Lecture on human pregnancy No.16 Progestogen treatment for recurrent miscarriage did not show efficacy; a new study published in the prestigious medical journal said. (1)

The literature said as follows.

The study objectives were to verify undetermined clinical question of if the treatment using progestogen, which is an essential (therefore most important) hormone for maintaining pregnancy, can significantly suppress recurrent miscarriage or not.

The study protocol they used were, administration of micronized progesterone vaginal suppository preparation 400mg twice-daily, from a time after a positive urinary pregnancy test (no later than 6 weeks of gestation) through 12 weeks of gestation. Spontaneous pregnant women who have several episodes of miscarriage in the past were enrolled in the study. Four hundred and four women in the active arm and 432 women assigned to placebo.

The primary endpoint was live birth after 24 weeks of gestation and at this point it was determined completion of treatment with success.

The study outcomes were 65.8% in the active treatment arm and 63.3% in the placebo arm, as a result, a statistical difference was not demonstrated.

The authors gave some discussions in the literature based on their results. I would, however, try to argue against their comments.

1.    Firstly, the study was conducted on a multicenter, large scale setting which was a strength of the study (investigation). A large number of enrolled cases indeed speaks to strength.

However, careful observation of patient condition -by physicians who are skilled in common with standardized medical judgement criteria- is important in the clinical studies. Socioeconomic background differs from one patient to another. Particularly, disparities may be large in the US between racial or ethnic characteristics, or among various income status.

Recently, healthcare professionals including physicians, who look after pregnant women would not advise women to undertake rest regimen. As an old generation obstetrician of myself, it was hammered into my head that to take adequate rest is a fundamental approach for miscarriage aversion.

The point I want to make here is if, in the study protocol, an advisory criteria for the rest regimen for participants had been controlled or not. It was not mentioned in the paper.

2.    The second argument is the dose and type of progestogen preparation. According to the authors, dose and administration were followed in accordance with that of luteal function maintenance method used in the in-vitro fertilization.

In the IVF technology, dose and type of hormone are critical factors for successful implantation of the embryo (i.e. conception) after transferred back into the uterus. The type of hormone preparation is also in question.

In the literature, the authors said the dose and dosage is based on a previous report using 400mg daily administration of progestogen vaginal suppository, which was said effective in maintaining luteal function in IVF. (2)  In addition, the authors referred to a number of literatures, including their own reports, that progestogen vaginal suppository was effective in the treatment of preterm labor. (3-5)

There are ample of reports suggesting estrogen (follicle hormone) should be used concomitantly for maintaining luteal function in IVF because, by this way, implantation rates improves. (6)

What about hormone dynamics after conception? Mechanisms of hormone dynamics after conception has been elucidated by A. Klopper and other obstetric scientists. (7)

It is well known that both hormones markedly secreted in amount from feto-placental unit in accordance with progression of gestation. Progesterone is produced by corpus luteum in the early phase of gestation thereafter shifted to the placenta, gradually with its formation and development.

This timing of hormone production shift is called “luteal– placental shift” and normally takes place during 6 to 11 weeks of gestation. This is however, a phenomenon seen in pregnancies with normal menstrual cycles.

The study protocol was; treatment with progestogen or placebo to be initiated at positive urinary pregnancy test through 12 weeks of gestation then compare outcomes. Either fetus of 42days of gestation at the start of treatment or cases of unconfirmed latest menstruation days were excluded. 

I have some doubt about accuracy of gestation weeks of women enrolled in the study as the setting was multicenter trial. The amount of progesterone production tends to decrease during “lutealplacental shift.” (8)

Perhaps the central drawback of this study, despite its large sample size, is its protocol; termination of the treatment at 12 weeks.

In other words, cases with 6-11 weeks of gestation, which may have been on “lutealplacental shift”, could have been included.

Next issue is the estrogen (follicle hormone) argument. We reported several times that the treatment of gestational hypertension or preterm labor using both progestogen and estrogen showed good results since, one trial case in 1969 of severe gestational hypertension, followed by many cases of threatened preterm labor have been witnessed. (9)

Here, I am referring to the dose escalating method using progesterone and estrogen concomitantly with reference to the concentration of these hormones measured in the normal pregnancy.

I wonder why estrogen supplemented treatment has not been tried would wide for preterm labor except for our cases.

Since ample of IVF clinical reports exist at present using estrogen (follicle hormone) for maintaining function of corpus luteum, would it not necessary to optimize clinical benefits of estrogen for the treatment of miscarriage?

Under the dynamic physiology of pregnancy, would it also not necessary to reconsider at this point of time, progesterone mono-dosing therapy to be tailored to flexible-dosing combination schedule? (9) 

(1)    Coomarasamy A et al. N Engl J Med 2015;373:2141-8

(2)    Nosarka S et al. Gynecol Obstet Invest 2005;60:67-74

(3)    Coomarasamy A et al. BMJ2011;342:d1914

(4)    Da Fonseca EB et al. Am J Obsetet Gynecol 2003; 188:419-24

(5)    Fonseca EB et al. N Engl J Med  2007;357:462-9

(6)    Kutlusoy F et al. Gynecol Endocrinol 2014;30:363-366

(7)    Tulchinsky D & Ryan KJ 1980 Maternal-fetal endocrinology WB

SaundersCo. Philadelphia USA

(8)    Creasy RK & Resnik R 2004 Maternal-fetal medicine, fifth edition

Saunders Co. Philadelphia USA

(9)    Mizutani S& Mizutani E Exp Clin Endocrinol Diabetes



















Dr水谷の女性と妊婦講座No.67: 世界トップ水準の医学雑誌が掲載した「流産を繰り返す妊婦の治療薬として黄体ホルモンは無効」という論文は正しいのでしょうか?

▽米国で発行されている『ニューイングランド・ジャーナル・オブ・メディスン』という世界トップレベルの医学雑誌があります。この雑誌の2015年11月号に「流産を繰り返す妊婦の治療薬として黄体ホルモンは無効」という趣旨の論文が掲載されました。英バーミンガム医科歯科大学のArri Coomarasamy(アリ・クマラスワミ)氏を中心とした、英国とオランダの大学の共同研究グループによる臨床研究です。
















英国のA. Klopper (クローパー)氏をはじめ多くの産科内分泌研究者によって、妊娠時の2つのホルモンの動態は明確になっています(7)。














(1)Coomarasamy A et al. N Engl J Med 2015;373:2141-8

(2)Nosarka S et al. Gynecol Obstet Invest 2005;60:67-74

(3)Coomarasamy A et al. BMJ2011;342:d1914


(4)Da Fonseca EB et al. Am J Obsetet Gynecol 2003; 188:419-24

(5) Fonseca EB et al. N Engl J Med  2007;357:462-9

(6)Kutlusoy F et al. Gynecol Endocrinol 2014;30:363-366

(7)Tulchinsky D & Ryan KJ 1980 Maternal-fetal endocrinology  WB Saunders Co. Philadelphia USA

(8)Creasy RK & Resnik R 2004 Maternal-fetal medicine, fifth edition Saunders Co. Philadelphia USA

(9)Mizutani S& Mizutani E Exp Clin Endocrinol Diabetes 2015;123:159-164
































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