The prevalence of short cervix between 20 and 24 weeks of gestation and vaginal progesterone for prolonging of gestation

Objective: The objective of this study is to understand the prevalence of short cervical length between 20 and 24 weeks gestation in China and to evaluate the efficacy of micronized progesterone for prolonging gestation in nulliparous patients with a short cervix.

Methods: From May 2010 to May 2015, a total of 25?328 asymptomatic women with singleton pregnancies at Peking University First Hospital had their cervical length routinely measured between 20 and 24 weeks of gestation. A cervical length of 25?mm or less was defined as a shortened cervical length. The therapies prescribed include vaginal micronized progesterone capsules (200?mg each night) or bed rest from 20 to 34 weeks of gestation. The primary outcome was spontaneous delivery before 33 weeks.

Results: (1) One hundred fourteen women had a cervical length of?≤25?mm (0.45%). (2) Twenty-nine of which with previous spontaneous preterm delivery or late pregnancy loss had cervical cerclage, the remaining 85 women by the use of vaginal progesterone or simply resting activity restriction to prevent preterm birth. (3) In 85 nulliparous women treated by progesterone or bed rest, progesterone use in cervical length between 10 and 20?mm was associated with a statistically significant reduction in the incidence of preterm birth at <33 weeks of gestation (9.5% versus 45.5%, p?=?0.02) compared with bed rest. There were no significant differences in cervical length between 20 and 25?mm in their rates of spontaneous preterm delivery at <33 (5.3% versus 3.2%, p?=?0.72), <37 (33.3% versus 54.5%, p?=?0.25), or <35 weeks (14.3% versus 45.5, p?=?0.06) of gestation between vaginal progesterone and bed rest.

Conclusion: The rate of short cervical length was less than expected. Vaginal progesterone is efficacious for the prolonging of gestation in women with a cervical length of 10–20?mm in the mid-trimester for a singleton gestation and nulliparous women. For a cervical length of 20–25?mm in the mid trimester, vaginal progesterone compared with bed rest did not prolong pregnancy.     

Cytokines and the Risk of Preterm Delivery in Twin Pregnancies

OBJECTIVE:: To estimate the association between cytokine levels in twin pregnancies and risk of spontaneous preterm delivery, including the effect of progesterone treatment. METHODS:: This secondary analysis of a randomized placebo-controlled trial investigating the effect of progesterone treatment on preterm delivery in twin pregnancies included 523 women with available dried blood spot samples collected before treatment with progesterone (n=258) or placebo (n=265) and after 4-8 weeks of treatment. Samples were analyzed for cytokines using a sandwich immunoassay. Cytokine levels in spontaneous preterm delivery at 34-37 weeks of gestation and spontaneous preterm delivery before 34 weeks of gestation were compared with delivery at 37 weeks of gestation or more for placebo-treated women. The association between interleukin (IL)-8 and risk of spontaneous preterm delivery before 34 weeks of gestation was estimated further, including comparison according to treatment. Statistical analyses included Kruskal-Wallis test, Mann-Whitney U test, linear regression, and Cox regression analysis. RESULTS:: We found a statistically significant association between IL-8 and spontaneous preterm delivery. At 23-33 weeks of gestation, the median IL-8 level was 52 pg/mL (interquartile range 39-71, range 19-1,061) for term deliveries compared with 65 pg/mL (interquartile range 43-88, range 14-584) for spontaneous preterm delivery at 34-37 weeks of gestation and 75 pg/mL (interquartile range 57-102, range 22-1,715) for spontaneous preterm delivery before 34 weeks of gestation (P<.001). Risk of spontaneous preterm delivery was associated with a large weekly increase in IL-8 (hazard ratio 2.0, 95% confidence interval [CI] 1.2-3.3). There was no effect of progesterone treatment on IL-8 levels. Levels of IL-8 at 18-24 weeks of gestation were associated with a cervix less than 30 mm (odds ratio 1.8, 95% CI 1.2-2.7). CONCLUSION:: Risk of spontaneous preterm delivery before 34 weeks of gestation is increased in women with high IL-8 levels. Progesterone treatment does not affect IL-8 levels. CLINICAL TRIAL REGISTRATION:: EudraCT, https://eudract.ema.europa.eu, 2006-000503-41, and ClinicalTrials.gov, www.clinicaltrials.gov, NCT00329914. LEVEL OF EVIDENCE:: II.     

Hormone production during pregnancy in the primigravid patient. I. Plasma levels of progesterone and 5-alpha-pregnane-3,20-dione throughout pregnancy of normal women and women who developed pregnancy-induced hypertension.

The plasma concentrations of progesterone and 5-alpha-pregnane-3,20-dione (5-alpha-dihydroprogesterone) were measured from as early as 12 weeks through 41 weeks of gestation in primigravid women. Two groups of primigravid women were assessed, those with uncomplicated pregnancies and those who developed pregnancy-induced hypertension. Plasma levels of progesterone and 5-alpha-dihydroprogesterone rose progressively throughout gestation in both groups of women. The ratio of the level of progesterone to that of 5-alpha-dihydroprogesterone in individual plasma samples of women with uncomplicated pregnancies was 7.0 from 12 to 15 weeks' gestation while at 35 to 41 weeks' gestation the ratio had declined to 4.6. Similar results were obtained in plasma samples of women who ultimately developed pregnancy-induced hypertension. Since no differences in plasma levels of progesterone or 5-alpha-dihydroprogesterone were detected between primigravid women with uncomplicated pregnancies and those who developed pregnancy-induced hypertension, we conclude that neither progesterone nor 5-alpha-dihydroprogesterone concentrations in plasma are of value in identifying women at risk of developing pregnancy-induced hypertension.     

Potassium homeostasis in pregnancy

We selectively reviewed potassium (K) metabolism during human gestation, focusing on the influence of progesterone on renal K excretion. Approximately 300 mEq of K is gained during pregnancy. Two-thirds of it are in the products of conception, but little is known about renal K handling during gestation. We have suggested that progesterone may play a role in preventing the kaliuresis that normally occurs when aldosterone levels are elevated and substantial quantities of sodium are presented to distal nephron sites. In addition, we hypothesize that subtle K secretory problems, such as those known to occur in sickle cell disease, may be aggravated during gestation, probably due to elevated circulating levels of progesterone.     

间苯三酚联合中药治疗早期先兆流产的临床探讨

目的：探讨间苯三酚联合中药治疗早期先兆流产的临床效果。方法：将妊娠8—12周的86例先兆流产的孕妇随机分为实验组（45例）和对照组（41例）。实验组给予间苯三酚联合中药及黄体酮治疗,对照组仅给予黄体酮及中药治疗。结果：实验组保胎成功有效率明显高于对照组（91．11％VS78．04％,P〈0．05）。治疗期间未见明显不良反应。结论：早期先兆流产患者出现宫缩时,可首选间苯三酚,间苯三酚联合中药及黄体酮治疗孕8—12周的先兆流产安全有效。     

Functional changes of mouse placental multidrug resistance phosphoglycoprotein (ABCB1) with advancing gestation and regulation by progesterone

Multidrug resistance phosphoglycoprotein (ABCB1) has been shown to limit maternal-fetal transfer by actively excluding ABCB1 substrates. The authors have previously demonstrated a marked decrease in placental ABCB1 expression in the human and mouse with advancing gestation. In the present study, it is hypothesized that the decrease in ABCB1 expression will result in increased transplacental transfer of ABCB1 substrates over the second half of gestation and that progesterone exhibits a regulatory role on placental ABCB1 expression and function. The authors demonstrate a significant increase in transplacental transfer of [(3)H]digoxin (an ABCB1 substrate) in late gestation (E18.5; P < .001) when compared to earlier embryonic days. Furthermore, maternal plasma progesterone levels did not influence expression or function of ABCB1. The authors conclude that the fetus is increasingly exposed to both endogenous and exogenous substrates of ABCB1 present in the maternal circulation with advancing gestation and that progesterone does not elicit a regulatory role on placental ABCB1 expression or function in vivo.     

Inhibition of ovarian, placental, and adrenal steroidogenesis in the rhesus monkey by trilostane.

Trilostane inhibits adrenal, ovarian, and placental steroidogenesis when administered orally to rhesus monkeys. By inhibiting 3 beta-hydroxysteroid dehydrogenase activity, it causes an increase in circulating levels of pregnenolone. Trilostane reverses the stimulation of luteal progesterone production and the delay in onset on menstruation induced by human chorionic gonadotropin. In pregnant monkeys it reduces circulating progesterone levels and is an effective interceptive agent if given for 5 days beginning on day 16, 25, or 50 of gestation. Concurrent administration of progesterone prevents this interceptive effect. Trilostane reduces plasma cortisol levels at doses lower than those necessary to terminate pregnancy.     

Ontogeny of human fetal plasma progesterone, deoxycorticosterone, and deoxycorticosterone sulfate

The concentrations of progesterone, deoxycorticosterone (DOC), and deoxycorticosterone sulfate (DOC-SO4) were determined in mixed umbilical cord plasma of abortuses and newborn infants delivered between 18 and 42 weeks' gestation. A wide range of values among individual samples was found for progesterone (224 to 2,152 ng/ml), DOC (1.6 to 10.4 ng/ml), and DOC-SO4 (17 to 154 ng/ml). Levels of progesterone and DOC in mixed umbilical cord plasma were not correlated; those of DOC and DOC-SO4 were positively correlated significantly (r = 0.3945, P less than 0.001). Whereas the mean plasma levels of DOC were similar throughout gestation, significant variation, as a function of gestational age, was found for progesterone and DOC-SO4, with levels of these steroids generally being higher near term than earlier in gestation. The administration of glucocorticosteroids to the mother resulted in a significant decrease (p less than 0.001) in plasma concentrations of DOC and DOC-SO4 in the newborn infant; levels of progesterone in umbilical cord plasma were not affected by maternal glucocorticosteroid treatment. These results suggest that the fetal adrenal glands play a direct, or possibly an indirect, role in the production of the DOC and DOC-SO4 that is present in the fetal compartment. In addition, since fetal plasma levels of progesterone are quite high throughout gestation, the potential exists for circulating progesterone to serve as a precursor for adrenal and extra-adrenal production of DOC and DOC-SO4.     

Glucocorticoid and progesterone receptors in yolk sac placenta

The parietal yolk sac (PYS) of the rat fetus at the 14th day of gestation contains glucocorticoid as well as progesterone receptors; both are present in the trophoblast cell layer. Following heat activation the receptors are capable of binding to deoxyribonucleic acid- (DNA-)cellulose. Glucocorticoid receptors, but not progesterone receptors, are also present in the visceral yolk sac (VYS) at the 14th day of gestation. Greater amounts (some 250 femtomoles/mg cytosol protein) of a glucocorticoid receptor are present in the VYS on the 17th day of gestation. The Kd is approximately 4 X 10(-9) M; following activation it also binds to DNA-cellulose. The elution pattern of the activated VYS receptor from diethylaminoethyl-(DEAE-)Sephadex, however, is similar to that found with kidney and colon rather than that of liver (i.e., it resembles corticosteroid binder IB rather than binder II) indicating a possible role in transport. Although the receptors are separate entities, progesterone competes as effectively as corticosterone for binding to the glucocorticoid receptors in both the PYS and and VYS, thus raising the question of the possible effect of changes in progesterone concentrations on the functioning of glucocorticoids during development.     

Risk screening for spontaneous preterm labour

Prevention of viable spontaneous preterm birth before 34 weeks' gestation through screening is one of the key aims of antenatal care as birth below this threshold of prematurity has implications for child, mother and society. If women can be identified to be at high risk of spontaneous preterm birth in early pregnancy, they can be targeted for more intensive antenatal surveillance and prophylactic interventions (primary prevention). However, the disease mechanisms behind preterm birth are not well understood. Consequently, tests for its prediction and treatments for its prevention are not well developed. Additionally, no randomised controlled trial focusing on prevention of spontaneous preterm birth related perinatal morbidity and mortality through a screening programme exists. This chapter describes a generic framework for combining screening information with therapeutic effect to delineate its role in a screening programme. We use test-treatment combination of previous history of preterm birth and progestational agents as an example. A decision-making framework is built using: (1) evidence for post-test probabilities; (2) evidence for therapeutic effectiveness; and (3) integration of the two evidences to estimate the effect of the test-treatment combination with numbers needed to treat (NNTs). The NNT to prevent one case of spontaneous preterm birth before 34 weeks' gestation with progesterone is seven in women with a previous history; NNT is 41 in women without a previous history; and it is 28 when previous history was not used to guide a decision about prevention. The proposed framework makes decisions about screening and prevention explicit.     

Placental production of estradiol and progesterone after oocyte donation in patients with primary ovarian failure

After oocyte donation 18 pregnancies were established in 17 patients with the absence of ovaries. Eight patients were delivered of nine healthy infants including one set of twins, six pregnancies were progressing normally, and four pregnancies were aborted. Four pregnancies were established after transfer of frozen-thawed embryos. In the simulated luteal phases, replaced with estradiol valerate and progesterone, pregnancies could be established and maintained as indicated by the profile of serum human chorionic gonadotropin concentrations. Weekly determinations of serum 17 beta-estradiol levels indicated significantly higher values at 7 weeks' gestation, as compared with week 5. This observation precludes that the luteoplacental shift occurred before 7 weeks' gestation. The weekly serum determinations of progesterone were significantly higher week 9, as compared with week 5. Two pregnancies were achieved after the vaginal administration of micronized progesterone.     

Progesteron zur Pr?vention der Frühgeburt

The rate of preterm delivery in Germany has remained constant for many years and there is currently no satisfactory solution particularly for spontaneous preterm labor. In recent years progesterone has become a focus of attention for prevention of preterm birth. At the moment there are two medications which can be used: 17-α hydroxyprogesterone caproat and progesterone whereby 17-α hydroxyprogesterone caproat can be used in pregnant women with a history of preterm labor. In 2011 the U.S. Food and Drug Administration (FDA) approved this application. Progesterone is given to women with a history of preterm labor or with an asymptomatic short cervix but there seems to be no positive effect for women with multiple gestations. There is also no effect on preterm rupture of membranes, cerclage or positive fibronectin test. At present there is evidence indicating that progesterone can be given for prevention of preterm labor in women with a history of preterm labor or a shortened cervix and a single gestation. Whether the use of progesterone will decrease the rate of spontaneous preterm labor in the coming years still has to be proven.     

How can we better predict the risk of spontaneous miscarriage among women experiencing threatened miscarriage?

Abstract

This study seeks to establish progesterone and progesterone-induced blocking factor (PIBF) levels as predictors of subsequent completed miscarriage among women presenting with threatened miscarriage between 6 and 10 weeks of gestation. Our secondary objective was to assess the known maternal risk factors, toward development of a parsimonious and clinician-friendly risk assessment model for predicting completed miscarriage. In this article, we present a prospective cohort study of 119 patients presenting with threatened miscarriage from gestation weeks 6 to 10 at a tertiary women’s hospital emergency unit in Singapore. Thirty (25.2%) women had a spontaneous miscarriage. Low progesterone and PIBF levels are similarly predictive of subsequent completed miscarriage. Study results (OR, 95% CI) showed that higher levels of progesterone (0.91, 95% CI 0.88–0.94) and PIBF (0.99, 95% CI 0.98–0.99) were associated with lower risk of miscarriage. Low progesterone level was a very strong predictor of miscarriage risk in our study despite previous concerns about its pulsatile secretion. Low serum progesterone and PIBF levels predicted spontaneous miscarriage among women presenting with threatened miscarriage between gestation weeks 6 to 10. Predictive models to calculate probability of spontaneous miscarriage based on serum progesterone, together with maternal BMI and fetal heart are proposed.     

Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis

AIM: The aim of this study is to assess the role of progesterone in preterm birth prevention. METHODS: A MEDLINE search (from 1966 to the present; date of last search January 2005) was performed - using the key words progesterone, pregnancy, preterm birth, preterm labor, and randomized, controlled trial - in order to identify randomized, controlled trials in which progesterone (either intramuscular or vaginal administration) was compared with placebo or no treatment. Data were extracted and a meta-analysis was performed. RESULTS: Seven randomized, controlled trials were identified. Women who received progesterone were statistically significantly less likely to give birth before 37 weeks (seven studies, 1020 women, RR = 0.58, 95% CI = 0.48-0.70), to have an infant with birth weight of < or =2.5 kg (six studies, 872 infants, RR = 0.62, 95% CI = 0.49-0.78), or to have an infant diagnosed with intraventricular hemorrhage (one study, 458 infants, RR = 0.25, 95% CI = 0.08-0.82). CONCLUSIONS: For progesterone supplementation to be advocated for women at the risk of preterm birth, the prolongation of gestation demonstrated in this meta-analysis must translate into improved infant outcomes, including a reduction in mortality. There is currently insufficient information to allow recommendations regarding the optimal dose, route, and timing of administration of progesterone supplementation.     

Progesterone support in IVF: is evidence-based medicine translated to clinical practice? A worldwide web-based survey

This worldwide web-based survey compared the clinical practice for luteal-phase supplementation (LPS) in stimulated IVF cycles to the current evidence-based literature. Eighty-four treatment centres in 35 countries, representing a total of 51,155 IVF cycles/year, responded. Vaginal progesterone alone was used for LPS in 64% of cycles and in another 16% of cycles in combination with either i.m. (15%) or oral progesterone (1%). As a single agent, i.m. progesterone was used in 13% of cycles, oral progesterone in another 2% and human chorionic gonadotrophin (HCG) was still used in 5% of cycles. Progesterone was administered until 10–12 weeks’ gestation in 67% of cycles and in 22% and 12% it was discontinued when fetal heart pulsations are recognized or until βHCG was positive, respectively. In conclusion, in almost two-thirds of the assisted cycles represented in this survey, vaginal administration of progesterone is preferred for LPS. Nevertheless, despite the available literature on the disadvantages of oral progesterone, i.m. progesterone and HCG for LPS, these agents are still used routinely by many practitioners. Furthermore, although there is no firm evidence to support the continuation of LPS until 10–12 weeks’ gestation, this practice is used in the majority of IVF cycles worldwide.This worldwide web-based survey assessed the clinical practice for luteal-phase support in stimulated cycles in comparison to the current evidence-based literature. The survey included the following questions: (i) ‘What is the progesterone you use for luteal support?’; and (ii) ‘How long does progesterone needs to be administered in an IVF cycle if the patient becomes pregnant?’. Eighty-four units from 35 countries representing a total of 51,155 treated IVF cycles/year were included. Vaginal progesterone alone was used for luteal-phase supplementation in 64% of cycles. In another 16% of cycles, vaginal progesterone was used in combination with either intramuscular (15%) or oral progesterone (1%). As a single agent, intramuscular progesterone was used in 13% of cycles, oral progesterone in another 2%, and human chorionic gonadotrophin (HCG) was still used in 5% of cycles. Progesterone was administered until 10–12 weeks’ gestation in 67% of cycles, in 22% of cycles it was discontinued when fetal heart pulsations are recognized, and in 12% it was administered until a positive pregnancy test. In conclusion, in agreement with the currently available literature, in almost two-thirds of assisted cycles worldwide, the vaginal route of progesterone administration is preferred for luteal-phase supplementation. Nevertheless, despite the described disadvantages of oral progesterone, intramuscular progesterone and HCG for LPS, these agents are still used routinely in clinical practice by many practitioners. Furthermore, although there is no firm evidence to support the continuation of LPS until 10–12 weeks of gestation, this practice is used in the majority of IVF cycles worldwide.     

Low saliva progesterone concentrations are associated with spontaneous early preterm labour (before 34 weeks of gestation) in women at increased risk of preterm delivery

Saliva progesterone and oestriol concentrations were determined weekly from 24 weeks of gestation in women at increased risk of preterm delivery. Samples were analysed from 28 women with spontaneous onset of labour and delivery before 37 weeks of gestation, and 64 who delivered at term. Saliva progesterone was lower in the 12 women delivering before 34 weeks than in those delivering later , between 34 and 37 weeks ( P  = 0.007) or at term ( P  = 0.009). Measurement of saliva progesterone may be of value in the prediction of early preterm labour and in determining which women might benefit from progesterone supplementation.     

Interceptive activity of azastene in rhesus monkeys.

Azastene is an orally effective "luteolytic" agent in rhesus monkeys. In nonpregnant monkeys it reverses the human chorionic gonadotropin-stimulated increase in progesterone production and delay in the onset of menstruation, and, in inseminated monkeys, it prevents pregnancy if given for 5 days beginning on day 24 of the menstrual cycle. The drug is also effective in terminating pregnancy if given for 5 days beginning on approximately day 26, day 50, or day 80 of gestation. Concurrent progesterone administration prevents the interceptive action of the drug. Although azastene inhibits gonadal and placental progesterone production, it has no effect on cortisol production in monkeys and is devoid of apparent hormonal activity.     

Calcium accumulation by human uterine microsomal preparations: Effects of progesterone and oxytocin.

A microsomal fraction was prepared from human pregnant uteri at term and at 6 to 19 weeks' gestation, and from nonpregnant uteri by differential centrifugation and purified on a discontinuous sucrose density gradient. This fraction bound calcium in the presence of adenosine triphosphate (ATP). ATP-dependent calcium binding in microsomal preparations was found to increase with advancing pregnancy. Addition of progesterone increased the ATP-dependent calcium binding, while addition of oxytocin decreased the ATP-dependent calcium binding. In combination, oxytocin and progesterone counteracted each other. The progesterone effect was specific for progesterone; three biologically inactive analogues had no effects on calcium binding. The actions of progesterone and of oxytocin on ATP-dependent calcium binding were found to be consistent with their respective in vivo uterine relaxing and contracting actions.     

Cerclage,progesterone and α-hydroxyprogeterone caproate treatment in women at risk for preterm delivery

Abstract

The most significant action of progesterone appears to be on the cervix and in prevention rather than on treatment of preterm delivery. In women with singleton gestations, no prior PTB, and CL <20?mm at <24 weeks, vaginal progesterone, either 90?mg gel or 200?mg suppository, is associated with reduction of both preterm birth (PTB) and perinatal morbidity/mortality. Cerclage is as effective as vaginal progesterone in women with CL <25?mm. Treatment of women with previous PTB with 17OHP-C from 16 to 20 weeks’ gestation until 36 weeks could reduce significantly both the risk of delivery at <37, <35 and <32 weeks’ gestation, as well as the rates of NEC, the need for supplemental oxygen and IVH. In women successfully treated with tocolytics progesterone combined with corticosteroid therapy lengthens pregnancy, reduces occurrence of respiratory distress syndrome and low birth weight. However, there is currently insufficient evidence on the role of progesterone after arrested preterm labor. It is reasonable to support an approach with CL screening of women with prior PTB starting at 16 to 19 weeks and administration of progesterone to women with a short cervix. Cerclage may be offered to those with a CL<25?mm. A combination of traditional tocolytics, corticosteroids and progesterone might be beneficial.     

Successful pregnancy and delivery after delaying the initiation of progesterone supplementation in a postmenopausal donor oocyte recipient

Progesterone luteal support has become a standard procedure during IVF cycles. Donor egg cycle women without inherent ovarian function require complete hormone replacement, in contrast with women undergoing IVF in which luteal support is used to supplement endogenous progesterone production. Progesterone support is clearly beneficial, although the timing of its initiation can affect overall outcomes. This paper describes a case in which a postmenopausal woman attending for oocyte donation did not receive her first progesterone injection at the correct time. Treatment with progesterone began when she arrived for the transfer of the donor embryos. The two embryos were maintained in culture and one was transferred on day 6 when the delayed progesterone administration had induced a secretory transformation in her endometrium. A single gestation sac was recorded 8 weeks later, and a healthy baby was subsequently born. On the morning of day 6, delayed progesterone supplementation had induced the secretory endometrial transformation typical of the second phase of the menstrual cycle.