The treatment of women in preterm labor with human chorionic gonadotropin offers potential benefits in preventing retinopathy of prematurity and cerebral palsy in prematurely newborn infants

Dear Editor,

Infants born before the 37^th completed gestational week are classified as preterm births.^[1,2] Approximately 85% of these births occur between 32 and 37 weeks of pregnancy.^[1,2] Preterm births are more prevalent in low- and middle-income countries.^[1,2] Infants born prematurely are susceptible to several medical complications, including retinopathy of prematurity (ROP), cerebral palsy (CP); neurological, visual, and hearing impairments; breathing and feeding difficulties; developmental delays; autism spectrum disorders; and motor and behavioral problems.^[1,2] These complications are more severe in early (<34 weeks) than in late (34–36 weeks) preterm births. The healthcare costs in the United States alone have been estimated to exceed 26 billion dollars annually.^[1,2] This figure does not include the long-term palliative care costs incurred by many preterm infants. Medical complications from preterm births account for about 900,000 deaths globally each year.^[1] The resulting deaths and disability-adjusted life years contribute substantially to the loss of human capital and economic productivity. Preterm birth complications impose significant burdens on caregivers, communities, and healthcare systems. The affected families often endure immense emotional distress, suffering, feelings of guilt, and potential financial ruin.^[1,2]

Several factors can contribute to preterm births, including infections, inflammation, premature rupture of membranes, placental complications, twin or triplet pregnancies, cervical insufficiencies, lifestyle factors, and environmental influences. All these factors prematurely initiate uterine contractions, which are essential for fetal expulsion.^[3] The precise mechanisms of these untimely contractions remain uncertain. To understand these mechanisms require extensive longitudinal studies comparing women with preterm labor with those who continue through the completion of full-term pregnancy. Such studies are impractical to conduct. Nevertheless, declines in progesterone and human chorionic gonadotropin (hCG) levels are potential causes of preterm birth. The placenta produces both hormones, and they can inhibit uterine contractions.^[3] The contributions of other factors, if any, cannot be entirely disregarded. The decline may commence due to a reduction in placental signaling or premature placental separation from the uterine wall. This results in a decrease in progesterone and hCG-mediated inhibition of uterine contractions, concurrently exposing the uterus to the contracting stimulating influence of oxytocin.^[3,4]

Several pharmaceutical agents have been used in the treatment of preterm labor, including beta-adrenergic agonists, calcium antagonists, calcium channel blockers (the same class of drugs), non-steroidal anti-inflammatory compounds, nitric oxide donors, oxytocin antagonists, and magnesium sulfate. However, magnesium sulfate was primarily used for safeguarding fetal neural development rather than delaying labor. The tocolytic use of these agents is limited due to their adverse side effects.^[3] Yet, some of them have been used to delay birth by 24–48 h, to enable mothers to receive corticosteroid treatment to enhance fetal lung maturity. Progesterone had been used, but it was replaced by its synthetic analog, 17-hydroxyprogesterone caproate (17-OHP-C). The analog exhibited efficacy in the prophylactic rather than therapeutic settings. It is not recommended for multiple gestations, threatened preterm labor, cessation of active labor, or subclinical infections. Furthermore, 17-OHP-C does not appear to inhibit myometrial contractions and has been associated with embryo-fetal toxicity and an elevated risk of gestational-induced type 2 diabetes.^[3] Consequently, the U.S. Food and Drug Administration withdrew its approval in 2023, citing insufficient evidence of its efficacy.

The possibility that hCG could be a tocolytic agent emerged from a 1990 publication by Reshef et al.^[5] This study demonstrated the presence of hCG/luteinizing hormone (LH) receptors in both human uterus and feto-placental tissues. Subsequent research not only validated these findings but also expanded them to include numerous other nongonadal tissues, thus fundamentally challenging the notion that hCG is solely a gonadal-regulating hormone.^[6]

Further studies elucidated that hCG can inhibit uterine contractions by disrupting gap junctions by various mechanisms and also can stimulate the growth of new blood vessels and dilatate the existing ones.^[3,7,8] Evaluation of hCG as a tocolytic agent in an experimental small animal model has shown its effectiveness.^[3] More importantly, hCG has been tested in five different small clinical studies on cohorts of women with preterm labor.^[3] They demonstrated that hCG was effective in women of different ethnic backgrounds, under vastly different conditions, during active labor, and in those with a previous history of preterm births. In head-to-head comparisons, while hCG treatment did not demonstrate significant adverse side effects, magnesium sulfate caused side effects in every instance. Similarly, the preterm birth rate was lower with hCG than with progesterone. Although these studies are very encouraging for hCG, they lack the vigor of large-scale, multicenter, randomized, and double-blind clinical trials.

The brain and neural retina are among the other nongonadal tissues that have been demonstrated to possess hCG/LH receptors.^[9,10] These discoveries prompted further studies that revealed these receptors also exist in the developing retina and brain of the fetus.^[11-14] The activation of these receptors, similar to what occurs in the uterus,^[8,15] can stimulate the production of vascular endothelial growth factor in the neural retina and brain,^[13,16] which promotes vascular growth. A diminished signaling, due to the premature decline in hCG levels during preterm labor, can disrupt this developmental process in the neural retina and brain, potentially contributing to the conditions such as ROP and CP.^[13,16]

Other human fetal organs, including the kidney, liver, pancreas, lungs, small and large intestines, and adrenals, also contain hCG/LH receptors.^[17] Nevertheless, the extent to which these receptors contribute to any of the medical complications in prematurely born infants remains uncertain. Given the diverse range of medical complications, which may manifest as the dysfunction of other organs, it is plausible that these receptors may play a role.

After a comprehensive evaluation of the advantages and disadvantages of all tocolytics, hCG represents a promising therapeutic agent that requires further evaluation. Notably, hCG not only extends the pregnancy duration but also potentially safeguards infants from developing conditions such as ROP, CP, and possibly other medical complications.^[13,16] There is no evidence for any other tocolytics offering such comparable benefits. Nevertheless, the widespread use of hCG for preterm birth prevention remains contingent upon demonstrating its safety and efficacy in large-scale, multicenter, randomized, and double-blind clinical trials. These trials are essential due to the societal, healthcare, suffering, and family costs associated with preterm births.