In a surprise result, a study of a drug designed to lower the risk of premature birth was shown to be no better than a placebo.
Update, October 30, 2019 An FDA Advisory Committee met to review Makena (17-α hydroxyprogesterone injection or 17-OHPC) in light of the new post-approval study indicating that Makena is no better than a placebo.
The Committee voted 16-0 that there is no substantial evidence that Makena reduces the risk of recurrent preterm birth. The Committee voted 13-3 that the new study did not show a clinical benefit of Makena on the health of infants born prenatally exposed to Makena. And, in the most important vote the panel split 9-7 in favor of withdrawing approval for Makena. If the FDA agrees, Makena would be pulled off the market.
The FDA most often follows the Advisory Committee’s recommendations, but is not obligated to do so. –Suzanne B. Robotti
Preterm infants, those born before 37 weeks of gestation, are at a much higher risk of complications. Babies born too early (especially before 32 weeks) have higher rates of death and disability. Even babies born only four to six weeks early can suffer from breathing difficulties, feeding problems, jaundice and effects on brain functions. Long-term challenges for all preterm infants include learning disabilities, visual and hearing problems. Given the lifetime risks of preterm birth, doctors and mothers are anxious to find ways to reduce the possibility of preterm birth.
Nearly half a million babies are born preterm each year in the United States, which has the worst rate of preterm birth among developed countries (and even many developing countries). Though the rate dropped from more than 12% a decade ago to just under 10% in 2017, it has started to tick up again.
One of the two drugs approved for pregnant women at risk for preterm birth is Makena. But recent data suggests Makena, a progesterone-based drug used for nearly a decade to reduce preterm birth, may not lower the risk at all. In fact, since a recent study failed to show it was any more effective than a placebo, the nonprofit consumer advocacy organization Public Citizen has petitioned the US Food and Drug Administration to withdraw the drug immediately.
History of Makena
An earlier version of Makena, called Delalutin, was withdrawn from the market in 1999 by Bristol-Myers-Squibb for financial reasons. A generic version, 17-alpha-hydroxyprogesterone caproate (17p), has been available as a vaginal gel or suppository for decades at compounding pharmacies. In 2011 AMAG Pharmaceuticals received accelerated approval from the FDA for its injectable version, called Makena, after a successful study showing it reduced risk of premature birth. At the time of approval, FDA advisers and other experts had concerns about inadvertent bias in the study. The FDA therefore approved the drug with the condition that AMAG Pharmaceuticals conduct a longer term study on the drug’s safety and effectiveness.
Recently AMAG released a study that involved about 1,700 women and showed that the preterm birth rate was no lower in women who took Makena than those who received a placebo. Fortunately, it also did not show an increased risk of complications, but some doctors have questioned whether enough research exists on long-term risks to continue recommending a drug that may not work as well as believed. More than two dozen studies on 17-alpha-hydroxyprogesterone caproate over the past decade have mixed results.
AMAG released those preliminary negative results in March, leading to a drop in AMAG’s stock shares. An FDA advisory panel meeting October 29 will now determine the fate of the drug.
What are current recommendations to reduce preterm birth risk?
Two different hormonal drugs can currently be used to reduce risk of preterm birth: Vaginal progesterone which is administered with capsules inserted into the vagina, and Makena which is administered as a weekly intramuscular injection from 16 to 36 weeks gestation. Vaginal progesterone is not FDA-approved for preterm birth but can be prescribed off-label. But whether either drug is prescribed to reduce preterm birth—or another treatment is recommended— depends on a woman’s medical and social history and current pregnancy.
Current clinical guidelines from the American College of Obstetricians and Gynecologists (ACOG) recommend that women “with a singleton gestation and a prior spontaneous preterm singleton birth should be offered progesterone supplementation starting at 16–24 weeks of gestation to reduce the risk of recurrent spontaneous preterm birth.” The statement does not specify what progesterone treatment to offer but 17-hydroxyprogesterone caproate, the generic of Makena, is one option.
ACOG issued a statement October 25 that its current guidance regarding preterm birth preventive treatment and indications related to Makena remains in effect for now.
“Consideration for offering 17p to women at risk of recurrent preterm birth should take into account the body of evidence for progesterone supplementation, the values and preferences of the pregnant woman, the resources available, and the setting in which the intervention will be implemented,” ACOG Vice President Christopher M. Zahn, MD, said in the statement. “Additional information from planned meta-analysis and secondary analyses will need to be evaluated to assess the impact this intervention has on women at risk of recurrent preterm birth in the United States.” He added that the organization will “will continue to monitor this topic, evaluate additional literature and any further analyses as published, and address findings as needed in relevant clinical guidance.”
Care for Immediate Risk of Preterm Birth
Women at immediate risk of delivering a very preterm baby (before 34 weeks) may be prescribed tocolytics, a group of drugs that delay delivery up to 2 days. Taking tocolytics gives women time to also take magnesium sulfate which reduces risk of cerebral palsy in the baby.
Women may also receive corticosteroids anywhere from 23 to 36 weeks + 6 days gestation to speed up fetal lung, brain and digestive system development if early delivery is likely. But Makena and vaginal progesterone are aimed at preventing preterm birth in at-risk women long before delivery is imminent.
Risk Factors for Preterm Birth
The biggest risk factors for premature birth include a history of previous preterm labor or birth, pregnancy with multiples (twins, triplets, etc), use of assisted reproductive technology to conceive (such as in vitro fertilization), conception within 6 months of a previous birth, an age under 18 or over 35, African-American race, a short cervix and prenatal exposure to diethylstilbestrol (DES), an estrogen drug thousands of pregnant women were prescribed between 1938-1971. For more information on DES visit our sister organization, DES Action.
But other health conditions, such as sexually transmitted or urinary tract infections, being underweight or overweight, placental abnormalities, gestational diabetes and high blood pressure, can also increase risk. Behavioral or social risk factors exist too, such as smoking or drinking alcohol during pregnancy, inadequate prenatal care, domestic violence, sustained high stress levels and exposure to pollutants in the environment, such as poor air quality.
Of all these risk factors, only women with a history of preterm birth are recommended to take Makena. Research shows that Makena does not reduce preterm birth in women with multiples (twins, triplets, etc.), a short cervix or premature rupture of membranes. Women with a history or risk of blood clots or breast cancer, uncontrolled hypertension or liver problems also may not be able to take Makena.
Vaginal progesterone—a different drug than Makena—appears to cut the risk of preterm birth nearly in half for women with short cervix though, again, it’s not effective in women carrying multiples. Common side effects of vaginal progesterone include the following: dizziness or confusion, drowsiness, fatigue, headache, irritability, gastrointestinal issues (pain, nausea, diarrhea, constipation), bloating, swelling in the hands or feet, breast swelling or tenderness, cramps, pelvic pain or vaginal itching, burning or discharge.
The only non-drug option for women with a short cervix is cerclage, a procedure that binds together and reinforces the cervix, typically with sutures or synthetic tape. But cerclage is not recommended with multiples, when it can increase risk of preterm birth. (No current treatments exist to prevent preterm birth in multiples pregnancies.)
What are Makena’s risks?
The most common side effects of Makena include pain, swelling, itching, bruising, nausea, diarrhea and a lump at the injection site. Those who take it should call a doctor if they experience jaundice, sudden depression symptoms, increased blood pressure, severe headaches, blurred vision, nosebleeds, sudden numbness or severe swelling in the hands, ankles or feet. Those these latter symptoms are rare, they could indicate a serious reaction to the drug.
One additional concern about Makena, noted in a March Wall Street Journal article, is an increased risk of gestational diabetes, as found in a 2017 study. But when researchers looked only at randomized controlled trials, in which two similar groups of pregnant women are randomly assigned to receive Makena or placebo, no increased risk of gestational diabetes appeared.
The handful of studies finding an increased risk were cohort studies—studies without a control group that can only use historical rates of gestational diabetes for comparison. This is not a reliable way to estimate risks since historical rates may be based on different populations with risk factors.
No other significant risks from Makena show up in the research literature. A couple studies found other benefits with Makena, such as increased birth weight, reduced complications or reduced newborn death. But these results only occurred in a few studies, sometimes with minor effects, so the evidence is not strong enough to attribute those benefits to Makena.
Not much long-term data exist on Makena’s use during pregnancy, but researchers have learned a great deal about hormone-based drugs given during pregnancy, particularly since the disaster of DES. Women born to mothers who took DES have an increased risk of many health problems, including a vaginal/cervical cancer called clear cell adenocarcinoma. Other risks for “DES Daughters” include infertility, an abnormally shaped uterus or cervix and pregnancy complications. “DES Sons” also have increased risks regarding reproductive organs and health.
Makena, however, is a progesterone, not an estrogen like DES. The body naturally produces extra progesterone during pregnancy. Based on today’s understanding of women’s reproductive systems, it’s unlikely that added progesterone would have long-term effects on the fetus. Still, if the evidence for using Makena is as weak as the recent AMAG study suggests, no risk of possible, currently unknown risks of Makena would be worth taking it.
What’s the bottom line?
The biggest limitation to studies of Makena is the diversity of study designs and populations. Some studies involve only women in the US while others include women only in Europe or elsewhere. Some have predominantly white participants while others have predominantly black participants. Some adequately took into account other risk factors, such as smoking, while others didn’t. Some studies were randomized controlled studies—the most reliable study for testing drugs—while others studies did not have a control group.
Currently, the evidence is not strong for Makena’s effectiveness in reducing preterm birth in the small group of at-risk women recommended to receive it. It may work in women with very specific characteristics that researchers have not yet identified. For anyone already at risk for preterm birth for any reason, the most important advice is to have an in-depth conversation with their prenatal care provider about options for their particular situation.
If your doctor recommends Makena, ask why and whether he or she has personally reviewed the most recent evidence. Ultimately, each woman must feel confident assessing the risks and benefits of Makena or any drug for her personal situation.