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CORRECT IDENTIFICATION OF PRETERM LABOUR & pPROM GIAN CARLO Di Renzo, MD, PhD, FACOG, FRCOG, ficog Dept of Obstetrics and Gynecology & Centre of Perinatal and Reproductive Medicine University of Perugia, Perugia Italy

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Page 1: CORRECT IDENTIFICATION OF PRETERM LABOUR & pPROMpgrc.sbmu.ac.ir/uploads/1_prediction ptl prrom.tehran 2016_gerard h.a. visser.pdf · CORRECT IDENTIFICATION OF PRETERM LABOUR & pPROM

CORRECT IDENTIFICATION

OF PRETERM LABOUR &

pPROM

GIAN CARLO Di Renzo, MD, PhD, FACOG, FRCOG, ficogDept of Obstetrics and Gynecology &

Centre of Perinatal and Reproductive Medicine

University of Perugia, Perugia Italy

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Prediction Preterm Labour

and pPROM

Gerard H.A. Visser

University Medical Center

Utrecht

The Netherlands

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Prediction Preterm Labour and PPROM

• Preventive measures • lifestyle

• Cerclage

• Progesteron

• Pessary

• Prevention unnecessary treatment• Hospitalization

• Antibiotics

• Tocolytics

• corticosteroids

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The short cervix at 24 wks

Iams et al NEJM, 1996

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Effect of vaginal progesteron on

preterm birth < 33 wks

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Do we have to screen all women for a

short cervix?

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Do we have to screen all women for a

short cervix?

• 400-600 exams to prevent 1 preterm birth<34

wks (Fonseca 1.7% cervix<15 mm; Hassan 2.3% CL 1-2 cm)

• In low risk patients more exams necessary(Parry & Elovitz Clin O&G, 2014)

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Do we have to screen all women for a

short cervix?

• 400-600 exams to prevent 1 preterm birth<34

wks (Fonseca 1.7% cervix<15 mm; Hassan 2.3% CL 1-2 cm)

• In low risk patients more exams necessary(Parry & Elovitz, Clin O&G, 2014)

• Sweden 0.5% CL <2.5 cm (Kuusela et al, Acta OGS, 2015

• Netherlands 0.8% CL <3 cm (van Os et al, Am J Perinatol, 2015

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Do we have to screen all women for a

short cervix?

• 400-600 exams to prevent 1 preterm birth<34

wks (Fonseca 1.7% cervix<15 mm; Hassan 2.3% CL 1-2 cm)

• In low risk patients more exams necessary(Parry & Elovitz, Clin O&G, 2014)

• Sweden 0.5% CL <2.5 cm (Kuusela et al, Acta OGS, 2015

• Netherlands 0.8% CL <3 cm (van Os et al, Am J Perinatol, 2015

In these countries we should do at least 3 times

as many exams to prevent 1 preterm birth

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Do we have to screen all women for a

short cervix?

• 400-600 exams to prevent 1 preterm birth<34

wks (Fonseca 1.7% cervix<15 mm; Hassan 2.3% CL 1-2 cm)

• In low risk patients more exams necessary(Parry & Elovitz, Clin O&G, 2014)

• Sweden 0.5% CL <2.5 cm (Kuusela et al, Acta OGS, 2015

• Netherlands 0.8% CL <3 cm (van Os et al, Am J Perinatol, 2015

NLs; n=20.234; short cervix PG 2 PTB; control

arm 4 PTB; i.e 5-10.000 exams to present 1 PTB

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Standards of quality and reproducibility

1 of 4 ultrasound images submitted

for certification did not meet

published quality criteriaIams et al, AJOG, 2013

Suhag 2015

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So, are we ready for nationwide

implementation of CL screening?

• Probably not yet

• Alternatives

- previous PT delivery

- all nullip’s or nullip’s with risk factors

- or

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So, are we ready for nationwide

implementation of CL screening?

• Probably not yet

• Alternatives

- previous PT delivery

- all nullip’s or nullip’s with risk factors

- or a ‘risk-based screening’

( previous PTD,Cerv proced, race-ethnicity, smoking. Miller et al O&G, 2015)

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Risk-based screening

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Shortening of the cervix; do

we have to manage/act?

• YES

• Should we screen every pregnant

woman:probably not yet

• Will depend on risk profile, expertise and

ongoing trials (OPPTIMUM)

Thank you

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Prediction Preterm Labour and PPROM

• Preventive measures• lifestyle

• Cerclage

• Progesteron

• Pessary

• Administration of MgSO4

• Prevention unnecessary treatment• Hospitalization

• Antibiotics

• Tocolytics

• corticosteroids

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Unnecessary treatment modalities

• Antibiotics may cause fetal brain damage

• Tocolytics: most cause maternal side-effects

without improving perinatal outcome

• Corticosteroids: poison with some positive

side-effects

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Antenatal CSs in low to middle income countries(Argentina,Guatemala, India, Kenya, Pakistan, Zambia)

Althabe et al, Lancet Febr 14, 2015

• Implementation program of CS in case of threatened

preterm birth versus standard care (n=98.000)

• Proxi for preterm birth: birthweight< 5th centile (36-

37wks)

• Intervention group CS in 45%, in control group 10%

• What will be neonatal outcome in infants weighing <

5th centile?

• What will be the overall perinatal mortality?

• And what about maternal morbidity?

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Antenatal CSs in low to middle income countries(Argentina,Guatemala, India, Kenya, Pakistan, Zambia)

Althabe et al, Lancet Febr 14, 2015

• Implementation program of Cs in case of threatened

preterm birth versus standard care (n=98.000)

• Proxi for preterm birth: birthweight< 5th centile (36-

37wks)

• Intervention group CS in 45%, in control group 10%

• Neonatal mortality (<28d; <5th c group): RR 0.96 (0.87-1.06)

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Antenatal CSs in low to middle income countries(Argentina,Guatemala, India, Kenya, Pakistan, Zambia)

Althabe et al, Lancet Febr 14, 2015

• Implementation program of Cs in case of threatened

preterm birth versus standard care (n=98.000)

• Proxi for preterm birth: birthweight< 5th centile (36-

37wks)

• Intervention group CS in 45%, in control group 10%

• Neonatal mortality (<28d; <5th c group): RR 0.96 (0.87-1.06)

• Total mortality : RR 1.12 (1.02-1.22)

• Maternal infections : RR 1.45 (1.33-1.58)

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Antenatal CSs in low to middle income countries(Argentina,Guatemala, India, Kenya, Pakistan, Zambia)

Althabe et al, Lancet Febr 14, 2015

• 87% of CS were given to infants weighing> 2000-

2500g, where there is no evidence of its usefulness

• With risks of side-effects such as reduced

fetal/placental growth, apoptosis in the brain, CP and

maternal infection, which may explain the overall

poorer outcome

• These data stress the importance of adequate dating of

the pregnancy and of identifying women at real risk

of preterm birth (Visser & DiRenzo, correspondence Lancet, 2015)

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Unnecessary treatment modalities

So, it is essential to restrict threatment to those

women who are less than 34 wks and who are

really going to deliver

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Identification of true Preterm Labour

• Treatment may well be reduced by a better identification of

women who really are at increased risk of preterm delivery (CL

measurement, fibronectin)

• 24-34 wks, preterm contractions n=665, PTD 12%; Van Baaren et al, O&G 2014

n PTD<1wk

• CL >30mm 255 2 0.7%

• CL 15-30mm 297 25 8 %• CL 15-30 FN- 139 4 3 %

• CL 15-30 FN+ 148 21 14 %

• CL < 15 mm 113 53 47 %

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Cervical length (TVUS)

EMG

Maternal BMI

Previous History

Bacterial vaginosis

IL-6

IL-8

IL1

fetal fibronectin (fFN)ferritin

α-fetoprotein

Placental alpha microglobulin-1

(PAMG-1)

human chorionic gonadotropin

prolactin

C-terminal propeptide of

procollagen

pIGFBP-1

Cervix or vagina Amniotic fluidcalgranulins

defensins

IL-6

IL-8

SerumG-CSF

ferritin

defensins

calgranulins

IGF BP-1 fragment

relaxin

Vitamins and micronutrients

CRP, CD163

Salivaoestriol

Prediction of PTB in Symptomatic Women

Biochemical and Biophysical Methods Overview

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PartoSure vs Fetal Fibronectin vs Cervical Length

Nikolova T, Bayev O, Nikolova N, Di Renzo GC. Comparison of a novel test for placental alpha microglobulin-1 with fetal fibronectin and cervical length measurement for the prediction of

imminent spontaneous preterm delivery in patients with threatened preterm labor. J Perinat Med. 2015 Jan 6. [Epub ahead of print]

PartoSure is the single most accurate test when compared to fFN

and CL for prediction of imminent spontaneous delivery in patients

presenting with signs, symptoms, or complaints suggestive of PTL.“

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Unnecessary Admissions

fFN1

32%29%

71%

68%87%

13%

“Admit”Necessary

Unnecessary

“Discharge”

PAMG-11

18%76%

24%

82%96%

4%

“Admit”Necessary

“Discharge”

+

-

+

-

Fetal

Fibronectin

(fFN)

Unnecessary

(1) Di Renzo et al. JPM 2015. (2) Lucovnik et al. AJOG 2013

Average cost of an

unnecessary admission

estimated at $20,372 USD 2

PartoSure may reduce

unnecessary admissions by

up to 80%1

Key Points

That the PartoSure test was found to be statistically superior to fFN and CL with respect to SP and

PPV (P < 0.01) provides evidence toward being able to significantly enhance current practice to

ultimately reduce the unnecessary administration of potentially harmful therapeutics to patients,

as well as reduce the economic burden associated with unnecessary hospital admissions.

“”

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NEW! Study Data (Medway Hospital, NHS Trust, UK)

Test Dates Audited # Pts Observed PPV (%) Patients Admitted % Patients Admitted

Fetal Fibronectin (fFN) Test Jan – April 2015 79 8% 18 23%

PAMG-1 Test May – August 2015 119 50% 16 13%

A retrospective analysis of fetal-fibronectin (fFN) related admissions vs. PartoSure (PAMG-1)

related admissions in a UK birthing center

• 43% reduction in admissions• No pts sent home unnecessarily

Brume D, Harris K, Basu M, & Griffin S. A retrospective cost-benefit analysis: real-world application of the PartoSure test for the prediction of imminent spontaneous delivery in a UK birthing center. Medway Hospital, NHS Trust, UK, 2015. (unpublished)

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PTL: diagnostic algorithmClinical signs of preterm labor:

Contractions of at least 30-40 seconds with at least 8 per hour

CL shortening by 80% or dilatation 1-3 cm

Changes in the cervix during 2 hours of observation

CL < 15 мм

Admission

Steroids

Tocolytics

CL 15-35 мм

PartoSure

(PAMG-1)

Positive (+)

Negative (-)

CL > 35 мм

Observation

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PROM MANAGEMENT OPTIONSA. Antibiotic therapy

A. Intrapartum prophylaxis against early-onset of neonatal GBS infection

B. Antibiotics to prolong latency

B. Antenatal corticosteroidsA. Proven benefit <32 weeks’

gestationB. Unclear benefit 32-34 weeks

(lack of data)

C. Elective Delivery

D. Tocolytics (?) A. No consistent evidence of

prolonged latency

B. No evidence of improved neonatal outcome

C. Significant maternal side-effects

Mercer Obstet Gynecol 2003

Survival by GA at delivery

COCHRANE, 2010

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40-47% of ROM cases are not obvious. These are the cases that diagnostic tests are used on.

Traditional ApproachesTrue Accuracy

Traditional Test SN (%) SP (%)

Ferning 50-63 71-86

Nitrazine (pH) 72-88 64-68

Pooling, AFI, Ferning 85 79

Pooling, AFI, nitrazine 72 98

Traditional Test NPV (%)

Pooling, nitrazine, ferning 55

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“Evaluation of ferning, nitrazine, and/or ultrasound has shown that they add little, if anything, to speculum examination alone and that none of them are as accurate as the test based on biochemical markers. Accordingly, we believe that there is little to merit their use in modern practice.“

Di Renzo et al JMFNM 2011.

Traditional ApproachesClinical Practice Guidelines - EAPM

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Sosa CG, Herrera E, Restrepo JC, Strauss A, Alonso J. Comparison of placental alpha microglobulin-1 in vaginal fluid with intra-amniotic injection of indigo carmine for the diagnosis of rupture of membranes. J Perinat Med. 2014 Sep;42(5):611-6.

Search for an Accurate TestPAMG-1 Indigo Carmine Study

• A prospective multi-site study incl. women reporting signs, symptoms, or complaints suggestive of ROM 21 - 42 weeks of gestation without obvious leakage of fluid from the cervical os during sterile speculum examination and without confirmation of ROM by traditional methods.

• A total of 140 patients were recruited with a prevalence of ROM of 19.3%.• The PAMG-1 immunoassay in vaginal fluid yielded results that were comparable to those of the

instillation of indigo carmine into the amniotic cavity; therefore, we propose that PAMG-1 is a sensitive and specific test to assess ROM in patients with an equivocal diagnosis based on simple tests.

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Search for an Accurate Test – META-ANALYSISAmniSure (PAMG-1) vs IGFBP-1 Tests

Ramsauer B1, Vidaeff AC, Hösli I, Park JS, Strauss A, Khodjaeva Z, de la Cruz ÁA, Martínez-Astorquiza T, Horovitz J, Coatleven F, Helmer H. The diagnosis of rupture of fetal membranes (ROM): a meta-analysis. J Perinat Med. 2013 May;41(3):233-40.

OBJECTIVE: to compare the performance of tests based on the detection of insulin-like growth factor binding protein 1 (IGFBP-1) and placental α-microglobulin-1 (PAMG-1) in diagnosing rupture of fetal membranes (ROM) across different patient populations.

METHODS: A meta-analysis was conducted on 39 prospective observational or cohort studies investigating ROM tests based on the detection of IGFBP-1 and PAMG-1 meeting the following criteria:

1) performance metrics calculated by comparing results to an adequate reference method;

2) sensitivity thresholds of the investigated tests matching those of the currently available tests;

3) study population, as a minimum, included patients between 25 and 37 weeks of gestation.

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Ramsauer B, Duwe W, Schlehe B, Pitts R, Wagner D, Wutkewicz K, Chuvashkin D, Abele H, Lachmann R. Effect of blood on ROM diagnosis accuracy of PAMG-1 and IGFBP-1 detecting rapid tests. J Perinat Med. 2014 Nov 8. [Epub ahead of print]

Search for an Accurate Test AmniSure (PAMG-1) vs IGFBP-1 Tests

in Patients w/ Vaginal Bleeding

OBJECTIVE: In up to 30% of patients presenting with signs and symptoms of a rupture of the fetal membranes (ROM), vaginal bleeding may be present. The presence of blood may lead to false positive results with biochemical markers.

METHODS: Herein data is presented from a multi-centric prospective observational clinical study that for the first time systematically evaluates the performance of PAMG-1 and IGFBP-1 detecting tests in 151 women with vaginal bleedings and signs and symptoms indicative of ROM.

RESULTS: Our data showed a better performance for the PAMG-1 detecting tests compared to the IGFBP-1 detecting tests in all quality parameters evaluated. In detail: Sensitivity is 97.8% (91.0%), Specificity is 91.5% (75.0%), PPV is 94.6% (83.5%) and NPV is 96.4% (85.7%) for PAMG-1 tests (and IGFBP-1 tests, respectively). This difference and also those in Specificity and PPV are statistically significant demonstrating superiority of PAMG-1 detecting tests over IGFBP-1 detecting tests.

“The PAMG-1 detecting test is significantly less susceptible to interference by blood than the IGFBP-1 detecting test.”

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Biomarker Tests SN(%) SP (%)

PAMG-1 94-100 99-100

IGFBP-1 71-81 71-88

Traditional Tests SN(%) SP (%)

Ferning 50-63 71-86

Nitrazine (pH) 72-88 64-68

Pooling, AFI, Ferning 85 79

Pooling, AFI, nitrazine 72 98

Traditional Tests NPV (%)

Pooling, nitrazine, ferning 55

Search for an Accurate Test - SUMMARYBiomarkers vs. Traditional Tests – True Accuracy

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TAKE HOME MESSAGE

• Preterm PROM is one leading cause of preterm birth, and its proper identification is essential

• Biochemical markers are better than the traditional methods, as they are specific to proteins found in amniotic fluid

• The rapid strip test based on PAMG-1 (AmniSure) seems to be a more sensitive bedside test compared with other tests

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- 6 comparative studies 2008-2011

- All arrive at the same conclusionthat PAMG-1 is superior to IGFBP-1

for ROM diagnosis

PAMG-1 vs. IGFBP-1

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Finally some progress as to preterm labour

• The old: -Corticosteroids

-Antibiotics

-Tocolytic drugs

-Cerclage

• The new: -MgSO4

-Progesteron

-Importance of short cervix:

-Cerclage

-Arabin pessary

-Progesteron

-

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Perinatal deaths

Cochrane data base; courtesy of Z.Alfirevic

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Preterm births

<37+0 weeks

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The Arabin pessary

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The Arabin pessary

However, Nicolaides et al: no

beneficial effects of pessary(presented in Marbella, June 2013)

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Progesteron and preterm birth

• Past history of preterm birth:

- 6 trials; 1453 women

- results independent of route of administration

- delivery< 34 wks RR 0.31 (0.14-0.69)

- perinatal mortality RR 0.50 (0.33-0.75)

• Short cervix:

- 2 studies; n=438

- delivery<34 wks RR 0.64 (0.45-0.90)

- delivery< 28 wks RR 0.59 (0.37-0.93) (n=1115)

- vaginal progesteron only?

Dodd et al, Cochrane, 2013

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Progesteron and preterm birth

• Past history of preterm birth:

- 6 trials; 1453 women

- results independent of route of administration

- delivery< 34 wks RR 0.31 (0.14-0.69)

- perinatal mortality RR 0.50 (0.33-0.75)

• Short cervix:

- 2 studies; n=438

- delivery<34 wks RR 0.64 (0.45-0.90)

- delivery< 28 wks RR 0.59 (0.37-0.93) (n=1115)

- vaginal progesteron only?

Dodd et al, Cochrane, 2013

20% of women with a

preterm delivery

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Progesteron and preterm birth

• Past history of preterm birth:

- 6 trials; 1453 women

- results independent of route of administration

- delivery< 34 wks RR 0.31 (0.14-0.69)

- perinatal mortality RR 0.50 (0.33-0.75)

• Short cervix:

- 2 studies; n=438

- delivery<34 wks RR 0.64 (0.45-0.90)

- delivery< 28 wks RR 0.59 (0.37-0.93) (n=1115)

- vaginal progesteron only?

Dodd et al, Cochrane, 2013

20% of women with a

preterm delivery

Do we have to manage/act?

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17 alpha hydroxy PG caproate

Cervix< 25 mm + other risk factors

N=105

Discontinued because of futility ( <34 wks 24-30%;

<32 wks 14-20%)

Winer et al AJOG 2015

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Short cervix: do we have to manage/act?

YES

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Gerard Visser

Poor Prof Antsaklis

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Should preterm labour be

stopped at all?

Gerard H.A. Visser

University Medical Center

Utrecht

The Netherlands

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Magnesium

- Not an effective tocolytic drug

- Blocks voltage dependent Ca2+ channels

- Glutamate N MDA receptor antagonist

extracellular Magnesium

calcium influx into cells is blocked

neural injury will be blocked

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Antenatal magnesium sulfate and

neuroprevention

• 5 RCTs (in 4 neuroprevention was primary aim)

• Meta-analysis:

• RR

• Cerebral Palsy 0.69 (CI 0.54-0.87)

• Motor dysfunction 0.61 (CI 0.44-0.85)

• No effects on mortality or on other neurological

impairments or disabilities in the first years of life

Doyle LW, Current Opinion in Pediatrics 2012;24:154-159

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Effect of magnesium sulfate on

cerebral palsy

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Magnesium sulphate

To prevent one case of moderate/severe CP:

<28 wks, number needed to treat : 30

<32 wks, number needed to treat : 63

Dosage:

4 g i.v. loading dose; 1-2g/h maintenance for 12-24 h*

Maternal side effects:

Vasodilatation

Neuromuscular blocking agent Prevent overdosing

*Guidelines Australian & Canadian COG

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Vogel et al(WHO) Lancet Nov 22, 2014

Use of CSs and tocolytic drugs in 29 low to

middle income countries

Main tocolytic drug: B-mimetics

Toc

21%

CSs

51%

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Tocolytic drugs

Treatment Side effects Positive effects

1 Indomethacin ++++ ++++

2 -agonists +++ ++

3 Calcium channel blockers ++ ++

4 Oxytocin antagonists + ++

Mg-SO4, NO donors do not work

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*Significant difference compared with atosiban

de Heus R, et al. BMJ 2009

Tocolytic drug N Severe Mild

Nifedipine 543 5 (0.9%)* 8 (1.5%)*

-agonists 158 3 (1.9%)* 4 (2.5%)*

Atosiban 576 0 (0%) 1 (0.2%)

Indomethacin 35 0 (0%) 0 (0%)

Side effects observed after a single course

of a tocolytic drug (n=1.333)

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Side effects observed after tocolytics

Treatment Patients (n) Severe* Mild

Single course 1,333 8 (0.6%) 10 (0.8%)

Sequential courses 282 1 (0.4%) 3 (1.1%)

Combined courses 311 5 (1.6%) 1 (0.3%)

*Dyspnoea n=6; hypotension n=4; lung edema n=2; hypoxia n=1; cardiac failure n=1.

de Heus R, et al. BMJ 2009

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Tocolytics and complicated pregnancies

Treatment (%) Atosiban Nifedipine -agonists

Overall distribution 43 40 12

Multiple gestations 50 40 10

Pre-existing CV disease 41 42 10

Diabetes 51 30 16

PIH/PE 43 26 24

Placenta praevia 39 27 25

R.De Heus et al, BMJ, 2009

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Tocolytic drugs

• So, apparently in the Netherlands and Flanders the

underlying maternal condition is not taken into account,

when deciding which tocolytic drug to use

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So…

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So…

• Do not use -agonists anymore

• Do not give combined courses

• Consider giving atosiban

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So…

• Do not use -agonists anymore

• Do not give combined courses

• Consider to give atosiban

• Especially in cases of multiple gestation, diabetes and

maternal cardiovascular problems

– i.e. take the maternal condition into account when deciding

which drug to use

Reassess the role of prostaglandin inhibitors (but not in MC twins)

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Nifedipine versus atosiban; RCT, n=500

• nifedipine atosiban

• Primary outcome (maternal level):

• Prolongation of pregnancy 6 (1-38) 4 (1-30)

(median n days and IQR)

Vliet et al. AJOG 2015 (SMFM; Suppl Jan 2015, S4)

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Nifedipine versus atosiban; RCT, n=500

• nifedipine atosiban RR

• Primary outcome (child level):

• Adverse perinatal outcome 12% 12%

• - perinatal death 5% 2% 2.2 (0.86-5.8)

• - BPD 3% 6%

• - sepsis 3% 1%

• - PVH> grade 2 1% 1%

• - NEC 3% 2%

Vliet et al. AJOG 2015 (SMFM; Suppl Jan 2015, S4)

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Treatment NMulti

gestCVD Inf Diab

Other

tocol

Myocardial infarction 2 2

Acute pulmonary

edema9 5 1 1 2

Severe dyspnoea 8 6 1 4 3

Hypotension, IUFD 1

Hypotension, em CS 18

Atrial fibrillation 1

Calcium channel blockers: Side effects

Case reports: Oei,1999;Hodges,2004;Verhaert,2004;Vaast,2004;Van Geijn,2005;Nassar,2007;Gatault, 2008;Perbet.2008

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Meta analyses on tocolytic drugs

placebo tocolytic

• Birth delay > 48 h 53% 75-93%

• Birth delay> 7 days 39% 61-78%

• With no lengthening of gestation beyond one week

Haas et al, Obstet Gynecol 2009;113:585-594

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Meta analyses on tocolytic drugs

placebo tocolytic

• Birth delay > 48 h 53% 75-93%

• Birth delay> 7 days 39% 61-78%

• And no significant difference in RDS or neonatal survival

(in studies in which corticosteroids were given in both

arms)

Haas et al, Obstet Gynecol 2009;113:585-594

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Meta analyses on tocolytic drugs

• placebo tocolytic

• Birth delay > 48 h 53% 75-93%

• Birth delay> 7 days 39% 61-78%

• No significant difference in RDS or neonatal survival ( in

studies in which corticosteroids were given in both arms)

Haas et al, Obstet Gynecol 2009;113:585-594

RCOG Greentop Guideline, 2010: no tocolytic

drug has been associated with a reduction in

prenatal or neonatal morbidity

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Reason for absence of beneficial effects?

• The majority of preterm labours –with or without intact

membranes- is associated with infections or

inflammation

• And both are related to neurological and respiratory

complications, including PVL and CP

• So, delaying delivery may not prevent neurological

damage, but may even make it worse ( see also Oracle

trial: increased incidence of CP after 7 years in intact

membranes group; Kenyon et al, Lancet 2008)

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Reason for absence of beneficial effects?

• The majority of preterm labours –with or without intact

membranes- is associated with infections or

inflammation

• And both are related to neurological and respiratory

complications, including PVL and CP

• So, delaying delivery may not prevent neurological

damage, but may even make it worse ( see also Oracle

trial: increased incidence of CP after 7 years in intact

membranes group; Kenyon et al, Lancet 2008)

So why don’t we only give a ( rescue) course

of corticosteroids and wait and see

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Reason for absence of beneficial effects?

• The majority of preterm labours –with or without intact

membranes- is associated with infections or

inflammation

• And both are related to neurological and respiratory

complications, including PVL and CP

• So, delaying delivery may not prevent neurological

damage, but may even make it worse ( see also Oracle

trial: increased incidence of CP after 7 years in intact

membranes group; Kenyon et al, Lancet 2008)

Or corticosteroids and MgSO4

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Reason for absence of beneficial effects?

• The majority of preterm labours –with or without intact

membranes- is associated with infections or

inflammation

• And both are related to neurological and respiratory

complications, including PVL and CP

• So, delaying delivery may not prevent neurological

damage, but may even make it worse ( see also Oracle

trial: increased incidence of CP after 7 years in intact

membranes group; Kenyon et al, Lancet 2008)

Or corticosteroids and MgSO4

The more so since MgSO4 works < 2 h*

* See also RCOG opinion paper 29, August 2011

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Anyhow,

• 2 days should be more than enough

• Also for the achievement of proper action of

corticosteroids

• And for in utero transfer to a level 3 hospital

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And what about maintenance tocolytic therapy?

• Oxytocin antagonists, one trial only

• Oral betamimetics, 13 trials

• Ca channel blockers, one trial only ( until 2102)

No effect on incidence of preterm birth or neonatal

morbiditiy

Cochrane databases: Papatsonis et al, 2009; Dodd et al, 2011; Gaunekaret al, 2010

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Nifedipine maintenance, Dutch RCT

• N=406

• Mean age at inclusion: 29.2 wks

• Adverse outcome:

--11.9% placebo

--13.7% nifedipine

Roos et al, JAMA, 2013

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Tocolytic maintenance therapy

• Who is still using oral maintenance therapy?

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Conclusions

• There is no convincing evidence that tocolytics improve

neonatal outcome

• So, if you want to treat, do it only for a short time ( i.e. in

utero transfer) and with a drug that is safe for the mother

• But you may also consider to give corticosteroids and

MgSO4, instead.

• There is no place for tocolytic maintenance therapy

• And should we restrict tocolytics for cases with a

CL>1cm?

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Asymptomatic patients with cervix< 15mm

• Women with intraamniotic inflammation ( AF MMP-

8>23ng/ml have a shorter cervix ( median1.5 mm (0-6.5)

vs 11 mm (4-13)

• And shorter diagnosis-delivery interval

Vaisbuch et al, AJOG 2010; gestational age at diagnosis 19-24 wks

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RCT vaginal progesterone ; women with cervical

length 10-20 mm at 19-24 wks

Hassan et al UOG 2011

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Anyhow

• There is no convincing evidence that tocolytics improve

neonatal evidence

• There is an indication for acute tocolysis during labour, in

case of overstimulation, for intrauterine resuscitation,

and/or to gain time for a CS

However,

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Antenatal corticosteroids

Poison with some positive side effects

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Sir Graham Liggins

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Serendipity

Lambs born preterm were more

viable after antenatal glucocorticoid

administration

(Liggins, 1969)

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Antenatal corticosteroids

1969 – Liggins

1972 – first RCT ( Liggins & Howie)

1994 – 15 RCT

2006 – 21 RCT

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So there is a case to give corticosteroids in women at risk of preterm

delivery between 24 weeks and 34 weeks

Betamethasone is more effective than dexamethasone; but be aware of its

effects on FHR variation and movements

(Roberts and Dalziel, Cochrane, 2006)

1970s 1980s 1990s

RDS 0.55 0.71 0.69

PVH 0.50 0.61 0.53

Neonatal death 0.73 0.98 0.50

Antenatal steroids: RCT’s over the decades

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Retrospective cohort studies

Corticosteroids also work at the threshold of

viability (22-24 weeks)

-Hayes et al, Obstet Gynecol 2008;111: 921-6; data from 1998-2007

-Abbasi et al, Am J Perinat.2010, 27:61-66; data from 1998-2008

-Mantlelow et al, Arch Child Fetal Neonatal Ed 2010, 95: F95-F98; data 1993-2007

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Antenatal corticosteroids

• Reduce inflammation

• Promote surfactant mediated increases in functional

residual capacity

• Induce alveolar thinning

• Increase air special volume

• Increase lung antioxidant capacity

• Accelerate lung fluid reabsorption

Arayama et al 1992, Thibeault et al 1993, Vyas et al 1997, Bolt et al

2001, Halliday et al 2009

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So,

Antenatal corticosteroids improve

outcome

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In 40% of 420 European Centres >3 courses will be given

(Eurail, 2001)

37%

22%

14%

0

20

40

60

80

100

120

140

160

1 2 3 4 5 6 7 8 9 10 11 12 20

Number of courses, Europe 2000

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Crowther and Harding, 5 RCTs

Repeated versus single corticosteroid doses

RR CI

Neonatal lung disease 0.82 0.72–0.93

Severe lung disease 0.60 0.48–0.75

Serious infant morbidity 0.79 0.67–0.93

Cochrane, 2007

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Should steroids be repeated?

Author N Reduction severe/comp morbidity

Total group Early

Guinn 01 502 No Yes <27 weeks

Wapner 06 495 No Yes <32 weeks

Crowther 06 982 Yes <32 weeks

MACS trial 08 2304 No No < 32 weeks

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MACS trial, results

Murphy et al, Lancet 2008

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MACS trial, delivered < 32 weeks

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Side effects multiple courses, at birth

Author N Side effect

Guinn 01 502 weight (ns p=0.10)

Wapner 06 495 weight, <10th centile*

Crowther 06 982 weight, head circumference

*Sadawy 07 93 Placental weight >32 weeks sign ↓

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Direct side effects

MACS, Lancet December 2008

Decreased birth weight and head circumference

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5-year follow up (MACS trial);Asztalos et al AJOG 2013(abstract)

Placebo Repeat

N 855 873

Composite mortality/morbidity 210 217

24.6% 24.9%

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2-year follow up (Crowther et al, NEJM, 2007)

Placebo Repeat

N 526 521

Weight/HC/Bayley – –

Absence major disability 81% 84.4%

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2-year follow up (Wapner et al, NEJM, 2007)

* 5 of 6 cases >3 courses, 5 >32 weeks of gestation

Placebo Repeat

N 236 248

Weight/HC/Bayley – –

CP 1 (0.5%) 6 (2.9%)*

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(data from 19 RCT; Halliday, 2001)

Early neonatal treatment with corticosteroids

• 14 more extubated by 7 days

• 11 less have CLD

• 7 less will die

• 14 avoid late CS treatment

• 6 more have GI bleeding

• 4 more have GI perforation

• 12 have cerebral palsy

• 14 have abnormal

neurological development

at follow-up

For every 100 babies treated…

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0.05–0.20 mg/day for 2 days

0.5 mg/kg/day for many days

Fetal versus neonatal dose

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Potent drugs may have potent side effects

0.05–0.20 mg/day for 2 days

0.5 mg/kg/day for many days

Fetal versus neonatal dose

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Corticosteroids

• Poison with some positive side

effects

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(Noorlander et al, Dev Neurobiol, 2008 and PLoSOne 2013)

Apoptosis in fetal hippocampus following

antenatal corticosteroids in mice

0

50

200

E16

Ap

op

toti

c c

ell

s in

CA

SalineDexamethasone

100

150

250

E18 P0 P5 P10 P20 Adult

0

20

80

E16

Ap

op

toti

c c

ell

s in

DG

40

60

140

E18 P0 P5 P10 P20 Adult

100

120

SalineDexamethasone

** *

*

**

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0

4,000

14,000

Ki-

67 p

osit

ive c

ell

s in

DG

8,000

10,000

20,000

E18 P0 P5 P10 P20 Adult

*

*

** *

18,000

16,000

12,000

6,000

2,000

(Noorlander et al, Dev Neurobiol, 2008 and PLoSOne 2013)

Cell proliferation following antenatal

corticosteroids in mice

SalineDexamethasone

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Apoptosis versus cell proliferation

Noorlander et al, 2013; similar findings pren/neon exposure: Zuloaga et al, 2011; Chun-I Sze et

al, 2013

controls

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Decreased number of proliferating cells in hippocampus after dexamethasone

Molecular analysis

0

100

200

300

400

500

600

Saline Dexamethasone

To

tal n

um

be

r K

i-67

po

sit

ive

ce

lls

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Morris water maze:Hippocampus dependent

learning and memory task

No difference in swimming speed

Behavioural analysis

02468

1012141618

1 2 3 4 5Time (days)

Velo

cit

y (

cm

/sec)

SalineDexamethasone

Camera

Visual Cue

Light

Hidden

Platform

Morris water maze

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*

*

*

Hidden platform

*

*

**

Impaired learning and memory after dexamethasone treatment

0

20

40

60

80

100

1 2 3 4 5

Late

ncy (

se

c)

0

20

40

60

80

100

1 2 3

0

400

800

1,200

1,600

1 2 3 4 5

Time (days)

Dis

tan

ce

sw

um

(cm

)

1 2 3

Visible platform

Behavioural analysis

SalineDexamethasone

SalineDexamethasone

SalineDexamethasone

SalineDexamethasone

Time (days)

Late

ncy (

sec)

0

400

800

1,200

1,600

Dis

tan

ce s

wu

m (

cm

)

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Pericentral areas of fibrosis that extends to portal fields

Saline Dexamethasone

Peripheral analysis: Liver

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Dexamethasone

Peripheral analysis: Heart

Saline

Myocytes → thin layer of collagen, indicating

degeneration of myocytes replaced by fibrous tissue

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Dexamethasone induces precocious

aging and reduced lifespan in mice

Implications for the human…?

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Follow-up after one course of

corticosteroids is reassuring

(McArthur et al, 1990; Smolders – de Haas et al, 1990; Schmand et al 1990;

Dessens et al, 2000; Dalziel et al, 2005 (2x),Karemaker 2006)

• no impairment at the age of 6 (maybe some

impaired visual memory)

. normal behaviour and motor function at 7-10 years

• normal physical and psychological development at

the age of 12 and 20 years

• normal cardiovascular and psychological development at

the age of 30 years (apart from increased insulin resistance)

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Impact of corticosteroids on the density of

large neurons in the human hippocampus

(22 infants, 25–32 weeks, who died <4 days after delivery; Thijsseling et al, PLoSOne 2013)

Density of neurons Antenatal CS No antenatal CS

High (4) 1 6

Moderate (3) 4 3

Moderate/low (2) 6 2

Low (1) 0 0

Total n of neonates 11 11 (p<0.02)

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Again, that was just to remind you, that…

• Corticosteroids are very potent drugs, and…

• Potent drugs may have serious side effects

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Should steroids be repeated?

• Multiple courses of antenatal steroids do not increase or decrease the risk of death or developmental difficulties by 5 y of age.

• Because there is no clear benefit, this approach is not recommended for routine use

• Future research may be warranted for a more specified use of repeated courses

MACS-5; Asztalos et al, AJOG 2013 (abstract)

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However,……WHO recommendations

• Interval Death RDS CVS haemorrhage

• <24 h RR 0.6 RR 0.87

• <48 h RR 0.59 RR 0.67 RR 0.26

• 1-7 d RR 0.81 RR 0.46

• >7 days RR 1.42 RR 0.82*

• * with a 150 g lower birth weight

A.Shennan Florence Sept 10, 2015

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Most importantly

• Use of corticosteroids may well be reduced by a better

identification of women who really are at increased risk

of preterm delivery (CL measurement, fibronectin); Van

Baaren et al O&G 2014

• And by determining fetal lung maturation by

amniocentesis before a planned preterm delivery (CS).

Note: almost 50% of IUGR infants at 32 wks will have

sufficient lung maturation and do not need CSs

• Question: How many of your patients who received

corticosteroids actually delivered preterm? Utrecht area: 34%

delivered < 1 wk; Boesveld et al AJOG, 2014)

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(Derks et al, BJOG,1995) ( Mulder et al, Ped Res 2004)

Betamethasone, FHR variation, F movements

Fetal Heart Rate Variation

Body and Breathing Movements

FHR var, Body moves & Breathing

moves day 2 as compared to day 0

Singleton Twins

FHR var -16 -14 %

Body Move’s -49 -42 %

Breathing Ms -86 -88 %

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Corticosteroids in twins

• Neon death,2 trials n=236 RR 0.79 (0.39-1.61)

• RDS, 4 trials n=320 RR 0.85 (0.60-1.20)

• CVH, 1 trial n=137 RR 0.39 (0.07-2.06)

Roberts & Dalziel, Cochrane, 2006

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Corticosteroids in twins

• Neon death,2 trials n=236 RR 0.79 (0.39-1.61) 0.69

• RDS, 4 trials n=320 RR 0.85 (0.60-1.20) 0.66

• CVH, 1 trial n=137 RR 0.39 (0.07-2.06) 0.28

Roberts & Dalziel, Cochrane, 2006

RRs more or less similar to those of overall analysis, though

small numbers meant the CIs were wide and crossed one

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SGA, normal Doppler ua

Torrance et al. 2009

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SGA, abnormal Doppler ua

Torrance et al. 2009

100 280 1.18 1.0 1.48

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2015

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2015

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Sir Graham Liggins

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And don’t forget:

• Women want to be treated

• And doctors want to treat

• but……………………..

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And don’t forget:

• Women want to be treated

• And doctors want to treat

• but……………………..

• Doctors should know better

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Thank you

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A myth ??

• Kenyon & Peebles 2x

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Finally some progress as to preterm labour

• The old:

-Corticosteroids

-Antibiotics?

-Tocolytic drugs?

-Cerclage?

• The new:-Importance of the short cervix

-Progesteron

-Arabin pessary

-MgSO4

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Summary of Studies on PAMG-1

Study Year N PPV (%) NPV (%)

Nikolova et al.1 2014 101 78% 97%

Nikolova et al.2 2015 203 76% 96%

Lotfi et al.3 2015 150 75% 98%

Heverhagen et al.4 2015 64 100% 94%

Bolotskih et al.5 2015 49 75% 100%

Van Holsbeke et al.6 2015 35 75% 94%

1. Nikolova et al. J Perinat Med. 2014 Jul;42(4):473-7.

2. Nikolova et al. J Perinat Med. 2015 Jan 6.

3. Lotfi et al. World Congress of Perinatal Medicine (WCPM). 2015 (submitted abstract).

PAMG-1 has demonstrated a high negative predictive value (NPV) and a positive predictive

value (PPV) across studies and geographies

Prediction of del ≤ 7 days in tPTL pts

4. Heverhagen et al. Swiss Society of Obstetrics and Gynecology Annual Congress. 2015 (abstract).

5. Bolotskikh et al. Scientific and Practical Journal of Obs and Gyn Russian Fed. 2015; 2:94-98.

6. Van Holsbeke et al. World Congress of Perinatal Medicine (WCPM). 2015 (submitted abstract).

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Because of inaccessibility of the gold standard that is essential to diagnose unknown/questionable PROM cases

IS INDIGO CARMINE STUDY AN UNREALISTICREFERENCE METHOD FOR A PROM STUDY?

Why would anyone conduct a ROM study on aknown/irrelevant population??

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