Micronised progesterone in preterm labour

Micronised progesterone in preterm labour

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  Dr. Meenakshi Sharma MBBS(AIIMS), MD (AIIMS), FICMCH Specialist Obs & Gyne Dr. Hedgewar Arogya Sansthan Govt NCT, Delhi 2008
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  Burden of pretermpregnancy 3 million newborns die each year due to complications related to pregnancy and childbirth Preterm birth is a leading cause of neonatal and infant mortality as well as short- and long-term disability. Rates for preterm birth range between 6% and 12% in developed countries and are generally higher in developing countries. About 40% of all preterm births occur before 34 weeks and 20% before 32 weeks. The contribution of these preterm births to overall perinatal morbidity and mortality is more than 50%World Health Organization 2007
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  Changinghormonelevelsinthemenstrualcycle
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  Natural progesterone
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  Physiological Action ofProgesterone in Target Tissues Tissue Function Uterus/ovaries Release of oocytes Facilitation of implantation Maintenance of pregnancy: via myometrial quietening • Suppresses contractile genes • Promotes relaxation systems • Suppresses cytokines, prostaglandins and response to oxytocin • Prevents formation of gap junctions Stimulation of stromal regeneration: luteal phase of cycle Mammary gland Lobular alveolar development Suppression of milk protein synthesis during pregnancy Brain Mediation of sexual responsiveness Bone Regulation of bone mass: prevention of bone loss
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  Indications Treatment of threatenedabortion Prevention of recurrent miscarriage Luteal phase support in assisted reproduction programmes Threatened preterm labour.
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  Micronized progesteron andpreterm delivery NMP suppresses te myometrial contraction by inibibiting estrogen in myometrium by replacement of cytosolic estrogen receptors. It also causes direct action of myometrial receptors
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  Indications Treatment of threatenedabortion Prevention of recurrent miscarriage Luteal phase in assisted reproduction programmes Threatened preterm labour.
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  Progesterone use inwomen with a history of prior spontaneous preterm birth (cochrane 2009) 4 studies (n=1329 comparing progesterone versus placebo. 2 studies -weekly 250 mg of 17 alpha-OHP caproate IM between 24 and 37 wks 2 studies- intravaginal progesteron 90–100 mg starting at between 24 and 28 weeks. Progesterone associated with a significant reduction in: Preterm birth at <34 wks [risk ratio 0.15; 95%CI 0.04, 0.64] Preterm birth at < 37 wks [RR 0.80; 95% CI 0.70–0.92] Birth of infant of <2.5kg [RR 0.64; 95% CI 0.49–0.83].
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  Progesterone use inwomen with a short cervix, as measured by vaginal ultrasound 250 pregnant women with a short cervix (<15 mm) as measured by vaginal ultrasound was included. Progesterone (200 mg nightly intravaginally) versus placebo, starting at 24–33 weeks. Progesterone was associated with a significant reduction in  Preterm birth <34 weeks (RR 0.58; 95% CI 0.38-0.87)  Neonatal sepsis (RR 0.28; 95% CI 0.08–0.97).
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  Progesterone in womenwith threatened preterm labour (cochrane 2009) Two studies, 130 pregnant women between 24 and35 weeks with threatened preterm labour. Progesterone 400 mg daily via intravaginal pessary versus placebo, or 341 mg every 4 days until 36 weeks or until delivery. Progesterone was associated with a significant reduction in  Preterm birth at <37 weeks (RR 0.29; 95% CI 0.12–0.69)  Low birth weight <2500 g (RR 0.52; 95% CI 0.28–0.98)  Respiratory distress syndrome (RR 0.30; 95% CI 0.11– 0.83)
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  Progesterone in womenat risk of preterm birth for other reasons (cochrane 2009) Two studies,267 patients  Inclusion criteria: A high preterm risk score or a condition of an active military service 250 mg or 1000 mg of 17 alpha-hydroxyprogesterone caproate x3 per week or weekly IM were compared with placebo between 20 wks to 36 wks. Progesterone was not associated with significant differences for the outcomes
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  Progesterone in womenwith a multiple pregnancy (cochrane 2009) Two studies, 738 pregnant women with twin pregnancy Doses of progesterone were 250 mg weekly IM, starting at 16–20 or at 28 weeks to 35–37 weeks. Progesterone was associated with a significant reduction in risk of tocolysis RR 0.75; 95% CI 0.57, 0.97 No significant differences were observed for primary outcomes.
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  Progesterone for Tripletpregnancy Placebo controlled RCT, 14 centers. 134 Healthy women with triplets were randomized to either 17 alpha-hydroxyprogesterone caproate (Wkly IM inj 250 mg) (n=71 Matching placebo, starting at 16-20 weeks and ending at delivery or 35 weeks (n=61) Primary study outcome : Delivery or fetal loss before 35 weeks. A composite of delivery or fetal loss before 35 0/7 weeks: Similar  83% of pregnancies in progesterone group and  84% in the placebo group,  Relative risk 1.0, 95% confidence interval 0.9-1.1. Rx with 17 alpha-OH-progesterone caproate did not reduce the rate of preterm birth in women with triplet gestations. Caritis et al, Obstrics and Gynecology 2009
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  Progesterone for preventionof preterm birth in twin pregnancy (STOPPIT) A randomized, double-blind, placebo-controlled study and meta-analysis. This trial studied the effect of daily use of 90 mg of a vaginal progesterone gel or placebo in a population of 500 women with twin pregnancies. Results: Combined proportion of IUD or delivery before 34 wks of pregnancy Progesterone group 24.7% (61/247) Placebo group 19.4% (48/247) (OR 1.36, 95% CI 0.89-2.09; p=0.16). rate of adverse events: Similar in both groups Meta-analysis confirmed that progesterone does not prevent early preterm birth in women with twin pregnancy (pooled OR 1.16, 95% CI 0.89-1.51 Norman J, Lancet 2009; 373: 2034-2040
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  Applicability of theresults Useful in the following situation: In women with a singleton pregnancy & history of previous preterm delivery, antenatal administration of progesterone reduces risk of preterm labour before 37 wks and 34 weeks. Reduces the risk of a newborn being born with a LBW < 2500 g. Progesterone use can also be recommended for pregnant women who are found incidentally to have a short cervix. Not useful in However, current data do not support the use of progesterone in women with multiple pregnancies. At the present time it is not known whether prolongation of gestation also leads to improved outcomes for mothers and their infants.
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  Follow-up of childrenexposed in utero to 17 alpha-OH progesterone caproate Outcome of children of mothers who participated in a multicenter placebo-contr trial of wkly IM 17 alpha-OH progesterone caproate, Guardian was interviewed about the child's general health. Children underwent a physical exam and developmental screen Of 348 eligible surviving children, 278 (80%) available for evaluation 194 in the progesterone caproate group and 84 in placebo Mean age at follow-up was 48 mo No significant differences seen in health status or physical examination, including genital anomalies, between the groups Scores for gender-specific roles were within the normal range 17 alpha-hydroxyprogesterone caproate seems to be safe for the fetus when administered in the second and third trimesters. Northen AT, Obstetrics and Gynecology, 2007
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  Implementation of the intervention
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  American College ofObstetrics & Gynecology (2008)  Use of antenatal progesterone to prevent preterm birth should be restricted to Women with a documented history of prior spontaneous preterm delivery at less than 37 weeks Women incidentally (i.e. without routine screening) found to have a short cervix with a short cervix (less than 15 mm) Progesterone should be used with caution on a case-by- case basis.
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  Future research To studythe effectiveness of antenatal progesterone in women in whom the symptoms (contractions) or specific conditions (short cervix, premature rupture of membranes) started for the first time in the current pregnancy. Optimal dose, timing and route of administration of progesterone. Larger randomized controlled trials are required to determine if antenatal administration of progesterone reduces perinatal mortality and long-term serious neonatal and child morbidity.
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  References  Maternal mortalityin 2005: estimates developed by WHO, UNICEF, UNFPA, and The World Bank. Geneva: World Health Organization; 2007.  Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth, The Lancet, 2008:371(9606);75-84.  Lang C, iams J. Goals and strategies for prevention of preterm birth: an obstetric perspective. Pediatric clinics of North America 2009;56:537–563.  Dodd JM, Flenady V, Cincotta R, Crowther CA. Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth. Cochrane Database of Systematic Reviews 2006;Issue 1. Art. No.: CD004947; DOI: 10.1002/14651858.CD004947.pub2 (last updated on 31 December 2008).  Pushpanjali R, Shalini R, Neerja G, Gopalakrishnan RA, Agarwal R, Mehta M. Oral micronized progesterone for prevention of preterm birth. International journal of gynecology and obstetrics. 2009;104:40-43.  Caritis S, Rouse D, Peaceman A, Scisciones A, Momirova V, Spong C, et al. Prevention of preterm birth in triplets using 17 alpha-hydroxyprogesterone caproate: a randomized controlled trial. Obstetrics and Gynecology 2009;113:285-292.  Norman J, Mackenzie F, Owen P, Mactier H, Hanretty K, Cooper S, et al. Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomized, double-blind, placebo-controlled study and meta-analysis. The Lancet 2009; 373: 2034-2040.  Northen A, Norman G, Anderson K, et al and The National Institute of Child Health and Human Development (NICHD), Maternal-Fetal Medicine Units Network (MFMU). Follow up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate compared with placebo. Obstetrics and Gynecology 2007;110:865-872.  American College of Obstetricians and Gynecologists. Use of progesterone to reduce preterm birth. Committee Opinion No. 419. Washington, DC: American College of Obstetricians and Gynecologists; 2008.  This document should be cited as: González R. Prenatal administration of progesterone for preventing preterm birth in women considered at risk of preterm birth: RHL commentary (last revised: 1 December 2009). The WHO Reproductive Health Library; Geneva: World Health Organization.