Vaginal progesterone scores at par with cerclage for preventing preterm births in women with previous mishap and short cervix: a comparison meta-analysis

Vaginal progesterone fares equal with cerclage for preventing preterm births in women who have a short cervix and history of previous mid-trimester miscarriage (MTM) and/or preterm labor (PTL) reports the results of an updated comparison meta-analysis published in July issue of American Journal of Obstetrics and Gynecology.

In a recent update by WHO, every year 15 million babies are born before 37 weeks of gestation and the figures continue to rise. Prematurity is the leading cause of death in children under 5 years of age and is responsible for causing about 1 million deaths worldwide.

In addition, prematurity is a major contributor towards lifelong neurological morbidities such as intellectual disability, cerebral palsy, hearing and visual impairments, and a higher risk of chronic diseases in adulthood.

Women with a previous history of PTL and a short cervix (≤25) face a 3-fold increased risk of recurrent preterm births as compared to women with a cervical length >25 mm in the midtrimester.

The efficacy of vaginal progesterone and cerclage in preventing PTL is a hotly debated topic, but to date, only 2 small RCTs have been conducted to compare these two treatment modalities. However, the sample size was too small to detect any treatment differences.

The 2016 multicenter double-blind randomized placebo-controlled OPPTIMUM trial refuted the claim that progesterone reduces the risk of PTL and helps decrease the associated neonatal morbidity and mortality.

Hence, this adjusted indirect comparison meta-analysis was performed which usually, but not always, provides results similar to head-to-head randomized controlled trials.

An updated literature search of MEDLINE, EMBASE, CINAHL, LILACS, the Cochrane Central Register of Controlled Trials, conference proceedings and research registers of ongoing trials was performed from their inception to March 31, 2018.

All the RCTs comparing vaginal progesterone to placebo/no treatment or cerclage to no cerclage in women with a singleton gestation, previous spontaneous preterm birth, and a sonographic cervical length <25 mm was included in the meta-analysis.

The researchers looked at prevention of preterm birth <35 weeks of gestation and perinatal mortality as the primary outcomes.

Five trials comparing vaginal progesterone vs placebo (265 women), 5 comparing cerclage vs no cerclage (504 women) and the OPPTIMUM study were included in the analysis.

The daily dose of vaginal progesterone used in the trials varied from 90 to 200 mg, and the treatment was administered from 18–25 to 34–36 weeks of gestation. Thirty women in two RCTs underwent a cerclage after randomization.

In direct comparison, the use of vaginal progesterone reduced the risk of preterm birth <35 weeks by 32%, <32 weeks of gestation by 40%, neonatal sepsis by 62%, neonatal morbidity by 71%, and admission to NICU by 54%.

The use of cerclage reduced the risk of preterm birth <35 weeks by 30%, <32 weeks of gestation by 34%, composite neonatal morbidity and mortality by 36%, and birthweight <1500 g by 36%.

Both interventions together were associated with a nonsignificant ∼36% reduction in the rate of perinatal death.

Adjusted indirect comparison meta-analyses didn’t show any differences between vaginal progesterone and cerclage in preventing preterm births and perinatal deaths.

The study has several advantages such as the use of individual patient data, similar patient demographics, and low rates of bias. There were few limitations such as the absence of data on respiratory distress syndrome in the OPPTIMUM study, some women with cerclage received 17-OHPC that could have affected the results and non-reporting of maternal side effects in the individual patient data (IPD) meta-analysis.

In the absence of adequately powered, high-quality, randomized controlled trials comparing vaginal progesterone and cerclage, our indirect comparison treatment meta-analysis provides the best available evidence regarding the comparative efficacy of the 2 interventions.

This meta-analysis results have huge implications in clinical practice. Both progesterone or cerclage show similar efficacy in preventing recurrent preterm births in patients with singleton pregnancy and short cervix. Thus, besides efficacy, the decision to use one intervention over other is based on physician preferences, cost-effectiveness, and maternal side effects.

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What should midlife women know about preventive cardiology?

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Dr. Beth Abramson is a preventive cardiologist and helps women manage the risk of heart disease.  In this video by North American Menopause Society (NAMS), she answers many vital questions about menopausal hormone therapy, midlife weight gain, smoking, alcohol, and aspirin therapy.  

KEYTRUDA gains FDA approval for treatment of recurrent or metastatic cervical cancer

The U.S. Food and Drug Administration (FDA) has approved Merck’s pembrolizumab (KEYTRUDA®), for the treatment of patients with recurrent or metastatic cervical cancer whose disease had worsened on or after chemotherapy and whose tumors express programmed cell death ligand 1 (PD-L1), as determined by an FDA approved test.

The US FDA has approved the Dako PD-L1 IHC 22C3 pharmDx assay for expanded use as a companion diagnostic test for Keytruda for cervical cancer.

The approval comes in way ahead of the previously decided date of June 28. Furthermore, the drug is approved under the FDA’s accelerated approval regulations based on tumor response rate and durability of response.

Continued approval in future will be based upon verification and description of clinical benefit in the ongoing trials ahead.

The accelerated approval was based on results of ongoing KEYNOTE-158, a multi-center, non-randomized, open-label, multi-cohort trial (NCT02628067). The trial enrolled patients with multiple types of advanced solid tumor, who have not responded to usual chemotherapy or are intolerant to it.

Patients with autoimmune diseases or requiring immunosuppression were excluded from the trial.

The patients received KEYTRUDA intravenously at a dose of 200 mg every three weeks until unacceptable toxicity or documented disease progression or for 24 months in patients without disease progression.

Among the 98 patients with advanced cervical cancer, 77 (79%) had tumors that expressed PD-L1 with a Combined Positive Score (CPS) ≥1 and have received at least one line of chemotherapy in the metastatic setting.

The objective response rate in these 77 patients was 14.3 percent, with a complete response in 2 patients (2.6%) and partial response in 9 patients (11.7%).

Ninety-one percent of patients experienced duration of response exceeding 6 months or longer. Eight patients discontinued the drug because of serious side effects like anemia, fistula, hemorrhage, and infection.

The other common side effects of KEYTRUDA are fatigue, musculoskeletal pain, diarrhea, pain and abdominal pain and decreased appetite (21%).

 No responses were observed in patients whose tumors did not have the PD-L1 expression (CPS<1).

KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells. This increases the ability of the body's immune system to help detect and fight tumor cells.

Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories said, “KEYTRUDA is now the first anti-PD-1 therapy approved for the treatment of advanced cervical cancer, providing an important new second-line option for certain patients with this disease. This approval also marks the first indication for KEYTRUDA in gynecologic cancer and reflects our ongoing commitment to bring forward innovative treatment options across a broad range of cancers, including cancers that disproportionately affect women,” in a news release.

KEYTRUDA has already been approved by FDA for treatment of melanoma, head and neck cancer, lung cancer, urothelial cancer, and gastric cancer.

Merck News Release 

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