Preventing Preterm Labour Presenter: Dr Lucas Luk Supervisor: Dr Muniswaran Sarawak General Hospital O&G Dept 12/9/2012
IncidenceIatrogenic ~20%PPROM ~20%Spontaneous preterm labour ~60% US ~12.5% (2008) UK ~7.6% Sarawak General Hospital ~11.1% (2011)
Magnitude of Problem 6.2 billion dollars in hospitalization costs 2010 in US, US2 billion dollars per year of life thereafter.
Epicure/Epicure 2 Studies Begain in 1995 Following Health and outcomes of babies born before 26wks Assessed survival rates, disabilities, medical complications, motor skills, visual skills, attention disorders Babies assessed at 1 year old, 2/12 yrs old, 6 yrs old and 11yrs old. (corrected ages)
Gestational Age Survival Rate (1/52) Survival (Discharge)25wks 75% 55%24wks 60% 35%Below 24wks 44% 20% •314/4004 babies survived and were discharged home •38% no recorded problems at term (40wks) •62% had some form of disability: -Oxygen Dependent (~50%) -Brain injury (20% with CP) -Visual problems
1 yr old: 31% with some major motor problem 2.5yrs: 48% with some form of impairment, 4% with significant chest infections 6yrs old: 20% no problems 11yrs old: IQ tests: 45% low scores vs 1.3%; only 39% with no impairment. More had special needs
SGH 2011: 11.1% Preterm Births 55% of infant deaths severely preterm (<34wks) No survival <26wks, 700-800g
Primary Prevention 1 Public Education Public & Professional Policies- ART limiting number of embryos transferred- Minimum paid pregnancy leave- Workplace hazards, Maximum work week, exemption from night shift Repeated Uterine Instrumentations Close Pregnancy (<6/12) Substance abuse - Smoking Cessation, coccaine Antenatal periodontal care Low Socio-Economic status Genetics Malnutrition (Africa during famines), omega-3, Zinc Extremes of Age
EUROPOP Working Night Shifts (~50% higher risk) Standing >6hrs/day(RR1.26) Working >42hrs/wk(RR1.22)
Periodontal Care Risk of preterm birth is associated with severity of periodontal disease Risk increases when periodontal disease progresses in pregnancy Haematogenous transmission, or more likely, through shared immunological response Randomized trials have not reported reduced rates of preterm birth in women treated for periodontal disease Effects of preconceptional periodontal care on preterm birth not reported.
Maternal Oral Therapy to Reduce Obstetric Risk Study were published and showed that periodontal therapy did not reduce the incidence of preterm delivery before 37, 35, or 32 weeks of gestation, weight for gestational age, or neonatal morbidity. This is the largest randomized controlled trial of the effects of maternal periodontal disease treatment on preterm birth rates; over 1800 pregnant women with periodontal disease were randomly assigned to receive treatment before 24 weeks of gestation or postpartum. Treatment consisted of up to four sessions of supra- and sub- gingival scaling and root planing using hand and ultrasonic instruments, full mouth tooth polishing, and oral hygiene instruction. Two subsequent large randomized trials of pregnant women with periodontal disease had a similar design and also found that treatment did not result in a significant improvement in any pregnancy outcome. One of these, the Periodontal Infections and Prematurity Study (PIPS), found that treatment might increase the risk of indicated preterm birth; this requires further study
Asymptomatic Bacteruria Pregnant women with asymptomatic bacteriuria should be treated with antibiotics to reduce the risk of preterm birth. A meta-analysis of 14 randomized trials comparing antibiotic treatment with placebo or no treatment in pregnant women with asymptomatic bacteriuria demonstrated that antibiotic treatment was effective in:(i) Clearing asymptomatic bacteriuria (OR 0.07, 95% CI 0.05-0.10),(ii) reducing the incidence of pyelonephritis (OR 0.24, 95% CI 0.19-0.32), and(iii) reducing preterm delivery and delivery of low-birth- weight infants (OR 0.60, 95% CI 0.45-0.80)
Genital Tract Infections Chlamydia and gonorrhea — There is no evidence that treatment of chlamydia or gonorrhea prolongs gestation. The only controlled trial that evaluated the effect of treatment of chlamydia on gestational duration did not show a reduction in preterm birth However, screening for and treatment of these infections is recommended to prevent other maternal and neonatal sequelae
Trichomanas The Vaginal Infections and Prematurity Study demonstrated that pregnant women with Trichomonas vaginalis have a 30% higher risk of having a preterm birth, a 2-fold risk of stillbirth or neonatal death, and PPROM. Treatment of asymptomatic Trichomonas infection is not recommended during pregnancy because it does not prevent, and may even increase, the risk of preterm delivery
Bacterial Vaginosis Lactobacillus, which normally resides in the vaginal tract, is replaced by Gardnerella vaginalis, Mobiluncus species, anaerobes, and genital mycoplasmas Prevalence in pregnancy 10-20%; 50% asymptomatic Some randomized trials showed decrease in preterm labour up to 50%(McGregor et al, Huth et al, Morales et.al)
the largest trials studying treatment of asymptomatic BV during pregnancy were done by McDonald et al  and Carey et al , consisting of 879 women and 1953 women, respectively. They concluded that the treatment of asymptomatic bacterial vaginosis in pregnant women does not reduce the rate of preterm birth. A metaanalysis done by Leitich et al, involving 10 studies with results for 3969 patients, showed that antibiotic treatment did not decrease preterm birth in all patients combined (OR 0.83; 95% CI 0.57-1.21) or in high risk patients with previous preterm birth (OR 0.50; 95% CI 0.22-1.12).
Klebanoff et. al –617 women with culture proven asymptomatic infection at 16 to 23 weeks of gestation were randomly assigned to receive either two doses of metronidazole (2 g) or placebo 48 hours apart. All women were retreated with the same regimen at 24 to 29 weeks of gestation. Trichomonas resolved in 93 percent of metronidazole treated women and 35 percent of the placebo group. The rate of preterm birth was higher in treated than control women (19 versus 11 percent, relative risk 1.8; 95% CI 1.2-2.7), primarily related to an increased frequency of spontaneous preterm labor (10.2 versus 3.5 percent, relative risk 3.0; 95% CI 1.5- 5.9).
UREAPLASMA UREALYTICUM Carey et al controlled for the presence of other organisms in 4934 women, and found there was no association between maternal genital tract colonization with U. Urealyticum and low birthweight, preterm birth or PPROM. In addition, a multicentre randomized trial of >900 patients with U. Urealyticum (excluding those with C. trachomatis and GBS) found there was no impact on adverse pregnancy outcomes when treated with erythromycin vs placeboCamille H. Raynes-Greenow et. al; Antibiotics for ureaplasma in the vagina in pregnancy; Cochrane Systematic Review September 2004 – insufficient evidence
Benjamin W. Chaffee; Janet C. et.al; Effect of ZincSupplemntation on Pregnancy and infant outcome: Systemic Review; Paediatric & Perinatal Epidemiology; Vol26, Issue Supplemnt 51, P118-137 July 2012 Zinc Supplementation is associated with a small, but significant reduction in preterm birth (RR 0.86)(5-50mg/day) Caulfield-82% of mothers have mild-moderate zinc deficiency Zinc is required for protein synthesis, cellular division and nuclic acid metabolism Zinc Deficiency a/w fetal loss, congenital malformation, IUGR, low BW, prolonged labour, preterm/post-term infants. Zinc supplementation a/w increase progesterone, better immune function and better growth in child(though not in utero)
Women allocated to receive fish oil had a lower risk of giving birth before 34 weeks of gestation (RR 0.69, 95% CI 0.49-0.99; two trials, 860 women), but the proportion delivering before 37 completed weeks was similar for both groups. These results were largely due to one large multicenter trial (Fish Oil Trials In Pregnancy [FOTIP]) Supplementation with docosahexaenoic acid (n-3 long chain polyunsaturated fatty acid) increased gestation by a mean of six days in women who received it in fortified eggs from 24 to 28 weeks of gestation until parturition (133 mg in fortified eggs versus 33 mg in unfortified eggs)
• Role of first trimester urine culture on all pregnant women?• Regular antenatal screening for women at high-risk of asymptomatic bacteriuria eg, women with sickle cell trait, recurrent urinary tract infections, diabetes mellitus, underlying renal disease
“MYTHS” Enhanced Prenatal Care (March of Dimes Trial) and Social Support do no seem to have an effect on preterm labour. Bed Rest, Hydration, hospitalization Measurement of uterine activity Abstinence Prophylactic antibiotics
Diagnostic Tools Fetal Fibronectin Assay Assessment of Cervical Length
Fetal Fibronectin Extremely high negative predictive value. >99% of symptomatic patients with a negative fFN overall will remain pregnant for at least 2 weeks Poor Positive Predictive value ~21% deliver before 35wks Positive predictive value of ~35% if history of preterm birth
Fetal Fibronectin In a secondary analysis of prospectively collected data, quantitative fFN screening was performed at 24 weeks gestation,(1) 0; (2)1 to 49; (3) 50 to 199; (4)200 ng/mL or more. As the fFN concentration increased, rates of recurrent PTB progressively rose Notably, 50% of asymptomatic patients with high fFN levels (≥200 ng/mL) delivered prior to 34 weeks.
Cervical Length Normal cervical length – singleton vs multiple gestation During TVS, if contractions present, observe ~3mins and take shortest cervical length Cervical length at 23wks is at or less than 25mm in 16% of the population
Correlation of cervical length at 22-24wks with preterm delivery (before 33wks)Cervical %Preterm Sensitivity NegativeLength PV36-48mm 826-35mm 11 6716-25mm 33 50 95.8%<15mm 67 33 94.8%Cerclage/progesterone/steroids not necessary if cervical length at or >15mm
Risks factors for short cervical length in singleton pregnancies: Afro-Caribbean descent Teenagers Low ponderal index Hx of previous miscarriage Hx preterm delivery Drug abusers
No established ideal time interval. Cervical length relatively stable over the 1st 2 trimesters Studies show that cervical length decreases at a rate of 0.5mm/wk to 8mm/wk. Taking an average of 5mm/wk, 1wk is probably too short a period – likely inter-observer error. Depending on cervical length at TVS and the respective center’s threshold for intervention, an appropriate time interval can be determined
Low risk pregnancies Positive predictive value only 4.5% No need for unnecessary intervention/tocolytics/steroids.High Risk Pregnancies: (Cervical length 2.5-3cm <24wks) Sensitivity 60-80% Positive Predictive Value 55-70% Negative predictive value 89-94% No studies on effect of cervical length >24wks
Cerclage Effective in High risk pregnancies (3 or more preterm labours – refer to RCOG May ’11 guideline History indicated, Ultrasound indicated Rescue cerclage
MANAGEMENT Progesterone Cervical Cerclage
Progesterone Steroid Hormone – 1934 isolated from corpus luteum Natural or Synthetic formulations Oral, IM, Vaginal administrations Preterm birth rate:25-31% versus 33-47% in controls
Progesterone - MOA Cervix- Decreases cervical stromal degradation- Barrier to ascending infection- Inhibits cervical ripening- Improves cervical length in short cervix Myometrium- Decreases myometrial oxytocin receptors- Decreases contraction frequency Decidua- Attenuates response to haemorrhage and inflammation Fetal membranes + Placenta- Suppress PG synthesis, decreases apoptosis
Progesterone Routes – Meis et. al Oral: Variable absorption and undergoes 1st pass metabolism. Bioavailability uncertain and higher risk of CNS sedation Vaginal: High endometrial concentration but difficult to achieve constant blood levelsS/Es: 7.9% bloated, nausea, vaginal soreness Intramuscular: Slow-release; optimal blood levels.S/Es: 19.1%; pain, injection site swelling, headache
(i)1 Previous Preterm Labour
Progesterone - Maternal-Fetal Medicine Units Network trial Meis and coinvestigators randomly assigned 459 patients with a documented history of spontaneous preterm delivery to weekly intramuscular injections of 17-alpha- hydroxyprogesterone caproate (250 mg) or placebo 16 to 20 weeks of gestation and continuing until 36 weeks. Active prophylaxis significantly reduced the risk of delivery:- <37 weeks (36 versus 55 percent in the placebo group [RR, 0.66; 95% CI, 0.54-0.81])- <35 weeks (21 versus 31 percent [RR, 0.67; 95% CI, 0.48-0.93])- <32 weeks (11 versus 20 percent [RR, 0.58; 95% CI, 0.37-0.91])
MFMU TRIAL (Cont)Progesterone exposed infants had less perinatal morbidity:- significantly reduced rates of NEC- IVH and- need for supplemental oxygen.* There was no evidence of virilization of female offspring, which was a theoretic concern of this therapy.
Progesterone:MFMU Conclusion Singletons with prior Spontaneous Preterm Birth can consider having IM 250mg 17P administered weekly, from 16-20wks til 36wks. Singletons without prior SPTB but with incidental findings of short cervix (CL<20mm) at 24wks – Progesterone gel/suppository until 36/52 No evidence of benefit in preventing preterm labour in multiple gestations
Progesterone: Da Fonseca Trial NEJM 2007; 357;462-9 Randomly assigned 142 women at high-risk for preterm delivery (based on at least one previous spontaneous preterm birth, prophylactic cervical cerclage, or uterine malformation) to daily supplementation with progesterone vaginal suppositories (100 mg) or placebo from 24 through 34 weeks of gestation. Active prophylaxis significantly reduced the risk of delivery:- <37 weeks (14 versus 29 percent in the placebo group)- <34 weeks (3 versus 19 percent in the placebo group)- (RR 0.54; NNT 1:7)
(ii) Incidental findings of Short Cervix; No Hx of PTB
If incidental findings of cervical length <25mm 20-24wks, for Vaginal suppository 200mg or gel 90mg daily til 36/52 RR 0.50-0.60; NNT 1:14- Romero et al;American Jouranl obstet Gynaec 2012; 206:124-144- Hassan et al; U/S obstet Gynaecol 2011; 38:18- SMFM clinical guidance may 2012
Even if all eligible women received progesterone prophylaxis, it would only reduce the overall preterm birth rate in the United States by approximately 2 percent (from 12.1 to 11.8 percent) 22.5 percent of preterm births in 2002 were recurrent and prophylaxis only reduces the incidence of recurrent preterm birth by 33 percent.
Progesterone – No Benefit The most recent and largest Randomized Trial did not find any benefit in preventing recurent preterm birth 659 women randomized to vaginal prog gel 90mg nightly or placebo
(iii) Multiple Gestations Randomized trial 661 healthy women with twin gestations compared outcomes of weekly intramuscular injections of 250 mg of 17-alpha-hydroxyprogesterone caproate or matching placebo, starting at 16 to 20 weeks of gestation and ending at 35 weeks Delivery or fetal death before 35 weeks occurred in 41.5 percent of pregnancies in the progesterone group and 37.3 percent of those in the placebo group (RR 1.1; 95% CI 0.9 to 1.3)* STOPPIT Trial of 500 twin gestations – similar findings
(iv) PPROM No evidence to suggest any benefit(V) Women with cerclage – no documented benefit(vi) Positive FFN – No Information
Follow-Up 4 year followup of 278 children exposed to proluton antenatally: No difference in physical function, health status, psychosocial performance
Price (USD)Formulation/dose Retail Price Price per Total Cost Dose (21wks)Endometrin $157 for 21 $7.48 $1099.55(100mg vaginal insert)Prometrium $69 for 30 $2.30 $339.10 capsules(100mg vaginal insert)Crinone $170 per 10 $17.00 $2499 cubes(90mg vaginal gel)Prochieve $221 per $12.28 $1805.15 18cues(90mg vaginal gel)Makena $690 per $690 $14490 injection(IM 250mg weekly)Proluton $136 per 10 $13.60 $285.60(IM 250mg compounded 17- injectionsalpha-OH-progesterone caproate)
TocolysisThe goals of treatment of PTL are: For Glucocorticoids to achieve optimum effect In-Utero Transfer Prolong pregnancy when there are underlying, self- limited conditions A systematic review noted that approximately 30 percent of PTL cases spontaneously resolved. In subsequent studies, 50 percent of patients hospitalized for PTL deliver at term.
Contraindications Intrauterine fetal demise Lethal fetal anomaly Nonreassuring fetal status Severe fetal growth restriction Severe preeclampsia or eclampsia Maternal haemorrhage with nemodynamic instability Chorioamnionitis
Efficacy of Tocolytics A meta-analysis of 58 randomized trials of tocolytic therapy of PTL concluded all of the commonly used tocolytic agents were more effective than placebo/no therapy for delaying delivery for 48 hours or seven days (75-93% versus 53%) However, this prolongation of pregnancy was not associated with a statistically significant reduction in overall rates of respiratory distress syndrome or neonatal death.
Comparative efficacy Ritodrine and atosiban are licensed in the UK for the treatment of threatened preterm labour. Although the use of nifedipine for preterm labour is an unlicensed indication it has the advantages of oral administration and a low purchase price.
Issues Beta-agonists have a high frequency of adverse effects. Nifedipine, atosiban and the COX inhibitors have fewer types of adverse effects, and they occur less frequently than for beta-agonists but how they compare with each other is unclear. Using multiple tocolytic drugs appears to be associated with a higher risk of adverse effects and so should be avoided US: Indomethacin + MgSo4, if <32wks (Issue: Indomethacin can cause earlier closure of ductus arteriosus) Nifedipine +MgSo4 use – higher risk of chest pain and ECG changes suggestive of myocardial ischaemia.
Antenatal Corticosteroids A single course of prenatal corticosteroids compared with placebo has not been shown to be effective in babies who are born more than seven days after treatment The Prenatal Repeat Corticosteroid International IPD Study Group: assessing the effects using the best level of Evidence (PRECISE) Group will conduct an IPD meta-analysis. The PRECISE International Collaborative Group was formed in 2010 and data collection commenced in 2011. Eleven trials with up to 5,000 women and 6,000 infants are eligible for the PRECISE IPD meta-analysis.
The primary study outcomes for the infants will be: serious neonatal outcome (death, severe respiratory disease; severe intraventricular haemorrhage (grade 3 and 4); chronic lung disease; necrotising enterocolitis; serious retinopathy of prematurity; and cystic periventricular leukomalacia); use of respiratory support (defined as mechanical ventilation or continuous positive airways pressure or other respiratory support); and birth weight (Z-scores).
For the children, the primary study outcomes will be death or any neurological disability (developmental delay or intellectual impairment cerebral palsy blindness deafness For the women, the primary outcome will be maternal sepsis (defined as chorioamnionitis; pyrexia after trial entry requiring the use of antibiotics; puerperal sepsis; intrapartum fever requiring the use of antibiotics; or postnatal pyrexia).
Choice of Agent Drug and dose — Two regimens of antenatal glucocorticoid treatment have evolved and are effective for accelerating fetal lung maturity: Betamethasone (two doses of 12 mg given intramuscularly 24 hours apart) Dexamethasone (four doses of 6 mg given intramuscularly 12 hours apart).Higher or more frequent doses do NOT increase the benefits of antenatal glucocorticoid therapy and may increase the likelihood of adverse effects
Reduction of IVH, NEC, NNM, infection — (RR 0.4-0.6) Multiple Gestations: Blood levels of bethametasone similar
Several larger cohort and case control studie suggested use of dexamethasone was neurotoxic and associated with adverse neurologic outcomes compared to use of betamethasone or no antenatal glucocorticoid Postnatal use of dexamethasone in premature infants was associated with shorter stature, smaller head circumference, poorer motor skills and coordination, lower IQ scores, and an increased frequency of clinically significant disabilities in survivors Sulfating agents in dexamethasone may be neurotoxic ?Insulin Resistance
Evidence from randomized trials Three large, multicenter randomized clinical trials of single course versus multiple courses of antenatal glucocorticoid therapy have been reported:1) the Maternal Fetal Medicine Units network (MFMU) trial2) Guinn et al multicenter trial3) the Australasian Collaborative Trial of Repeat doses of prenatal Steroids (ACTORDS)
Systemic Review Neonates exposed to repeat courses of glucocorticoids had a reduction in RDS (RR 0.82, 95% CI 0.72-0.93) and were less likely to have severe RDS (RR 0.60, 95% CI 0.48-0.75), particularly those infants delivered at the earliest gestational ages (eg, less than 28 weeks of gestation). Neonates exposed to repeat courses of glucocorticoids were significantly less likely to have serious composite morbidity (RR 0.79, 95% CI 0.67-0.93) No difference in maternal sepsis
MACS Trial This international multicenter placebo-controlled randomized trial is the largest trial on this issue and included 1858 women between 25 to 32 weeks of gestation who remained at risk for preterm birth 12 to 21 days after an initial course of antenatal glucocorticoids. Repeat course of glucocorticoids or placebo every 14 days to a maximum gestational age of 33 weeks. Repeated courses of glucocorticoids after the initial course did not improve neonatal outcome, either composite or individual parameters of morbidity, compared with placebo; Mortality was also similar for both groups. However, neonates who received multiple courses of glucocorticoids had significantly lower mean birthweight, length, and head circumference than those in the placebo group.
ACTORDS In the ACTORDS trial, although multiple steroid courses were associated with decreased birth weight and head circumference at birth, this was no longer true at discharge, suggesting the potential for catch up growth
Salvage (rescue) therapy Placebo-controlled randomized trial (Garite et al; Obstetrix collaborative research network;imopact of ‘rescue course’ of antenatal corticosteroids; a multicenter randomized placebo-controlled trial; Am J obstet Gynecol 2009; 200;248.e1) a complete course of betamethasone (two 12 mg injections) was offered to women <33 weeks of gestation who were ≥14 days beyond a complete course of antenatal glucocorticoids and at risk of delivery within the next 7 days; women with PPROM were excluded (n = 437 pregnancies) showed a significant reduction in the incidence of RDS (41.4 percent with betamethasone versus 61.6 percent with placebo)
PPROM antenatal glucocorticoids for women with preterm premature rupture of membranes (Grade 1A ). We give them at 24 to 32 weeks of gestation in the absence of any clinical signs of chorioamnionitis.• After 32wks, unless documented lung prematurity, higher risk of choriomanionitis negates the potential positive effects of repeated steroids.• (RCOG GTG recommends steroids til 34wks)
Preterm labor triage algorithm for high risk patientsMonica rincon, Leonardo Pereira; Ambulatory Mangement of Preterm Labor; Clinical Obstetrics andGynecology Volume 55 ; Sept 2012; Number 3;756-64CL indicates cervical length by endocervical ultrasound; CX, cervix; CTXs, contractions; fFN, fetalfibronectin; PG, progesterone; PPROM, preterm premature rupture of membrane; PTB, preterm birth;PV, per vagina.
Recurrent preterm labor triage algorithm for patients who havereceived antental corticosteroids. (ACS indicates antenatal corticosteroids; CL, cervical length by endocervical ultrasound; CX, cervix.)
Conclusions1) Health policies are important (Europe)2) Early Sex Education/Prenatal Counselling essential – Diet, Prenatal periodontal care, instrumentation3) No evidence for role of: bed rest, prophylactic antibiotics, hydration, uterine activity monitors4) Progesterone may beneficial in prolonging pregnancy, especially in high risk groups, but data inconclusive5) Role of cervical cerclage – history indicated or u/s indicated6) Repeat course of antenal corticosteroids – exact dosage, timing and long term effects debatable7) PPROM – beyond 32wks?8) Tocolytics – role of MgSo4 in neuroprotection <32wks?
References1) Jay D Iams, Roberto Romero, Jennifer F Culhane et al; Lancet 2008; 371:164-175; Primary, Secondary and tertiary interventions to reduce the morbidity and mortality of preterm birth.2) ACOG Guidelines on antenal corticosteroid use 20123) Greentop guidelines- Cervical Cerclage- PPROM- Tocolytics in preterm labour4) Roberts, D, Dalziel, S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006; 3:CD004454.5) Brownfoot, FC, Crowther, CA, Middleton, P. Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2008; :CD006764.6) Australian & New Zealand Neonatal Network. Report of the Australian and New Zealand Neonatal Network 2006. Sydney: ANZNN; 2009