Hydroxyprogesterone caproate

Hydroxyprogesterone caproate, sold under the brand name Delalutin among others, is a medication used to reduce the risk of preterm birth in women pregnant with one baby who have a history of spontaneous preterm birth. In March 2023, the manufacturer, Covis Pharma, agreed to withdraw the drug from the US market. The approval of this drug substance was withdrawn by the US Food and Drug Administration (FDA) in April 2023. In May 2024, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency recommended suspending the marketing authorizations of medications containing 17-hydroxyprogesterone caproate in the European Union.

Hydroxyprogesterone caproate is a progestin medication which was used to prevent preterm birth in pregnant women with a history of the condition and to treat gynecological disorders. It has also been formulated in combination with estrogens for various indications (brand names Gravibinon and Primosiston) and as a form of long-lasting injectable birth control (brand name Chinese Injectable No. 1). It is not used by mouth and is instead given by injection into muscle or fat.

Hydroxyprogesterone caproate is generally well tolerated and produces few side effects. Injection site reactions such as pain and swelling are the most common side effect of hydroxyprogesterone caproate. The medication may increase the risk of gestational diabetes when used in pregnant women. Hydroxyprogesterone caproate is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. It has some antimineralocorticoid activity and no other important hormonal activity. The medication shows a number of differences from natural progesterone.

Hydroxyprogesterone caproate was discovered in 1953 and was introduced for medical use in 1954 or 1955. It was marketed in the United States under the brand name Delalutin and throughout Europe under the brand name Proluton. The medication was discontinued in the United States in 1999. However, hydroxyprogesterone caproate was subsequently reintroduced in the United States under the brand name Makena for the treatment of preterm birth in 2011 until the FDA banned 17α-OHPC in 2023.

The use of hydroxyprogesterone caproate in pregnancy to prevent preterm birth in women with a history of preterm delivery between 20 weeks and 36 weeks and 6 days is supported by the Society of Maternal Fetal Medicine Clinic Guidelines put out in May 2012 as Level I and III evidence, Level A recommendation. Level I evidence refers to a properly powered randomized controlled trial, and level III evidence is support from expert opinion, while a Level A recommendation confers that the recommendation is made based on good and consistent scientific evidence. Hydroxyprogesterone caproate 250 mg IM weekly preferably starting at 16–20 weeks until 36 weeks is recommended. In these women, if the transvaginal ultrasound cervical length shortens to <25 mm at < 24 weeks, cervical cerclage may be offered. In the 2013 study the guideline recommendation is based on, there was also a significant decrease of neonatal morbidity including lower rates of necrotizing enterocolitis (0 in the treatment group vs 4 in the control), intraventricular hemorrhage (4 in the treatment group compared with 8 in the control for a relative risk of 0.25), and need for supplemental oxygen (14% in the treatment group vs 24% in the placebo for a relative risk of 0.42). Furthermore, this study contained 463 women, 310 of whom received injection. Of these women, 9 had infants with congenital malformations (2%), but there was no consistent pattern and none involved internal organs.

There is no evidence of fetal risk with use of hydroxyprogesterone caproate during pregnancy.^{[medical citation needed]} A review concluded that information about the potential harms was lacking. Three clinical studies in singleton pregnancies of 250 mg/week of intramuscular hydroxyprogesterone caproate have all shown a trend for an increase in pregnancy loss due to miscarriage compared to placebo. One of them, a large National Institutes of Health (NIH) study in 2003, looked at the effect of hydroxyprogesterone caproate injections in women at risk for repeat premature birth and found that the treated group experienced premature birth in 37% versus 55% in the controls. A follow-up study of the offspring showed no evidence that hydroxyprogesterone caproate affected the children in the first years of life. Based on these NIH data, hydroxyprogesterone caproate was approved by the US Food and Drug Administration (FDA) in 2011, as a medication to reduce the risk of premature birth in selected women at risk.^{[citation needed]}

The FDA expressed concern about miscarriage at the 2006 advisory committee meeting; the committee voted unanimously that further study was needed to evaluate the potential association of hydroxyprogesterone caproate with increased risk of second trimester miscarriage and stillbirth. A toxicology study in rhesus monkeys resulted in the death of all rhesus fetuses exposed to 1 and 10 times the human dose equivalent of hydroxyprogesterone caproate. As of 2008^[update], hydroxyprogesterone caproate was a category D progestin according to the FDA (that is, there is evidence of fetal harm). There is speculation that the castor oil in the hydroxyprogesterone caproate formulation may not be beneficial for pregnancy. Of note, the above-mentioned NEJM study by Meirs et al. compares the effect of hydroxyprogesterone caproate (with the castor oil component) to castor oil injection as the placebo.

A study published in February 2016, found amongst other findings: