A BRIEF REVIEW OF PROGESTINS IN PREGNANCY (January 2008)

 

OVERVIEW

The purpose of this brief review is to promote participation in clinical trials to further define the safety and efficacy of the use of progestins in the prevention of preterm birth.

 

In 2003 results from two randomized clinical trials^[1],[2] and an ACOG Committee Opinion^[3] were published in support of the use of progesterone to reduce preterm birth. The data from the Meis trial¹ along with other data were submitted to the FDA in support of 17 alpha-hydroxyprogesterone caproate (17-OHP-C) as a treatment for the prevention of preterm birth in women with a history of preterm birth.^[4] The FDA held an Advisory Committee Meeting August 29, 2006 to discuss FDA’s concerns about the primary endpoint, about the unexpectedly high placebo rate, and about the occurrence of miscarriage and fetal death in the trial. A majority of the committee voted that the primary endpoint of the trial was not adequate, that the data from the trial did not provide substantial evidence of a reduction in fetal and neonatal mortality or morbidity, and there was unanimous agreement that further study was needed to evaluate the association of 17-OHP-C with an increased risk of miscarriage and stillbirth.^[4]  As of January 2008, 17-OHP-C is still not approved by the FDA as safe and effective for use in pregnancy.

 

In 2007, three additional publications presented data on natural progesterone (not 17-OHP-C) in the prevention of preterm birth in singleton pregnancies. The first presented evidence that the use of vaginal progesterone can prevent preterm birth in women with an extremely short cervix, ≤15mm^[5]; infant outcomes were not significantly improved in that trial. The second trial was designed to evaluate the use of vaginal progesterone in women with a history of preterm birth.^[6] While women with a preterm birth did not benefit from progesterone therapy in that trial^[6], a secondary analysis of women with a shortened cervix prior to treatment suggested a benefit in the delay of delivery and the infants of these women were significantly healthier.^[7] A scientific review of the prevention of spontaneous preterm birth focusing on the role of a shortened cervix in identifying patients who may benefit from protesterone was also published last year.^[8]

 

Prior to the FDA advisory committee meeting, a Cochrane Review published online regarding the use of progestins to prevent preterm birth concluded: Not enough evidence for progesterone in pregnancy for women at increased risk of giving birth too soon.^[9] They included in their summary that important maternal and infant outcomes have been poorly reported to date and that information regarding the potential harms of progesterone therapy to prevent preterm birth is limited.

 

Based on the conclusion of the FDA advisory committee, the Cochrane Review and on the data discussed below, there is not enough evidence of safety and efficacy at this time to make a progestin the standard of care in the prevention of preterm birth. The patient population to be treated, the ideal progesterone formulation, the optimal route of drug delivery, and the safety of the treatments remain unknown. Thus, it is reasonable to support ongoing placebo controlled trials of progestins in the prevention of preterm birth in women at risk.

 

REVIEW

 

1.     NATURAL (BIOIDENTICAL) PROGESTERONES
    There are two natural progesterone hormones that are commonly discussed

a.      PROGESTERONE (P) – This is the progestin produced by the corpus luteum in the luteal phase of the menstrual cycle and during the first trimester of pregnancy and (following the luteal-placental shift) in the largest quantity by the placenta. Natural progesterone is FDA approved for use in the first trimester of pregnancy in some formulations.

b.     17 hydroxyprogesterone (17 OHP) - This is also a natural hormone produced in much lower quantities during pregnancy.

 

2.     SYNTHETIC (ARTIFICIAL) PROGESTINS

a.      17 hydroxyprogesterone caproate (17-OHP-C) – This synthetic progestin is made artificially by converting natural progesterone into a synthetic progestin. It is a similar artificial progestin to the progestin drug commonly used in hormone replacement therapy, medroxyprogesterone acetate (MPA), which was recently shown to have unexpected side effects when used in thousands of women in menopause.^[10],[11] It is also similar to an artificial progestin used in cancer therapy, megesterol acetate (MEGACE). It is not the same chemical as the natural 17 hydroxyprogesterone.
(Attachment 1)

b.   17-OHP-C, MPA, and MEGACE are all FDA pregnancy category D progestins meaning the FDA believes there is evidence of fetal harm.
(Attachment 2)

c.   Although in test-tube experiments there is evidence that human liver microsomes are capable of metabolizing 17-OHP-C to natural hydroxyprogesterone (17OHP), the delivery of 17-OHP-C by injection bypasses hepatic first-pass metabolism. There is already evidence that some women receiving weekly injections of 250 mg of the synthetic 17-OHP-C still have below normal levels of natural hydroxyprogesterone during this treatment.^[12] (Attachment 3) A recent study was reported that shows that after a 250mg injection of 17-OHP-C, 17-OHP-C can be measured in the plasma and remains in the plasma possibly for 45 days (5 times the T1/2).^[13] (Attachment 4) This confirms that 17-OHP-C is neither rapidly nor appreciably converted to a natural progesterone.

 

 

3.     Lack of SUFFICIENT FETAL AND Infant Outcomes Data

Fetal adverse events are rare even in clinical trials. Events possibly related to fetal toxicity and to fetal teratogenicity need to be evaluated. Long-term infant outcomes were not evaluated in either the NIH trial published in the New England Journal of Medicine comparing 17-OHP-C to placebo in the prevention of preterm birth, or the Fonseca trial published in the American Journal of Obstetrics and Gynecology comparing natural progesterone administered vaginally to placebo in the prevention of preterm birth.

a.      The NIH trial reported in the New England Journal of Medicine (2003) did not include infant outcomes beyond the initial hospitalization in the original protocol. ^{NOTEREF _Ref188412224 \h  \* MERGEFORMAT 1}  While there is considerable evidence that 17-OHP-C is not teratogenic,^[14] in the NIH study there was a signal regarding fetal harm ^{NOTEREF _Ref188412224 \h  \* MERGEFORMAT 1}  relating to fetal toxicity (not teratogenicity).

i.      All 5 pregnancy losses before 20 weeks occurred in the women receiving 17-OHP-C, there were none with placebo.

ii.      There was a 50% increase in intrauterine fetal death among women receiving 17-OHP-C compared to placebo although due to the sample size this increase was not statistically significant.

iii.      In the most conservative assessment, if the lost-to-follow-up cases are considered cases of fetal loss, then there was evidence of a possible statistically significant increase in fetal loss with  compared with placebo using a significance level of 5.7% (i.e., the p-value was 0.057) rather than the nominal 5% level. (Attachment 5)

b.     A meta-analysis of 17-OHP-C published in BJOG in 1990 by Keirse^[15] showed a possible signal for an increase in miscarriage with an odds ratio 1.3 (0.61-2.74).

c.     A meta-analysis of the only 3 trials conducted to date evaluating 250 mg of 17-OHP-C given by weekly injections beginning 12-17 weeks gestation in the prevention of preterm birth shows a statistically significant increase in miscarriage. (Attachment 6)

d.   Two previous reproductive toxicology studies of 17-OHP-C in animals are noteworthy. The first, in mice, had an increased fetal loss with 17-OHP-C compared to placebo which was statistically significant for only the middle dose.^[16] No dose response was evident. The study was not conducted to current reproductive toxicology standards. (Attachment 7)

      The second, in rhesus monkeys, showed that total embryolethality resulted following the administration of 17-OHP-C alone and in combination with estradiol valerate at both 1X and 10X the human dose equivalent dose. The authors concluded that long-term in utero exposure to 17-OHP-C is embryolethal but not teratogenic at doses up to ten times the human therapeutic dose.^[17]

      (Attachment 8)

e.   A complete review of the embryo-fetal toxicity signals of 17 alpha-hydroxyprogesteorne caproate in high-risk pregnancies was recently published by Christian et. al. ^[18]
(Attachment 9)

f.    The FDA presented a view of the Meis trial data that suggested an association between 17-OHP-C use and the occurrence of miscarriage and early fetal death. ⁴ (Attachment 10) The FDA presented a view of the Meis trial data that suggested that the risk of fetal/neonatal death was greatest for 17-OHP-C in the first 66 days of therapy. ⁴ (Attachment 11)

 

g.   The FDA advisory committee was in unanimous agreement that further study was needed to evaluate the association of with an increased risk of miscarriage and stillbirth.⁴ (Attachment 12)

 

4.     Questions about placebo response in NIH study.

A letter to the editor in the New England Journal of Medicine in 2003 from the OB/GYN department at Duke University^[19] questioned the efficacy results in the NIH trial of 17-OHP-C versus placebo in the prevention of preterm birth due to the presence of castor oil in the placebo. (Attachment 13)

a.      Castor oil is known to induce labor.

i.      Castor oil has been used for over 2000 years (since ancient Egypt) to induce labor.^[20]

ii.      93% of nurse midwives surveyed in 1999 used castor oil to induce labor.^[21]

iii.      The only study published which evaluated castor oil in the induction of labor found that among women 40-42 weeks gestation without contractions: 58% went into labor within 24 hours of ingesting castor oil compared to only 4% of untreated controls. ^{NOTEREF _Ref188427786 \h  \* MERGEFORMAT 20} (Attachment 14)

b.     The methods section of the NIH publication in the NEJM predicted that “On the basis of data from a previous study by the Maternal-Fetal Medicine Units Network, we estimated that 37% of the women in the placebo group would deliver before 37 weeks of gestation.” ^{NOTEREF _Ref188412224 \h  \* MERGEFORMAT 1},^[22]

i.      A survey of birth certificates in the state of Georgia over a 15 year period showed that if a first birth lasted <28 weeks the chance of delivering the second pregnancy preterm was 29-36%.^[23]  

ii.      The Fonseca trial placebo rate was 29%. ^{NOTEREF _Ref188427987 \h  \* MERGEFORMAT 2}

iii.      It has been published that the risk of delivering preterm with 1 previous preterm birth is 16-19%, with 2 previous   preterm births is 32-41%, and with 3 previous preterm births is 67%.^[24]  The average number of previous preterm births in the NIH trial was 1.5. ^{NOTEREF _Ref188412224 \h  \* MERGEFORMAT 1}

v.         At  the advisory committee meeting the FDA presented the results of the 150 patients who were excluded from the Meis trial analysis. ⁴(Attachment 15) The FDA expressed concern that the placebo rate in the published trial data was not consistent with the results from the excluded trial data.⁴ (Attachment 16)

vi.         In the transcript from the Advisory committee meeting several of the committee members expressed concern over whether or not efficacy has been demonstrated in the trial. ⁴

 

5.   NATURAL PROGESTERONE’s EFFECT ON MYOMETRIAL CONTRACTIONS

The Fonseca trial showed that natural progesterone given vaginally significantly reduced the background myometrial contraction rate compared to placebo. ^{NOTEREF _Ref188427987 \h  \* MERGEFORMAT 2} In addition, Fonseca also showed a significant reduction in the preterm birth rate associated with the use of natural progesterone given vaginally (29% placebo rate reduced to 14% with vaginal progesterone). Infant outcomes were not reported in the manuscript. ^{NOTEREF _Ref188427987 \h  \* MERGEFORMAT 2}
The NIH trial of 17-OHP-C did not evaluate myometrial contractions. A recent study reported in Reproductive Biology and Endocrinology showed that 17-OHP-C does not inhibit oxytocin induced myometrial contractions.^[25](Attachment 17)
 

6.   Additional placebo controlled trials of progestins in the prevention of preterm birth are warranted.

In September 2004 Marc Keirse published a review and opinion of the NIH trial and the Fonseca trial.^[26] In his review Dr. Keirse wrote: “Critical analysis of the reports provides no convincing evidence that either one of these treatments is worth pursuing outside the context of controlled research to determine, first, whether and, second, how the treatments might work.”
 

According to the 2006 Cochrane Review by Dodd⁹, there is not enough evidence of safety and efficacy to make a progestin the standard of care in the prevention of preterm birth at this time. (Attachment 18)

It is very reasonable to support ongoing placebo controlled trials of progestins in the prevention of preterm birth in women at risk due to a previous preterm birth.

 

7.   recent trials suggesting a benefit of progesterone in women with a short cervix.

 

In August 2007 Fonseca and Nicolaides published their findings on the evaluation of progesterone to prolong gestation in women with a very short cervix (≤15mm)in mid-pregnancy (24 weeks).^[27] While the frequency of preterm birth was significantly decreased, there was no significant improvement in infant outcomes in that trial.

 

In October 2007 O’Brien⁶ (Attachment 19) and DeFranco⁷ (Attachment 20) published the results of the largest randomized trial to date of the use of progesterone for the prevention of preterm birth in singleton pregnancies. While the use of progesterone did not appear to delay delivery in women with a baseline cervical length over 32mm at the 17-23week ultrasound, in women with a baseline cervical length less than 32mm there appeared to be a progesterone effect; and the progesterone effect increased as the length of the cervix at baseline decreased such that in the cohort with a baseline cervical length <28mm significantly fewer deliveries occurred ≤32 weeks in women randomized to progesterone compared to placebo. In addition, the infants of women with a cervical length <28mm at baseline were healthier based on significantly fewer admissions to the NICU and significantly fewer NICU days overall. An editorial review by Roberto Romero ⁸ (Attachment 21) addresses the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment.

 

For more information. please visit : http://www.clinicaltrials.gov/ct2/show/NCT00615550?term=Short+Cervix&rank=3

 

 

[REFERENCES] 

---