Preventing Preterm LabourPreventing Preterm Labour

Presenter: Dr Lucas LukPresenter: Dr Lucas LukSupervisor: Dr MuniswaranSupervisor: Dr Muniswaran

Sarawak General Hospital O&G Sarawak General Hospital O&G DeptDept

12/9/201212/9/2012

IncidenceIncidenceIatrogenic ~20% Iatrogenic ~20%

PPROM ~20% PPROM ~20%

Spontaneous preterm labour ~60%Spontaneous preterm labour ~60% US ~12.5% (2008)US ~12.5% (2008) UK ~7.6%UK ~7.6% Sarawak General Hospital ~11.1% Sarawak General Hospital ~11.1%

(2011)(2011)

Magnitude of ProblemMagnitude of Problem

6.2 billion dollars in hospitalization 6.2 billion dollars in hospitalization costs 2010 in US, US2 billion dollars costs 2010 in US, US2 billion dollars per year of life thereafter. per year of life thereafter.

Epicure/Epicure 2 StudiesEpicure/Epicure 2 Studies

Begain in 1995Begain in 1995 Following Health and outcomes of babies Following Health and outcomes of babies

born before 26wksborn before 26wks Assessed survival rates, disabilities, Assessed survival rates, disabilities,

medical complications, motor skills, visual medical complications, motor skills, visual skills, attention disordersskills, attention disorders

Babies assessed at 1 year old, 2/12 yrs Babies assessed at 1 year old, 2/12 yrs old, 6 yrs old and 11yrs old. (corrected old, 6 yrs old and 11yrs old. (corrected ages)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 1 yr old: 31% with some major motor problemproblem

2.5yrs: 48% with some form of 2.5yrs: 48% with some form of impairment, 4% with significant chest impairment, 4% with significant chest infectionsinfections

6yrs old: 20% no problems6yrs old: 20% no problems 11yrs old: IQ tests: 45% low scores vs 11yrs old: IQ tests: 45% low scores vs

1.3%; only 39% with no impairment. More 1.3%; only 39% with no impairment. More had special needshad special needs

SGH 2011:SGH 2011:

11.1% Preterm Births11.1% Preterm Births 55% of infant deaths severely 55% of infant deaths severely

preterm (<34wks) preterm (<34wks) No survival <26wks, 700-800g No survival <26wks, 700-800g

ContentContent

Primary PreventionPrimary Prevention Secondary PreventionSecondary Prevention- Risk FactorsRisk Factors- Screening/Diagnostic ToolsScreening/Diagnostic Tools- ManagementManagement Tertiary PreventionTertiary Prevention ConclusionConclusion

Primary PreventionPrimary Prevention11

Public Education Public Education Public & Professional PoliciesPublic & Professional Policies- ART limiting number of embryos transferredART limiting number of embryos transferred- Minimum paid pregnancy leaveMinimum paid pregnancy leave- Workplace hazards, Maximum work week, exemption Workplace hazards, Maximum work week, exemption

from night shiftfrom night shift Repeated Uterine InstrumentationsRepeated Uterine Instrumentations Close Pregnancy (<6/12)Close Pregnancy (<6/12) Substance abuse - Smoking Cessation, coccaineSubstance abuse - Smoking Cessation, coccaine Antenatal periodontal careAntenatal periodontal care Low Socio-Economic statusLow Socio-Economic status Genetics Genetics Malnutrition (Africa during famines), omega-3, Malnutrition (Africa during famines), omega-3,

ZincZinc Extremes of AgeExtremes of Age UTIUTI

EUROPOPEUROPOP

Working Night Shifts (~50% higher Working Night Shifts (~50% higher risk)risk)

Standing >6hrs/day(RR1.26)Standing >6hrs/day(RR1.26) Working >42hrs/wk(RR1.22)Working >42hrs/wk(RR1.22)

Periodontal CarePeriodontal Care Risk of preterm birth is associated with severity Risk of preterm birth is associated with severity

of periodontal diseaseof periodontal disease

Risk increases when periodontal disease Risk increases when periodontal disease progresses in pregnancyprogresses in pregnancy

Haematogenous transmission, or more likely, Haematogenous transmission, or more likely, through shared immunological response through shared immunological response

Randomized trials Randomized trials have nothave not reported reduced reported reduced rates of preterm birth in women treated for rates of preterm birth in women treated for periodontal diseaseperiodontal disease

Effects of preconceptional periodontal care on Effects of preconceptional periodontal care on preterm birth not reported. preterm birth not reported.

Maternal Oral Therapy to Reduce Obstetric Risk Study were Maternal Oral Therapy to Reduce Obstetric Risk Study were published and showed that periodontal therapy did not published and showed that periodontal therapy did not reduce the incidence of preterm delivery before 37, 35, or reduce the incidence of preterm delivery before 37, 35, or 32 weeks of gestation, weight for gestational age, or 32 weeks of gestation, weight for gestational age, or neonatal morbidity.neonatal morbidity.

This is the largest randomized controlled trial of the effects This is the largest randomized controlled trial of the effects of maternal periodontal disease treatment on preterm birth of maternal periodontal disease treatment on preterm birth rates; over 1800 pregnant women with periodontal disease rates; over 1800 pregnant women with periodontal disease were randomly assigned to receive treatment before 24 were randomly assigned to receive treatment before 24 weeks of gestation or postpartum. weeks of gestation or postpartum.

Treatment consisted of up to four sessions of supra- and Treatment consisted of up to four sessions of supra- and sub-gingival scaling and root planing using hand and sub-gingival scaling and root planing using hand and ultrasonic instruments, full mouth tooth polishing, and oral ultrasonic instruments, full mouth tooth polishing, and oral hygiene instruction. hygiene instruction.

Two subsequent large randomized trials of pregnant women Two subsequent large randomized trials of pregnant women with periodontal disease had a similar design and also found with periodontal disease had a similar design and also found that treatment did not result in a significant improvement in that treatment did not result in a significant improvement in any pregnancy outcome.any pregnancy outcome.

One of these, the Periodontal Infections and Prematurity One of these, the Periodontal Infections and Prematurity Study (PIPS), found that treatment might increase the risk of Study (PIPS), found that treatment might increase the risk of indicated preterm birth; this requires further study indicated preterm birth; this requires further study

Asymptomatic BacteruriaAsymptomatic Bacteruria Pregnant women with asymptomatic bacteriuria Pregnant women with asymptomatic bacteriuria

should be treated with antibiotics to reduce the should be treated with antibiotics to reduce the risk of preterm birth.risk of preterm birth.

A meta-analysis of 14 randomized trials A meta-analysis of 14 randomized trials comparing antibiotic treatment with placebo or comparing antibiotic treatment with placebo or no treatment in pregnant women with no treatment in pregnant women with asymptomatic bacteriuria demonstrated that asymptomatic bacteriuria demonstrated that antibiotic treatment was effective in:antibiotic treatment was effective in:

(i)(i) Clearing asymptomatic bacteriuria (OR 0.07, 95% Clearing asymptomatic bacteriuria (OR 0.07, 95% CI 0.05-0.10),CI 0.05-0.10),

(ii)(ii) reducing the incidence of pyelonephritis (OR reducing the incidence of pyelonephritis (OR 0.24, 95% CI 0.19-0.32), and 0.24, 95% CI 0.19-0.32), and

(iii)(iii)reducing preterm delivery and delivery of low-reducing preterm delivery and delivery of low-birth-weight infants (OR 0.60, 95% CI 0.45-0.80) birth-weight infants (OR 0.60, 95% CI 0.45-0.80)

Genital Tract InfectionsGenital Tract Infections

Chlamydia and gonorrheaChlamydia and gonorrhea — There is no  — There is no evidence that treatment of chlamydia or evidence that treatment of chlamydia or gonorrhea prolongs gestation. gonorrhea prolongs gestation.

The only controlled trial that evaluated the The only controlled trial that evaluated the effect of treatment of chlamydia on effect of treatment of chlamydia on gestational duration did not show a gestational duration did not show a reduction in preterm birthreduction in preterm birth

However, screening for and treatment of However, screening for and treatment of these infections is recommended to prevent these infections is recommended to prevent other maternal and neonatal sequelae other maternal and neonatal sequelae

TrichomanasTrichomanas

The Vaginal Infections and Prematurity Study demonstrated The Vaginal Infections and Prematurity Study demonstrated that pregnant women with that pregnant women with Trichomonas vaginalis Trichomonas vaginalis have a have a 30% higher risk of having a preterm birth, a 2-fold risk of 30% higher risk of having a preterm birth, a 2-fold risk of stillbirth or neonatal death, and PPROM.stillbirth or neonatal death, and PPROM.

Treatment of asymptomatic Trichomonas infection is not Treatment of asymptomatic Trichomonas infection is not recommended during pregnancy because it does not recommended during pregnancy because it does not prevent, and may even increase, the risk of preterm prevent, and may even increase, the risk of preterm deliverydelivery

Bacterial VaginosisBacterial Vaginosis

Lactobacillus, which normally resides in the vaginal tract, is Lactobacillus, which normally resides in the vaginal tract, is replaced by replaced by Gardnerella vaginalis, Mobiluncus Gardnerella vaginalis, Mobiluncus species, species, anaerobes, and genital mycoplasmasanaerobes, and genital mycoplasmas

Prevalence in pregnancy 10-20%; 50% asymptomatic Prevalence in pregnancy 10-20%; 50% asymptomatic

Some randomized trials showed decrease in preterm labour Some randomized trials showed decrease in preterm labour up to 50%up to 50%

(McGregor et al, Huth et al, Morales et.al) (McGregor et al, Huth et al, Morales et.al)

the largest trials studying treatment of asymptomatic BV during the largest trials studying treatment of asymptomatic BV during pregnancy were done by McDonald pregnancy were done by McDonald et al et al [10] and Carey [10] and Carey et al et al [11], consisting of 879 women and 1953 women, respectively. [11], consisting of 879 women and 1953 women, respectively.

They concluded that the treatment of asymptomatic bacterial They concluded that the treatment of asymptomatic bacterial vaginosis in pregnant women vaginosis in pregnant women does not reduce does not reduce the rate of the rate of preterm birth. preterm birth.

A metaanalysis done by Leitich A metaanalysis done by Leitich et alet al, involving 10 studies with , involving 10 studies with results for 3969 patients, showed that antibiotic treatment did results for 3969 patients, showed that antibiotic treatment did not decrease preterm birth in all patients combined (OR 0.83; 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 95% CI 0.57-1.21) or in high risk patients with previous preterm birth (OR 0.50; 95% CI 0.22-1.12).birth (OR 0.50; 95% CI 0.22-1.12).

Klebanoff et. al –617 women with culture proven Klebanoff et. al –617 women with culture proven asymptomatic infection at 16 to 23 weeks of gestation were asymptomatic infection at 16 to 23 weeks of gestation were randomly assigned to receive either two doses randomly assigned to receive either two doses of metronidazole (2 g) or placebo 48 hours apart. All of metronidazole (2 g) or placebo 48 hours apart. All women were retreated with the same regimen at 24 to 29 women were retreated with the same regimen at 24 to 29 weeks of gestation. Trichomonas resolved in 93 percent of weeks of gestation. Trichomonas resolved in 93 percent of metronidazole treated women and 35 percent of the metronidazole treated women and 35 percent of the placebo group. The rate of preterm birth was higher in placebo group. The rate of preterm birth was higher in treated than control women (19 versus 11 percent, relative treated than control women (19 versus 11 percent, relative risk 1.8; 95% CI 1.2-2.7), primarily related to an increased risk 1.8; 95% CI 1.2-2.7), primarily related to an increased frequency of spontaneous preterm labor (10.2 versus 3.5 frequency of spontaneous preterm labor (10.2 versus 3.5 percent, relative risk 3.0; 95% CI 1.5- 5.9). percent, relative risk 3.0; 95% CI 1.5- 5.9).

UREAPLASMA UREALYTICUMUREAPLASMA UREALYTICUM

Carey Carey et alet al controlled for the presence of other organisms controlled for the presence of other organisms in 4934 women, and found there was no association in 4934 women, and found there was no association between maternal genital tract colonization with between maternal genital tract colonization with U. U. Urealyticum Urealyticum and low birthweight, preterm birth or PPROM. and low birthweight, preterm birth or PPROM.

In addition, a multicentre randomized trial of >900 patients In addition, a multicentre randomized trial of >900 patients with with U. Urealyticum U. Urealyticum (excluding those with (excluding those with C. trachomatis C. trachomatis and GBS) found there was no impact on adverse pregnancy and GBS) found there was no impact on adverse pregnancy outcomes when treated with erythromycin vs placebooutcomes when treated with erythromycin vs placebo

Camille H. Raynes-Greenow et. al; Antibiotics for ureaplasma Camille H. Raynes-Greenow et. al; Antibiotics for ureaplasma in the vagina in pregnancy; Cochrane Systematic Review in the vagina in pregnancy; Cochrane Systematic Review September 2004 – insufficient evidenceSeptember 2004 – insufficient evidence

MalnutritionMalnutrition

1)1) Zinc Zinc

2)2) Polyunsaturated Fatty Acids (PUFA)Polyunsaturated Fatty Acids (PUFA)

Benjamin W. Chaffee; Janet C. et.al; Effect of Zinc Benjamin W. Chaffee; Janet C. et.al; Effect of Zinc Supplemntation on Pregnancy and infant outcome: Supplemntation on Pregnancy and infant outcome:

Systemic Review; Paediatric & Perinatal Epidemiology; Systemic Review; Paediatric & Perinatal Epidemiology; Vol26, Issue Supplemnt 51, P118-137 July 2012Vol26, Issue Supplemnt 51, P118-137 July 2012

Zinc Supplementation is associated with a small, but Zinc Supplementation is associated with a small, but significant reduction in preterm birth (RR 0.86)significant reduction in preterm birth (RR 0.86)

(5-50mg/day)(5-50mg/day) Caulfield-82% of mothers have mild-moderate zinc Caulfield-82% of mothers have mild-moderate zinc

deficiencydeficiency

Zinc is required for protein synthesis, cellular division and Zinc is required for protein synthesis, cellular division and nuclic acid metabolismnuclic acid metabolism

Zinc Deficiency a/w fetal loss, congenital malformation, Zinc Deficiency a/w fetal loss, congenital malformation, IUGR, low BW, prolonged labour, preterm/post-term infants. IUGR, low BW, prolonged labour, preterm/post-term infants.

Zinc supplementation a/w increase progesterone, better Zinc supplementation a/w increase progesterone, better immune function and better growth in child(though not in immune function and better growth in child(though not in utero)utero)

Omega 3: Inhibits PgE2 & PgF2alphaOmega 3: Inhibits PgE2 & PgF2alpha

10x bluefish intake required 10x bluefish intake required (EPA:DHA 1:2.5); 1.6g/day to (EPA:DHA 1:2.5); 1.6g/day to prolong pregnancy 4-6days.prolong pregnancy 4-6days.

Women allocated to receive fish oil had a lower risk of Women allocated to receive fish oil had a lower risk of giving birth before 34 weeks of gestation (RR 0.69, giving birth before 34 weeks of gestation (RR 0.69, 95% CI 0.49-0.99; two trials, 860 women), but the 95% CI 0.49-0.99; two trials, 860 women), but the proportion delivering before 37 completed weeks was proportion delivering before 37 completed weeks was similar for both groups. These results were largely due similar for both groups. These results were largely due to one large multicenter trial (Fish Oil Trials In to one large multicenter trial (Fish Oil Trials In Pregnancy [FOTIP])Pregnancy [FOTIP])

Supplementation with docosahexaenoic acid (n-3 long Supplementation with docosahexaenoic acid (n-3 long chain polyunsaturated fatty acid) increased gestation chain polyunsaturated fatty acid) increased gestation by a mean of six days in women who received it in by a mean of six days in women who received it in fortified eggs from 24 to 28 weeks of gestation until fortified eggs from 24 to 28 weeks of gestation until parturition (133 mg in fortified eggs versus 33 mg in parturition (133 mg in fortified eggs versus 33 mg in unfortified eggs) unfortified eggs)

• Role of first trimester urine culture Role of first trimester urine culture on all pregnant women? on all pregnant women?

• Regular antenatal screening for Regular antenatal screening for women at high-risk of asymptomatic women at high-risk of asymptomatic bacteriuria eg, women with sickle cell bacteriuria eg, women with sickle cell trait, recurrent urinary tract trait, recurrent urinary tract infections, diabetes mellitus, infections, diabetes mellitus, underlying renal diseaseunderlying renal disease

““MYTHS”MYTHS”

Enhanced Prenatal Care (March of Enhanced Prenatal Care (March of Dimes Trial) and Social Support do no Dimes Trial) and Social Support do no seem to have an effect on preterm seem to have an effect on preterm labour. labour.

Bed Rest, Hydration, hospitalizationBed Rest, Hydration, hospitalization Measurement of uterine activityMeasurement of uterine activity AbstinenceAbstinence Prophylactic antibioticsProphylactic antibiotics

Secondary PreventionSecondary Prevention

Risk FactorsRisk Factors Fetal AnomaliesFetal Anomalies History of prior preterm labourHistory of prior preterm labour Mutiple gestationMutiple gestation PolyhydramniosPolyhydramnios Intrauterine fetal demiseIntrauterine fetal demise Cervical InsufficiencyCervical Insufficiency Uterine AnomaliesUterine Anomalies Placenta Previa/Abruptio PlacentaPlacenta Previa/Abruptio Placenta Serious Maternal DiseaseSerious Maternal Disease Prior Cervical/Uterine manipulationPrior Cervical/Uterine manipulation IdiopathicIdiopathic

Diagnostic ToolsDiagnostic Tools

Fetal Fibronectin AssayFetal Fibronectin Assay Assessment of Cervical LengthAssessment of Cervical Length

Fetal FibronectinFetal Fibronectin

Extremely high negative predictive value.Extremely high negative predictive value.

>99% of symptomatic patients with a >99% of symptomatic patients with a negative fFN overall will remain pregnant negative fFN overall will remain pregnant for at least 2 weeksfor at least 2 weeks

Poor Positive Predictive value ~21% Poor Positive Predictive value ~21% deliver before 35wksdeliver before 35wks

Positive predictive value of ~35% if history Positive predictive value of ~35% if history of preterm birthof preterm birth

Fetal FibronectinFetal Fibronectin In a secondary analysis of prospectively In a secondary analysis of prospectively

collected data, quantitative fFN screening collected data, quantitative fFN screening was performed at 24 weeks' gestation, was performed at 24 weeks' gestation,

(1) 0; (2)1 to 49; (3) 50 to 199; (4)200 (1) 0; (2)1 to 49; (3) 50 to 199; (4)200 ng/mL or more. ng/mL or more.

As the fFN concentration increased, rates As the fFN concentration increased, rates of recurrent PTB progressively roseof recurrent PTB progressively rose

Notably, 50% of asymptomatic patients Notably, 50% of asymptomatic patients with high fFN levels (≥200 ng/mL) with high fFN levels (≥200 ng/mL) delivered prior to 34 weeks. delivered prior to 34 weeks.

Cervical LengthCervical Length

Normal cervical length – singleton vs Normal cervical length – singleton vs multiple gestationmultiple gestation

During TVS, if contractions present, During TVS, if contractions present, observe ~3mins and take shortest observe ~3mins and take shortest cervical lengthcervical length

Cervical length at 23wks is at or less Cervical length at 23wks is at or less than 25mm in 16% of the populationthan 25mm in 16% of the population

Correlation of cervical length at 22-24wks Correlation of cervical length at 22-24wks with preterm delivery (before 33wks)with preterm delivery (before 33wks)

Cerclage/progesterone/steroids not necessary if cervical length at or Cerclage/progesterone/steroids not necessary if cervical length at or >15mm>15mm

Cervical Cervical LengthLength

%Preterm%Preterm SensitivitSensitivityy

NegativeNegative

PVPV

36-48mm36-48mm 88

26-35mm26-35mm 1111 6767

16-25mm16-25mm 3333 5050 95.8%95.8%

<15mm<15mm 6767 3333 94.8%94.8%

Risks factors for short cervical Risks factors for short cervical length in singleton length in singleton

pregnancies:pregnancies:

Afro-Caribbean descentAfro-Caribbean descent TeenagersTeenagers Low ponderal indexLow ponderal index Hx of previous miscarriageHx of previous miscarriage Hx preterm deliveryHx preterm delivery Drug abusersDrug abusers

No established ideal time interval. No established ideal time interval. Cervical length relatively stable over the 1st 2 Cervical length relatively stable over the 1st 2

trimesterstrimesters Studies show that cervical length decreases at Studies show that cervical length decreases at

a rate of 0.5mm/wk to 8mm/wk. a rate of 0.5mm/wk to 8mm/wk. Taking an average of 5mm/wk, 1wk is probably Taking an average of 5mm/wk, 1wk is probably

too short a period – likely inter-observer error. too short a period – likely inter-observer error. Depending on cervical length at TVS and the Depending on cervical length at TVS and the

respective center’s threshold for intervention, respective center’s threshold for intervention, an appropriate time interval can be an appropriate time interval can be determined determined

Low risk pregnanciesLow risk pregnancies Positive predictive value only 4.5%Positive predictive value only 4.5% No need for unnecessary No need for unnecessary

intervention/tocolytics/steroids.intervention/tocolytics/steroids.High Risk Pregnancies: (Cervical length 2.5-High Risk Pregnancies: (Cervical length 2.5-

3cm <24wks)3cm <24wks) Sensitivity 60-80%Sensitivity 60-80% Positive Predictive Value 55-70%Positive Predictive Value 55-70% Negative predictive value 89-94%Negative predictive value 89-94% No studies on effect of cervical length No studies on effect of cervical length

>24wks>24wks

CerclageCerclage Effective in High risk pregnancies (3 Effective in High risk pregnancies (3

or more preterm labours – refer to or more preterm labours – refer to RCOG May ’11 guideline RCOG May ’11 guideline

History indicated, Ultrasound History indicated, Ultrasound indicatedindicated

Rescue cerclageRescue cerclage

MANAGEMENTMANAGEMENT ProgesteroneProgesterone Cervical CerclageCervical Cerclage

Progesterone Progesterone

Steroid Hormone – 1934 isolated Steroid Hormone – 1934 isolated from corpus luteum from corpus luteum

Natural or Synthetic formulationsNatural or Synthetic formulations Oral, IM, Vaginal administrationsOral, IM, Vaginal administrations

Preterm birth rate: Preterm birth rate:

25-31% versus 33-47% in controls 25-31% versus 33-47% in controls

Progesterone - MOAProgesterone - MOA

1) TH2 shift (less cell-mediated 1) TH2 shift (less cell-mediated immune response)immune response)

2) Progesterone induced blocking 2) Progesterone induced blocking factor – decreases decidual NK cell factor – decreases decidual NK cell activityactivity

3) Increases asymmetrical antibodies – 3) Increases asymmetrical antibodies –

Masks fetal antigens Masks fetal antigens

Progesterone - MOAProgesterone - MOA CervixCervix- Decreases cervical stromal degradationDecreases cervical stromal degradation- Barrier to ascending infectionBarrier to ascending infection- Inhibits cervical ripeningInhibits cervical ripening- Improves cervical length in short cervixImproves cervical length in short cervix

MyometriumMyometrium- Decreases myometrial oxytocin receptorsDecreases myometrial oxytocin receptors- Decreases contraction frequencyDecreases contraction frequency

DeciduaDecidua- Attenuates response to haemorrhage and - Attenuates response to haemorrhage and

inflammationinflammation

Fetal membranes + PlacentaFetal membranes + Placenta- Suppress PG synthesis, decreases apoptosis- Suppress PG synthesis, decreases apoptosis

Progesterone Routes – Meis et. Progesterone Routes – Meis et. alal

Oral:Oral: Variable absorption and undergoes 1 Variable absorption and undergoes 1stst pass pass metabolism. Bioavailability uncertain and higher metabolism. Bioavailability uncertain and higher risk of CNS sedationrisk of CNS sedation

Vaginal:Vaginal: High endometrial concentration but High endometrial concentration but difficult to achieve constant blood levelsdifficult to achieve constant blood levels

S/Es: 7.9% bloated, nausea, vaginal soreness S/Es: 7.9% bloated, nausea, vaginal soreness

Intramuscular:Intramuscular: Slow-release; optimal blood Slow-release; optimal blood levels.levels.

S/Es: 19.1%; pain, injection site swelling, headacheS/Es: 19.1%; pain, injection site swelling, headache

(i)1 Previous Preterm (i)1 Previous Preterm LabourLabour

Progesterone - Maternal-Fetal Progesterone - Maternal-Fetal Medicine Units Network trialMedicine Units Network trial

Meis and coinvestigators randomly assigned 459 Meis and coinvestigators randomly assigned 459 patients with a documented history of spontaneous patients with a documented history of spontaneous preterm delivery to weekly intramuscular injections of preterm delivery to weekly intramuscular injections of 17-alpha-hydroxyprogesterone caproate (250 mg) or 17-alpha-hydroxyprogesterone caproate (250 mg) or placebo placebo

16 to 20 weeks of gestation and continuing until 36 16 to 20 weeks of gestation and continuing until 36 weeks. Active prophylaxis significantly reduced the weeks. Active prophylaxis significantly reduced the risk of delivery:risk of delivery:

- <37 weeks (36 versus 55 percent in the placebo group <37 weeks (36 versus 55 percent in the placebo group [RR, 0.66; 95% CI, 0.54-0.81])[RR, 0.66; 95% CI, 0.54-0.81])

- <35 weeks (21 versus 31 percent [RR, 0.67; 95% CI, <35 weeks (21 versus 31 percent [RR, 0.67; 95% CI, 0.48-0.93])0.48-0.93])

- <32 weeks (11 versus 20 percent [RR, 0.58; 95% CI, <32 weeks (11 versus 20 percent [RR, 0.58; 95% CI, 0.37-0.91])0.37-0.91])

MFMU TRIAL (Cont)MFMU TRIAL (Cont)

Progesterone exposed infants had less Progesterone exposed infants had less perinatal morbidity:perinatal morbidity:

- significantly reduced rates of NEC significantly reduced rates of NEC - IVH and IVH and - need for supplemental oxygen. need for supplemental oxygen.

* There was no evidence of virilization of * There was no evidence of virilization of female offspring, which was a theoretic female offspring, which was a theoretic concern of this therapy.concern of this therapy.

Progesterone:MFMU Progesterone:MFMU ConclusionConclusion

Singletons with prior Spontaneous Preterm Singletons with prior Spontaneous Preterm Birth can consider having IM 250mg 17P Birth can consider having IM 250mg 17P administered weekly, from 16-20wks til administered weekly, from 16-20wks til 36wks. 36wks.

Singletons without prior SPTB but with Singletons without prior SPTB but with incidental findings of short cervix (CL<20mm) incidental findings of short cervix (CL<20mm) at 24wks – Progesterone gel/suppository until at 24wks – Progesterone gel/suppository until 36/5236/52

No evidence of benefit in preventing preterm No evidence of benefit in preventing preterm labour in multiple gestationslabour in multiple gestations

Progesterone: Da Fonseca TrialProgesterone: Da Fonseca TrialNEJM 2007; 357;462-9NEJM 2007; 357;462-9

Randomly assigned 142 women at high-risk for Randomly assigned 142 women at high-risk for preterm delivery (based on at least one previous preterm delivery (based on at least one previous spontaneous preterm birth, prophylactic cervical spontaneous preterm birth, prophylactic cervical cerclage, or uterine malformation) to daily cerclage, or uterine malformation) to daily supplementation with progesterone vaginal supplementation with progesterone vaginal suppositories (100 mg) or placebo from 24 through 34 suppositories (100 mg) or placebo from 24 through 34 weeks of gestation.weeks of gestation.

Active prophylaxis significantly reduced the risk of Active prophylaxis significantly reduced the risk of delivery:delivery:

- <37 weeks (14 versus 29 percent in the placebo group)- <37 weeks (14 versus 29 percent in the placebo group)- <34 weeks (3 versus 19 percent in the placebo group)<34 weeks (3 versus 19 percent in the placebo group)- (RR 0.54; NNT 1:7)(RR 0.54; NNT 1:7)

(ii) Incidental findings of Short (ii) Incidental findings of Short Cervix; No Hx of PTBCervix; No Hx of PTB

If incidental findings of cervical length If incidental findings of cervical length <25mm 20-24wks, for Vaginal suppository <25mm 20-24wks, for Vaginal suppository 200mg or gel 90mg daily til 36/52200mg or gel 90mg daily til 36/52

RR 0.50-0.60; NNT 1:14RR 0.50-0.60; NNT 1:14

- Romero et al;American Jouranl obstet Romero et al;American Jouranl obstet Gynaec 2012; 206:124-144Gynaec 2012; 206:124-144

- Hassan et al; U/S obstet Gynaecol 2011; Hassan et al; U/S obstet Gynaecol 2011; 38:1838:18

- SMFM clinical guidance may 2012SMFM clinical guidance may 2012

Even if all eligible women received Even if all eligible women received progesterone prophylaxis, it would only progesterone prophylaxis, it would only reduce the overall preterm birth rate in reduce the overall preterm birth rate in the United States by approximately 2 the United States by approximately 2 percent (from 12.1 to 11.8 percent) percent (from 12.1 to 11.8 percent)

22.5 percent of preterm births in 2002 22.5 percent of preterm births in 2002 were recurrent and prophylaxis only were recurrent and prophylaxis only reduces the incidence of recurrent preterm reduces the incidence of recurrent preterm birth by 33 percent.birth by 33 percent.

Progesterone – No BenefitProgesterone – No Benefit

The most recent and largest The most recent and largest Randomized Trial did not find any Randomized Trial did not find any benefit in preventing recurent benefit in preventing recurent preterm birthpreterm birth

659 women randomized to vaginal 659 women randomized to vaginal prog gel 90mg nightly or placeboprog gel 90mg nightly or placebo

(iii) Multiple Gestations(iii) Multiple Gestations

Randomized trial 661 healthy women with twin Randomized trial 661 healthy women with twin gestations compared outcomes of weekly gestations compared outcomes of weekly intramuscular injections of 250 mg of 17-alpha-intramuscular injections of 250 mg of 17-alpha-hydroxyprogesterone caproate or matching placebo, hydroxyprogesterone caproate or matching placebo, starting at 16 to 20 weeks of gestation and ending at starting at 16 to 20 weeks of gestation and ending at 35 weeks 35 weeks

Delivery or fetal death before 35 weeks occurred in Delivery or fetal death before 35 weeks occurred in 41.5 percent of pregnancies in the progesterone 41.5 percent of pregnancies in the progesterone group and 37.3 percent of those in the placebo group group and 37.3 percent of those in the placebo group (RR 1.1; 95% CI 0.9 to 1.3) (RR 1.1; 95% CI 0.9 to 1.3)

* STOPPIT Trial of 500 twin gestations – similar findings* STOPPIT Trial of 500 twin gestations – similar findings

(iv) PPROM(iv) PPROM

No evidence to suggest any benefitNo evidence to suggest any benefit

(V) Women with cerclage – no (V) Women with cerclage – no documented benefitdocumented benefit

(vi) Positive FFN – No Information(vi) Positive FFN – No Information

Follow-UpFollow-Up

4 year followup of 278 children 4 year followup of 278 children exposed to proluton antenatally:exposed to proluton antenatally:

No difference in physical function, No difference in physical function, health status, psychosocial health status, psychosocial performance performance

Price (USD)Price (USD)Formulation/doseFormulation/dose Retail PriceRetail Price Price per Price per

DoseDoseTotal Cost Total Cost (21wks)(21wks)

EndometrinEndometrin(100mg vaginal insert)(100mg vaginal insert)

$157 for 21$157 for 21 $7.48$7.48 $1099.55$1099.55

PrometriumPrometrium(100mg vaginal insert)(100mg vaginal insert)

$69 for 30 $69 for 30 capsulescapsules

$2.30$2.30 $339.10$339.10

CrinoneCrinone(90mg vaginal gel)(90mg vaginal gel)

$170 per 10 $170 per 10 cubescubes

$17.00$17.00 $2499$2499

ProchieveProchieve(90mg vaginal gel)(90mg vaginal gel)

$221 per $221 per 18cues18cues

$12.28$12.28 $1805.15$1805.15

MakenaMakena(IM 250mg weekly)(IM 250mg weekly)

$690 per $690 per injectioninjection

$690$690 $14490$14490

ProlutonProluton(IM 250mg (IM 250mg compounded compounded 17-alpha-OH-progesterone 17-alpha-OH-progesterone caproate)caproate)

$136 per 10 $136 per 10 injectionsinjections

$13.60$13.60 $285.60$285.60

Tertiary PreventionTertiary Prevention

TocolyticsTocolytics- Beta-2 AgonistsBeta-2 Agonists- Oxytocin AgonistOxytocin Agonist- Cox-2 InhibitorCox-2 Inhibitor- Calcium Channel BlockersCalcium Channel Blockers- Nitric Oxide DonorNitric Oxide Donor- Magnesium SulphateMagnesium Sulphate

TocolysisTocolysis

The goals of treatment of PTL are:The goals of treatment of PTL are: For Glucocorticoids to achieve optimum effectFor Glucocorticoids to achieve optimum effect In-Utero TransferIn-Utero Transfer Prolong pregnancy when there are underlying, Prolong pregnancy when there are underlying,

self-limited conditionsself-limited conditions

A systematic review noted that approximately 30 A systematic review noted that approximately 30 percent of PTL cases spontaneously resolved. In percent of PTL cases spontaneously resolved. In subsequent studies, 50 percent of patients subsequent studies, 50 percent of patients hospitalized for PTL deliver at term.hospitalized for PTL deliver at term.

ContraindicationsContraindications

Intrauterine fetal demiseIntrauterine fetal demise Lethal fetal anomalyLethal fetal anomaly Nonreassuring fetal statusNonreassuring fetal status Severe fetal growth restrictionSevere fetal growth restriction Severe preeclampsia or eclampsiaSevere preeclampsia or eclampsia Maternal haemorrhage with Maternal haemorrhage with

nemodynamic instabilitynemodynamic instability ChorioamnionitisChorioamnionitis

Efficacy of TocolyticsEfficacy of Tocolytics

A meta-analysis of 58 randomized trials of tocolytic therapy A meta-analysis of 58 randomized trials of tocolytic therapy of PTL concluded all of the commonly used tocolytic agents of PTL concluded all of the commonly used tocolytic agents were more effective than placebo/no therapy for delaying were more effective than placebo/no therapy for delaying delivery for 48 hours or seven days (75-93% versus 53%) delivery for 48 hours or seven days (75-93% versus 53%)

However, this prolongation of pregnancy was not However, this prolongation of pregnancy was not associated with a statistically significant reduction in overall associated with a statistically significant reduction in overall rates of respiratory distress syndrome or neonatal death.rates of respiratory distress syndrome or neonatal death.

Comparative efficacyComparative efficacy

Ritodrine and atosiban are licensed Ritodrine and atosiban are licensed in the UK for the treatment of in the UK for the treatment of threatened preterm labour. Although threatened preterm labour. Although thethe

use of nifedipine for preterm labour use of nifedipine for preterm labour is an unlicensed indication it has the is an unlicensed indication it has the advantages of oral administration advantages of oral administration and a low purchase price.and a low purchase price.

IssuesIssues

Beta-agonists have a high frequency of adverse effects. Beta-agonists have a high frequency of adverse effects. Nifedipine, atosiban and the COX inhibitors haveNifedipine, atosiban and the COX inhibitors have fewer fewer

types of adverse effects, and they occur less frequently types of adverse effects, and they occur less frequently than for beta-agonists but how they comparethan for beta-agonists but how they compare with each with each other is unclear.other is unclear.

Using multiple tocolytic drugs appears to be associated Using multiple tocolytic drugs appears to be associated with a higher risk of adverse effects and so shouldwith a higher risk of adverse effects and so should be be avoidedavoided

US: Indomethacin + MgSo4, if <32wks US: Indomethacin + MgSo4, if <32wks

(Issue: Indomethacin can cause earlier closure of ductus (Issue: Indomethacin can cause earlier closure of ductus arteriosus)arteriosus)

Nifedipine +MgSo4 use – higher risk of chest pain and ECG Nifedipine +MgSo4 use – higher risk of chest pain and ECG changes suggestive of myocardial ischaemia. changes suggestive of myocardial ischaemia.

Antenatal CorticosteroidsAntenatal Corticosteroids

A single course of prenatal corticosteroids compared with A single course of prenatal corticosteroids compared with placebo has not been shown to be effective in babies who placebo has not been shown to be effective in babies who are born more than seven days after treatment are born more than seven days after treatment

The Prenatal Repeat Corticosteroid International IPD Study The Prenatal Repeat Corticosteroid International IPD Study Group: assessing the effects using the best level of Group: assessing the effects using the best level of Evidence (PRECISE) Group will conduct an IPD meta-Evidence (PRECISE) Group will conduct an IPD meta-analysis. analysis.

The PRECISE International Collaborative Group was formed The PRECISE International Collaborative Group was formed in 2010 and data collection commenced in 2011. in 2010 and data collection commenced in 2011.

Eleven trials with up to 5,000 women and 6,000 infants are Eleven trials with up to 5,000 women and 6,000 infants are eligible for the PRECISE IPD meta-analysis. eligible for the PRECISE IPD meta-analysis.

The primary study outcomes for the infants will be: The primary study outcomes for the infants will be: serious neonatal outcome (death, severe respiratory disease; serious neonatal outcome (death, severe respiratory disease;

severe intraventricular haemorrhage (grade 3 and 4); severe intraventricular haemorrhage (grade 3 and 4); chronic lung disease; necrotising enterocolitis; serious chronic lung disease; necrotising enterocolitis; serious retinopathy of prematurity; and cystic periventricular retinopathy of prematurity; and cystic periventricular leukomalacia); leukomalacia);

use of respiratory support (defined as mechanical ventilation use of respiratory support (defined as mechanical ventilation or continuous positive airways pressure or other respiratory or continuous positive airways pressure or other respiratory support);support);

and birth weight (Z-scores).and birth weight (Z-scores).

For the children, the primary study outcomes will be For the children, the primary study outcomes will be death or death or any neurological disability (developmental delay or any neurological disability (developmental delay or

intellectual impairment intellectual impairment cerebral palsycerebral palsy blindness blindness deafness deafness For the women, the primary outcome will be For the women, the primary outcome will be maternal sepsis (defined as chorioamnionitis; maternal sepsis (defined as chorioamnionitis;

pyrexia after trial entry requiring the use of pyrexia after trial entry requiring the use of antibiotics; puerperal sepsis; intrapartum fever antibiotics; puerperal sepsis; intrapartum fever requiring the use of antibiotics; or postnatal requiring the use of antibiotics; or postnatal pyrexia).pyrexia).

Choice of AgentChoice of Agent

Drug and doseDrug and dose — Two regimens of antenatal  — Two regimens of antenatal glucocorticoid treatment have evolved and are glucocorticoid treatment have evolved and are effective for accelerating fetal lung maturity:effective for accelerating fetal lung maturity:

Betamethasone (two doses of 12 mg given Betamethasone (two doses of 12 mg given intramuscularly 24 hours apart)intramuscularly 24 hours apart)

Dexamethasone (four doses of 6 mg given Dexamethasone (four doses of 6 mg given intramuscularly 12 hours apart).intramuscularly 12 hours apart).

Higher or more frequent doses do NOT increase Higher or more frequent doses do NOT increase the benefits of antenatal glucocorticoid the benefits of antenatal glucocorticoid therapy and may increase the likelihood of therapy and may increase the likelihood of adverse effects adverse effects 

Reduction of IVH, NEC, NNM, Reduction of IVH, NEC, NNM, infectioninfection — (RR 0.4-0.6) — (RR 0.4-0.6)

Multiple Gestations: Blood levels of Multiple Gestations: Blood levels of bethametasone similarbethametasone similar

Several larger cohort and case control studie Several larger cohort and case control studie suggested use of dexamethasone was neurotoxic suggested use of dexamethasone was neurotoxic and associated with adverse neurologic outcomes and associated with adverse neurologic outcomes compared to use of betamethasone or no antenatal compared to use of betamethasone or no antenatal glucocorticoid glucocorticoid

Postnatal use of dexamethasone in premature Postnatal use of dexamethasone in premature infants was associated with shorter stature, smaller infants was associated with shorter stature, smaller head circumference, poorer motor skills and head circumference, poorer motor skills and coordination, lower IQ scores, and an increased coordination, lower IQ scores, and an increased frequency of clinically significant disabilities in frequency of clinically significant disabilities in survivors survivors

Sulfating agents in dexamethasone may be Sulfating agents in dexamethasone may be neurotoxicneurotoxic

?Insulin Resistance?Insulin Resistance

Evidence from randomized Evidence from randomized trialstrials

Three large, multicenter randomized Three large, multicenter randomized clinical trials of single course versus clinical trials of single course versus multiple courses of antenatal multiple courses of antenatal glucocorticoid therapy have been reported: glucocorticoid therapy have been reported:

1)1) the Maternal Fetal Medicine Units network the Maternal Fetal Medicine Units network (MFMU) trial (MFMU) trial

2)2) Guinn et al multicenter trialGuinn et al multicenter trial3)3) the Australasian Collaborative Trial of the Australasian Collaborative Trial of

Repeat doses of prenatal Steroids Repeat doses of prenatal Steroids (ACTORDS) (ACTORDS)

Systemic ReviewSystemic Review

Neonates exposed to repeat courses of Neonates exposed to repeat courses of glucocorticoids had a reduction in RDS (RR 0.82, glucocorticoids had a reduction in RDS (RR 0.82, 95% CI 0.72-0.93) and were less likely to have 95% CI 0.72-0.93) and were less likely to have severe RDS (RR 0.60, 95% CI 0.48-0.75), severe RDS (RR 0.60, 95% CI 0.48-0.75), particularly those infants delivered at the earliest particularly those infants delivered at the earliest gestational ages (eg, less than 28 weeks of gestational ages (eg, less than 28 weeks of gestation).gestation).

Neonates exposed to repeat courses of Neonates exposed to repeat courses of glucocorticoids were significantly less likely to glucocorticoids were significantly less likely to have serious composite morbidity (RR 0.79, 95% have serious composite morbidity (RR 0.79, 95% CI 0.67-0.93) CI 0.67-0.93)

No difference in maternal sepsisNo difference in maternal sepsis

MACS TrialMACS Trial

This international multicenter placebo-controlled This international multicenter placebo-controlled randomized trial is the largest trial on this issue and randomized trial is the largest trial on this issue and included 1858 women between 25 to 32 weeks of included 1858 women between 25 to 32 weeks of gestation who remained at risk for preterm birth 12 to gestation who remained at risk for preterm birth 12 to 21 days after an initial course of antenatal 21 days after an initial course of antenatal glucocorticoids. glucocorticoids.

Repeat course of glucocorticoids or placebo every 14 Repeat course of glucocorticoids or placebo every 14 days to a maximum gestational age of 33 weeks. days to a maximum gestational age of 33 weeks.

Repeated courses of glucocorticoids after the initial Repeated courses of glucocorticoids after the initial course did not improve neonatal outcome, either course did not improve neonatal outcome, either composite or individual parameters of morbidity, composite or individual parameters of morbidity, compared with placebo; compared with placebo;

Mortality was also similar for both groups. However, Mortality was also similar for both groups. However, neonates who received multiple courses of neonates who received multiple courses of glucocorticoids had significantly lower mean glucocorticoids had significantly lower mean birthweight, length, and head circumference than those birthweight, length, and head circumference than those in the placebo group.in the placebo group.

ACTORDSACTORDS

In the ACTORDS trial, although In the ACTORDS trial, although multiple steroid courses were multiple steroid courses were associated with decreased birth associated with decreased birth weight and head circumference at weight and head circumference at birth, this was no longer true at birth, this was no longer true at discharge, suggesting the potential discharge, suggesting the potential for catch up growth for catch up growth

Salvage (rescue) therapySalvage (rescue) therapy  

Placebo-controlled randomized trial (Garite et al; Placebo-controlled randomized trial (Garite et al; Obstetrix collaborative research network;imopact of Obstetrix collaborative research network;imopact of ‘rescue course’ of antenatal corticosteroids; a ‘rescue course’ of antenatal corticosteroids; a multicenter randomized placebo-controlled trial; Am multicenter randomized placebo-controlled trial; Am J obstet Gynecol 2009; 200;248.e1)J obstet Gynecol 2009; 200;248.e1)

a complete course of betamethasone (two 12 mg a complete course of betamethasone (two 12 mg injections) was offered to women <33 weeks of injections) was offered to women <33 weeks of gestation who were ≥14 days beyond a complete gestation who were ≥14 days beyond a complete course of antenatal glucocorticoids and at risk of course of antenatal glucocorticoids and at risk of delivery within the next 7 days; women with PPROM delivery within the next 7 days; women with PPROM were excludedwere excluded

(n = 437 pregnancies) showed a significant (n = 437 pregnancies) showed a significant reduction in the incidence of RDS (41.4 percent with reduction in the incidence of RDS (41.4 percent with betamethasone versus 61.6 percent with placebo) betamethasone versus 61.6 percent with placebo)

PPROMPPROM

antenatal glucocorticoids for women with antenatal glucocorticoids for women with preterm premature rupture of membranes preterm premature rupture of membranes ((Grade 1AGrade 1A). We give them at 24 to 32 weeks ). We give them at 24 to 32 weeks of gestation in the absence of any clinical signs of gestation in the absence of any clinical signs of chorioamnionitis. of chorioamnionitis.

After 32wks, unless documented lung After 32wks, unless documented lung prematurity, higher risk of choriomanionitis prematurity, higher risk of choriomanionitis negates the potential positive effects of negates the potential positive effects of repeated steroids. repeated steroids.

(RCOG GTG recommends steroids til 34wks)(RCOG GTG recommends steroids til 34wks)

Preterm labor triage algorithm for high risk patientsMonica rincon, Leonardo Pereira; Ambulatory Mangement of Preterm Labor; Clinical Obstetrics and Gynecology Volume 55 ; Sept 2012; Number 3;756-64

CL indicates cervical length by endocervical ultrasound; CX, cervix; CTXs, contractions; fFN, fetal fibronectin; PG, progesterone; PPROM, preterm premature rupture of membrane; PTB, preterm birth; PV, per vagina.

Recurrent preterm labor triage algorithm for patients who Recurrent preterm labor triage algorithm for patients who have received antental corticosteroids. have received antental corticosteroids.

(ACS indicates antenatal corticosteroids; CL, cervical length by endocervical ultrasound; CX, cervix.)

ConclusionsConclusions

1)1) Health policies are important (Europe)Health policies are important (Europe)

2)2) Early Sex Education/Prenatal Counselling essential – Diet, Early Sex Education/Prenatal Counselling essential – Diet, Prenatal periodontal care, instrumentation Prenatal periodontal care, instrumentation

3)3) No evidence for role of: bed rest, prophylactic antibiotics, No evidence for role of: bed rest, prophylactic antibiotics, hydration, uterine activity monitorshydration, uterine activity monitors

4)4) Progesterone may beneficial in prolonging pregnancy, Progesterone may beneficial in prolonging pregnancy, especially in high risk groups, but data inconclusive especially in high risk groups, but data inconclusive

5)5) Role of cervical cerclage – history indicated or u/s indicatedRole of cervical cerclage – history indicated or u/s indicated

6)6) Repeat course of antenal corticosteroids – exact dosage, Repeat course of antenal corticosteroids – exact dosage, timing and long term effects debatabletiming and long term effects debatable

7)7) PPROM – beyond 32wks? PPROM – beyond 32wks?

8)8) Tocolytics – role of MgSo4 in neuroprotection <32wks? Tocolytics – role of MgSo4 in neuroprotection <32wks?

ReferencesReferences

1)1) Jay D Iams, Roberto Romero, Jennifer F Culhane et al; Lancet 2008; Jay D Iams, Roberto Romero, Jennifer F Culhane et al; Lancet 2008; 371:164-175; Primary, Secondary and tertiary interventions to 371:164-175; Primary, Secondary and tertiary interventions to reduce the morbidity and mortality of preterm birth. reduce the morbidity and mortality of preterm birth.

2)2) ACOG Guidelines on antenal corticosteroid use 2012ACOG Guidelines on antenal corticosteroid use 2012

3)3) Greentop guidelinesGreentop guidelines- Cervical CerclageCervical Cerclage- PPROMPPROM- Tocolytics in preterm labourTocolytics in preterm labour

4) 4) Roberts, D, Dalziel, S. Antenatal corticosteroids for accelerating fetal lung Roberts, D, Dalziel, S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006; 3:CD004454.2006; 3:CD004454.

5) Brownfoot, FC, Crowther, CA, Middleton, P. Different corticosteroids and 5) Brownfoot, FC, Crowther, CA, Middleton, P. Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm regimens for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2008; :CD006764.birth. Cochrane Database Syst Rev 2008; :CD006764.

6) Australian & New Zealand Neonatal Network. Report of the Australian and New 6) Australian & New Zealand Neonatal Network. Report of the Australian and New Zealand Neonatal Network 2006. Sydney: ANZNN; 2009Zealand Neonatal Network 2006. Sydney: ANZNN; 2009