodynamics and development during various gestational stages.

This study used CD-1 mice (2-month-old) and employed acute and chronic heat exposure models. In the acute exposure model, we quantified placental blood oxygenation levels and perfusion before and after heating at 40°C for 30 minutes, followed by a 50-minute recovery phase at room temperature at E7.5, 10.5, 13.5, 16.5, or 18.5 using a high-resolution and high-speed functional photoacoustic microscopy. For chronic exposure, mice were exposed to either heat (40°C, 50% humidity for 2-h daily) or room temperature (25°C, 50% humidity) from E0.5 to E18.5. Tissues and data were collected at E13.5, E16.5, and E18.5. Placental development was analyzed using H&E and immunofluorescence staining for the syncytiotrophoblast biomarkers MCT1 and MCT4, while the expression of a hypoxic biomarker, HIF-1α, and angiogenesis biomarker sFlt-1 was evaluated by qPCR at E18.5.

No maternal mortality occurred. However, we noted pregnancy loss in 4 out of 48 dams in the chronic exposure model. Fetal weight and placental efficiency (fetal weight/placental weight ratio) were significantly reduced (P < 0.05) compared to the controls at E13.5, E16.5, and E18.5. Placental insufficiency indicates that the placenta cannot deliver enough oxygen and nutrients to the fetus, aligning with our photoacoustic microscopy observation of heat-induced placental hypoxia shortly after acute heat exposure. Additionally, the hypoxia biomarker HIF-1α was significantly upregulated in chronic heat-exposed placentas. Histopathological analysis revealed decidual hemorrhage, thrombosis, and chronic hypoxia-induced erythropoiesis. MCT1 and MCT4 immunofluorescence staining demonstrated deficits in syncytiotrophoblast layers, essential for oxygen and nutrient transfer. Moreover, the expression of sFlt-1, a vascular endothelial growth factor antagonist, was significantly upregulated in chronic heat-exposed placentas at E18.5, consistent with abnormal placental angiogenesis.

These findings suggest that heat stress at any stage of pregnancy leads to rapid placental hypoxia and prolonged heat exposure results in hypoxia-related placental developmental defects and fetal growth restriction. This research underscores the importance of addressing the risks of extreme heat during pregnancy and provides essential evidence to raise public health awareness, particularly in educating women of childbearing age about the potential risks associated with heat exposure during pregnancy.