ROLE OF PROGESTERONE IN PREGNANCY MAINTENANCE & LATER IN PREGNANCY Dr. M.Moshfeghi fellowship of perinatology OBS&GYN RUYAN INSTITUTE

refers to a delivery that occurs before 37 0/7ths  Preterm birth refers to a delivery that occurs before 37 0/7ths refers to a delivery that occurs before 37 0/7ths

The percentage of newborns delivered at very low birthweight has declined only minimally 1.46 percent in 2008 1.45 percent in 2010 preterm birth continues to be a major determinant of short- and long-term morbidity in infants and children has declined only minimally 1.46 percent in 2008 1.45 percent in 2010 major determinant of short- and long-term morbidity in infants and children

functional progesterone withdrawal pathophysiologic events occurring with mother, placental fetal compartment. Therefore, functional progesterone withdrawal failure of transformation of the spiral arteries fetal stress due to uteroplacental vascular insufficiency functional progesterone withdrawal

challenge of distinguishing true labor (contractions result in cervical change) from false labor (contractions that do not result in cervical change). challenge of distinguishing

Transvaginal ultrasound the most reliable method for measuring cervical length Is the most reliable method for measuring cervical length. In symptomatic and asymptomatic preterm patients, a short cervix (<30 mm) is predictive . In symptomatic and asymptomatic preterm patients,

Progesterone supplementation to reduce the risk of spontaneous preterm birth ROLE OF PROGESTERONE IN PREGNANCY MAINTENANCE EFFICACY OF PROGESTERONE FOR PREVENTION OF PRETERM BIRTH

Efforts to delay delivery have been largely unsuccessful. Preterm birth complicates 1 in 8 over 85 percent of all perinatal morbidity and mortality. Efforts to delay delivery have been largely unsuccessful. much attention has focused on preventative strategies. Efforts to delay delivery have been largely unsuccessful. much attention has focused on preventative strategies

Sonographic imaging imaging of the cervix across gestation has enhanced our understanding of cervical performance Cervical effacement is one of the first steps in the parturition process, preceding labor by at least four to eight weeks. Cervical effacement is one of the first steps in the parturition process, preceding labor by at least four to eight weeks.

Sonographic imaging it can be seen by ultrasound, Effacement begins at the internal cervical os and proceeds caudally, . , it can be seen by ultrasound, but is NOT by digital or visual examination

less reproducible; . Transabdominal images of the cervix are thus, they should not be used for clinical management

high-risk pregnancies, prior second trimester losses Timing CL before 14 weeks have limited clinical value . However, high-risk pregnancies, prior second trimester losses and/or large (or multiple) cone biopsies, cervical shortening has been seen as early as 10 to 13 weeks Reproducible measurement of at about 14 weeks, when the cervix normally becomes distinct from the lower uterine segment. high-risk pregnancies, prior second trimester losses and/or large (or multiple) cone biopsies, cervical shortening has been seen as early as 10 to 13 weeks

With proper technique, the intra- and inter-observer variabilities are <10 percent.

after 28 to 32 weeks. after 28 to 32 weeks.  Cervical length is stable between 14 - 28 weeks, declines substantially after 28 to 32 weeks. stable between 14 - 28 weeks after 28 to 32 weeks.

Between about 14 and 28 weeks , the length of the cervix is described by a normal bell-shaped curve : Between about 14 and 28 weeks , the length of the cervix is described by a normal bell-shaped curve : 2nd centile at 15 mm 5th centile at 20 mm 10th centile at 25 mm 50th centile at 35 mm 90th centile at 45 mm

the median cervical length is 40 mm before 22 weeks, 35 mm at 22 to 32 weeks, 30 mm after 32 weeks. Cervical length is not significantly affected by parity, race/ethnicity, or maternal height

The significance of differences in the rate of cervical change (eg, 30 mm to 20 mm Versus 20 mm to 15 mm over two weeks) for prediction of preterm birth is unclear,

ROLE OF PROGESTERONE IN PREGNANCY MAINTENANCE  — Progesterone initially produced by the corpus luteum. is critical for the maintenance of early pregnancy the placenta takes over this function at 7 to 9 weeks removal of the source of progesterone (the corpus aluteum) or administration of a progesterone receptor antagonist induces abortion before 7 weeks (49 days) of gestation.

The role of progesterone later in pregnancy , less clear. maintaining uterine quiescence , less clear. maintaining uterine quiescence , the onset of labor both at term and preterm is associated with a functional withdrawal of progesterone activity at the level of the uterus a functional withdrawal of progesterone activity at the level of the uterus

The role of progesterone later in pregnancy Progesterone has been shown to prevent apoptosis in fetal membrane explants, under both basal Prevent pro-inflammatory conditions may help to prevent preterm premature rupture of membranes (PPROM), prevent apoptosis in fetal membrane Prevent pro-inflammatory conditions may help to prevent preterm premature rupture of membranes (PPROM),

EFFICACY OF PROGESTERONE FOR PREVENTION OF PRETERM BIRTH depends primarily on appropriate patient selection reduces the risk of preterm birth by one-third

prior spontaneous singleton preterm birth, normal cervical length Singleton pregnancy, prior spontaneous singleton preterm birth, normal cervical length Progesterone supplementation? YES Hydroxyprogesterone caproate 250 mg IM weekly beginning between 16 and 20 w and continuing through 36 w of gestation or until delivery and monitor cervical length. Short (<25 mm) cervix → perform cerclage

prior spontaneous twin preterm birth, normal cervical length Singleton pregnancy, prior spontaneous twin preterm birth, normal cervical length Progesterone supplementation indicated? Possibly Hydroxyprogesterone caproate 250 mg weekly beginning 16 and 20 weeks through 36 weeks or until delivery and monitor cervical length. Short (<25 mm) cervix → perform cerclage

Yes Singleton pregnancy, no prior spontaneous preterm birth, short cervix (≤20 mm) Progesterone supplementation indicated? Yes

Progesterone suppository 90 to 200 mg vaginally each night from time of diagnosis through 36 weeks. a 100 mg micronized progesterone vaginal tablet an 8 percent vaginal gel containing 90 mg micronized progesterone per dose. Both preparations are commercially available in US, but not approved for prevention of preterm birth in cervical shortening.

Multiple pregnancy (twins or triplets) without prior preterm birth, normal cervical length No No progesterone, no cerclage

Twins, prior preterm birth Possibly Hydroxyprogesterone caproate 250 mg IM weekly beginning between 16 and 20 weeks of gestation and continuing through 36 weeks of gestation or until delivery.

Twins, short cervix Possibly Vaginal progesterone, no cerclage

Twin pregnancy the efficacy of high dose vaginal progesterone (400 mg/day) no more effective than lower dose therapy (200 mg/day) or a placebo,

Spontaneous twin preterm birth in prior pregnancy YES We suggest 17P supplementation for women with a singleton pregnancy who have had a prior preterm birth, singleton or twin.

No Preterm premature rupture of membranes No Positive fetal fibronectin test No Undelivered after an episode of preterm labor No

significant difference By monitoring with an external tocodynamometer once a week for 60 min , significant difference in the frequency of spontaneous uterine contractions between the two groups, SO progesterone supplementation may exert its effect by maintaining uterine quiescence in the latter half of pregnancy. significant difference progesterone supplementation may exert its effect by maintaining uterine quiescence in the latter half of pregnancy

if all eligible women had received progesterone prophylaxis, it would only have reduced the overall preterm birth rate in the United States by approximately 2 percent

after placement of a cerclage Cerclage — a prior preterm birth, continuing 17P supplementation has not been proven to be useful, ?????????

women with a history of preterm birth due to PPROM YES, appear to benefit from progesterone supplementation in subsequent pregnancies;

NO NO Acute preterm labor do not routinely recommend progesterone  . do not routinely recommend progesterone supplementation in this setting. NO NO

NO Uterine anomaly or ART NO  — There are no data on the effectiveness of progesterone therapy for prevention of preterm birth in uterine malformations OR who conceive with assisted reproductive technology NO

SIDE EFFECTS AND ADVERSE EFFECTS   three-fold increase in risk of developing gestational diabetes in some studies

Progesterone exposed infants less perinatal morbidity, reduced rates of necrotizing enterocolitis, intraventricular hemorrhage, need for supplemental oxygen. There was no evidence of virilization of female offspring, which is a theoretic concern of this therapy

Several studies have reported a nonstatistical increase in risk of miscarriage and stillbirth in pregnancies exposed to progestins but others could not confirm this observation or observed a nonstatistical decrease in these risks

PROGESTERONE PREPARATIONS, ROUTES, AND DOSES  — have been effective at reducing the risk of preterm birth compared with no treatment/placebo all formulations

Evidence is insufficient to define the optimum gestational age for starting treatment

17-alpha-hydroxyprogesterone (17P) 17-alpha-hydroxyprogesterone (17P) natural progesterone metabolite made by the corpus luteum and placenta minimal to no androgenic activity. intramuscularly. 25 mg every five days to 1000 mg weekly, beginning as early as 16 weeks of gestation. We use a 250 mg dose

Standard contraindications to progesterone administration include hormone-sensitive cancer , liver disease, uncontrolled hypertension .

for the prevention of preterm birth This is the first time that the FDA has approved a medication , and represents the first approval of a drug specifically for use in pregnancy in more than 15 years. for the prevention of preterm birth

Vaginal progesterone preparations Natural progesterone is typically administered vaginally. high uterine bioavailability since uterine exposure occurs before the first pass through the liver. few systemic side effects, but vaginal irritation needs to be administered daily. Doses of 90 to 400 mg , beginning as early as 18 weeks of gestation. We use 100 mg administered vaginally each evening; however, in some areas a 200 mg suppository may be more readily available and less costly Vaginal progesterone preparations

An oral micronized preparation of natural progesterone also exists An oral micronized preparation of natural progesterone also exists. Daily doses of 900 to 1600 mg have been given. Reported side effects include sleepiness, fatigue and headache Oral progesterone

For women with a singleton pregnancy who have had a previous spontaneous singleton PTL suggest intramuscular injections of 17-alpha- hydroxyprogesterone caproate rather than vaginal progesterone (16 to 20 weeks) and continuing through the 36 th week a previous spontaneous singleton PTL intramuscular injections of 17-alpha- hydroxyprogesterone caproate

vaginal progesterone vaginal progesterone cervical shortening (defined as ≤20 mm before 24 weeks) and no prior spontaneous singleton preterm birth, suggest vaginal progesterone through the 36 th week. vaginal suppository (100 or 200 mg), gel (90 mg), or tablet (100 mg micronized progesterone) vaginal progesterone

Use of progesterone for indications other than is not supported prior preterm birth and short cervix

Progestational Agents to Prevent Preterm Birth. Progesterone supplementation for women at risk for preterm birth was investigated with regard to several plausible mechanisms of action, including reduced gap junction formation and oxytocin antagonism leading to relaxation of smooth muscle, maintenance of cervical integrity, and anti-inflammatory effects.

Although the benefit of progesterone supplementation has been observed in multiple research trials, the optimal clinical protocols for progesterone have not yet been developed