Abstract
Fetal growth restriction (FGR), where a fetus fails to reach its genetic growth potential, affects up to 8% of pregnancies and is a major risk factor for stillbirth and adulthood morbidity. There are currently no treatments for FGR, but candidate therapies include the phosphodiesterase-5 inhibitor sildenafil citrate (SC). Randomized clinical trials in women demonstrated no effect of SC on fetal growth in cases of severe early onset FGR; however, long-term health outcomes on the offspring are unknown. This study aimed to assess the effect of antenatal SC treatment on metabolic and cardiovascular health in offspring by assessing postnatal weight gain, glucose tolerance, systolic blood pressure, and resistance artery function in a mouse model of FGR, the placental-specific insulin-like growth factor 2 (PO) knockout mouse. SC was administered subcutaneously (10 mg/kg) daily from embryonic day (E)12.5. Antenatal SC treatment did not alter fetal weight or viability but increased postnatal weight gain in wild-type (WT) female offspring (P < 0.05) and reduced glucose sensitivity in both WT (P < 0.01) and P0 (P < 0.05) female offspring compared with controls. Antenatal SC treatment increased systolic blood pressure in both male (WT vs. WT-SC: 117 ± 2 vs. 140 ± 3 mmHg, P < 0.0001; P0 vs. P0-SC: 113 ± 3 vs. 140 ± 4 mmHg, P < 0.0001; means ± SE) and female (WT vs. WT-SC: 121 ± 2 vs. 140 ± 2 mmHg, P < 0.0001; P0 vs. P0-SC: 117 ± 2 vs. 144 ± 4 mmHg, P < 0.0001) offspring at 8 and 13 wk of age. Increased systolic blood pressure was not attributed to altered mesenteric artery function. In utero exposure to SC may result in metabolic dysfunction and elevated blood pressure in later life.NEW & NOTEWORTHY Sildenafil citrate (SC) is currently used to treat fetal growth restriction (FGR). We demonstrate that SC is ineffective at treating FGR, and leads to a substantial increase systolic blood pressure and alterations in glucose homeostasis in offspring. We therefore urge caution and suggest that further studies are required to assess the safety and efficacy of SC in utero, in addition to the implications on long-term health.
Highlights
Fetal growth restriction (FGR), the inability of a fetus to reach its predetermined genetic growth potential, is a major complication of pregnancy affecting up to 8% of births in the UK [13]
The 5th centile of saline control WT fetal weights was 1.08 g, with 70% of P0 littermates falling below this 5th centile value; 70% of P0 mice from sildenafil citrate (SC)-treated dams fell below the 5th centile of saline control WT weight
For the first time, demonstrated that exposure to SC in utero is associated with raised systolic blood pressure (SBP) in offspring independent of sex or genotype
Summary
Fetal growth restriction (FGR), the inability of a fetus to reach its predetermined genetic growth potential, is a major complication of pregnancy affecting up to 8% of births in the UK [13]. There are no current therapies for FGR, in part due to the possible teratogenic effects of pharmaceutical agents [48]. This risk has led to a reluctance within the pharmaceutical industry to develop drugs for obstetric complications and the repurposing of therapies currently used in nonpregnant individuals [8, 14, 39]. In the absence of treatments, in cases of severe early onset FGR, the only clinical option is premature delivery of the baby, which, in itself, increases the risk of adverse effects on maternal and fetal health [22] and is associated with increased morbidity in adulthood [9, 21]
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