7232019 Martinez 2015

httpslidepdfcomreaderfullmartinez-2015 12

REPLY

We particularly appreciate the interest that your authors

showed in our study1 Regarding the clinical relevance of amild signi1047297cant increase of nuchal translucency (NT) in the

treatment group we completely agree and have already

underlined in the article1 that clinicalpractical implicationswere not the objective of our study

Concerning the high grade of statistical difference of NT inthe 1047297rst weeks we have already explained in our article the

possible mechanism of this 1047297nding stating that it is probably

related to an immature fetal cardiac function However thepresence of a difference that is not statistically signi1047297cant does

not mean that the effect on a fetus that is present at 11 weeksrsquo

gestation will be resolved completely later Therefore if wewanted to make a clinical recommendation it would have

regarded discouraging the use of progesterone unless it isreally necessary

Your authors wondered if different routes formulationsand doses of progestin could alter the correct interpretation

of data We have already explained that (in a subanalysis

in which we strati1047297ed our sample according to treatmentroute and dosage) no statistically signi1047297cant differences were

found1

Another of your points concerns the declaration that there

is extensive evidence concerning the lack of in1047298uence of

progesterone on NT in assisted reproductive techniquepregnancies However this issue is still very controversial

within the scienti1047297c community 2 and is the reason that we

decided to exclude the assisted reproductive technique preg-

nancies in the secondary analysis in any case in which thesepregnancies where excluded the statistically signi1047297cant dif-ference remained

We decided not to take into account the indication in

favor of progesterone therapy because there is widespreadevidence that NT size increases during miscarriages but not

during threatened abortions the latter is characterized by an

augmentation of placental blood vessel resistance witha reduction of blood 1047298ow to the embryo that does not

affect the pregnancy outcome if clinically resolved3 We donot agree with the unpublished data of NT multiples of

the median because no adjustment for maternal age or other

confounders was carried out and no information about thegestational age calculation was available Finally twin preg-

nancy is not particularly useful to demonstrate the absence of

any in1047298

uence of progesterone because it is a natural modelrather than iatrogenic as in the case of supplementation

We believe that further research and well-designed studiesare needed to better understand the balances that regulate the

development of the fetus Therefore we are now testing theCYP17A1 gene which regulates progesterone metabolism in

women who have undergone progestin therapy and also the

in1047298uence of this gene on NT size -

Pietro Cignini MD

Claudio Giorlandino MD

ldquoALTAMEDICA rdquo Fetal-Maternal Medical Centre

Department of Prenatal Diagnosis

Rome Italy infopietrocigniniit

Roberto Angioli MD

Alessia Aloisi

Campus Bio Medico University of Rome

Department of Obstetrics and Gynaecology

Rome Italy

The authors report no con1047298ict of interest

REFERENCES

1 Giorlandino C Cignini P Padula F et al Effects of exogenous pro-

gesterone on fetal nuchal translucency an observational prospective

study Am J Obstet Gynecol 2015212335e1-72 Gjerris AC Loft A Pinborg A Christiansen M Tabor A First-trimester

screening markers are altered in pregnancies conceived after IVFICSI

Ultrasound Obstet Gynecol 2009338-17

3 Jaffe R Dorgan A Abramowicz JS Color Doppler imaging of

the uteroplacental circulation in the 1047297rst trimester value in predicting

pregnancy failure or complication AJR Am J Roentgenol 1995164

1255-8

ordf 2015 Elsevier Inc All rights reserved httpdxdoiorg101016jajog

201505036

Vaginal progesterone for maintenance tocolysis a systematicreview and metaanalysis of randomized trials

TO THE EDITORS We commend Suhag et al1 for their

systematic review and metaanalysis of randomized trials onvaginal progesterone for maintenance tocolysis However we

take issue with the included articles and especially about

authorsrsquo conclusions We have published the largest trialon vaginal progesterone in women with preterm labor2

The 4P trial was performed in Switzerland (9 centers) andin Argentina (20 centers) and evaluated 379 women (193

received progesterone and 186 received placebo) Preterm

birth occurred in 425 of women in the progesterone group

vs 355 in the placebo group (relative risk 12 95 con-1047297dence interval 093e15) There were also no differences

about delivery at lt32 and lt34 weeks of gestation and

neonatal morbidity When indicated preterm deliveries wereexcluded there was a higher risk of spontaneous preterm

deliveries in the progesterone group (relative risk 14 95con1047297dence interval 104e188 P frac14 03) In a secondary

analysis of the 4P trial that was presented at Society of

438 American Journal of Obstetrics amp Gynecology SEPTEMBER 2015

Letters to the Editors ajogorg

7232019 Martinez 2015

httpslidepdfcomreaderfullmartinez-2015 22

Maternal Fetal Medicine (San Diego CA 2015) we showedthat in Switzerland as compared with placebo progesterone

use increased the risk for spontaneous delivery within 14 days

and preterm birth at lt37 weeks of gestation3

Suhag et al1 might argue that the 4P trial was not included in

their review because progesterone was given within 24 hours of

the start of acute tocolysis and therefore could not be consid-ered as ldquomaintenancerdquo tocolysis The study medication was

initiated after stabilization of the patient (diminutionarrestof uterine contractions with acute tocolysis) and continued

until 36 weeks of gestation or delivery if it happened beforeThere were only 9 women who delivered within the 1047297rst

48 hours Analysis that included only women who were sta-

bilized for at least 48 hours showed the same result (ie pro-gesterone did not decrease the risk of preterm delivery)24

Reg arding the studies included in the review of Suhag et al1 they were all small (between 52 and 183 cases) and

only 2 were compared with placebo Metaanalysis is of great

help in clinical practice especially when large studies are notavailable The decision to exclude trials should be based on

strict inclusion criteria We do not understand why Suhag

et al decided not to include the largest randomized trial onvaginal progesterone in women with preterm labor to be

published until nowOn the basis of existing literature progesterone should not

be given as maintenance tocolysis in women with preterm

labor Bene1047297ts have not been found and harms have not beenexcluded New large randomized and placebo-controlled

studies will be soon published and will help in drawing

conclusions -

Begontildea Martinez de Tejada MD PhDDepartment of Gynecology and Obstetrics

University of Geneva Hospitals and Faculty of Medicine

University of Geneva

Geneva Switzerland

Begonamartinezdetejadahcugech

Ariel Karolinski MD MSc

Centro de Investigacioacuten en Salud Poblacional-CISAP-(Population

Health Research Centre)

Hospital GA Carlos G Durand

Buenos Aires Argentina

The authors report no con1047298ict of interest BMT reports receiving

lectures fees from Vifor ObsEva and Janssen receiving travel grantsfrom Medinova Besins and Ferring and receiving an unrestricted grant

from Cepheid

REFERENCES

1 Suhag A Saccone G Berghella V Vaginal progesterone for mainte-

nance tocolysis a systematic review and metaanalysis of randomized

trials Am J Obstet Gynecol 2015 [Epub ahead of print]

2 Martinez de Tejada B Karolinski A Ocampo MC et al Prevention of

preterm delivery with vaginal progesterone in women with preterm labour

(4P) randomised double-blind placebo-controlled trial BJOG 2015122

80-91

3 Hermans F Karolinski A Othenin-Girard V et al Population differ-

ences in1047298

uence effectiveness of progesterone in women with threatenedpreterm labor Am J Obstet Gynecol 2015212(suppl)s386

4 Martinez de Tejada B Karolinski A Othenin-Girard V et al Prevention

of preterm delivery with vaginal progesterone in women with arrested

preterm labor secondary analysis of the 4P trial Am J Obstet Gynecol

2014210(suppl)s378

ordf 2015 Elsevier Inc All rights reserved httpdxdoiorg101016jajog

201505037

REPLY

Thank you for the interest in our metaanalysis1 We

congratulate Dr Martinez de Tejada et al2 on their recentpublication on vaginal progesterone for prevention of pre-

term birth (4P trial)

One of the most important aspects of a metaanalysis is theinclusion criteria Strict inclusion criteria are needed to

reduce both clinical and statistical heterogeneity Moreover

the protocol of every metaanalysis should be decided a prioribefore the data extraction and should not be modi1047297ed These

are key elements that are needed to evaluate the reliability of a metaanalysis In 2011 the 1047297rst international prospective

register of systematic reviews (PROSPERO) was launched by

the Centre for Reviews and Dissemination University of York UK All journals should encourage prospective regis-

tration of all planned systematic review protocols because

it helps to promote transparency and safeguards againstpublication bias and duplication of reviews Recently pre-

ferred reporting items for systematic review and meta-analysis guidelines for protocols have also been published3

In our protocol which is registered with PROSPERO

(CRD42014013706) we a priori decided to include all pub-

lished randomized controlled trials (RCTs) of singleton ges-tations that had arrested preterm labor (PTL) and were

randomized to maintenance tocolysis treatment with eithervaginal progesterone or control1

As Martinez de Tejada et al2 knows well we tried our best

to include their trial in our metaanalysis as we can con1047297rm

by the several emails that we exchanged directly with her early in 2015 In their RCT2 vaginal progesterone was given within

48 hours of the start of acute tocolysis and was used as an

additional agent with primary tocolysis not as maintenancetocolysis4 w hich was also pointed out by the Commentary to

their study5 Indeed in their RCT vaginal progesterone ap-

pears to be used for women both who had (perhaps) arrestedPTL and those who did not2 Maintenance tocolysis means

that preterm contractions have resolved at least 48 hourshave elapsed from presentation and steroids have been given

now the patient is being considered for discharge This is not

at all what happened in the 4P RCT The 4P authors did notmention whether the study subjects were assessed for arrestedPTL before randomization and allocation of vaginal proges-

terone vs placebo For these reasons including their RCT

would have been methodologically incorrect which wouldhave compromised the reliability of our metaanalysis on

maintenance tocolysis We had already explained this well in

several emails to Martinez de Tejada who was aware Thereare indeed other RCTs that use progesterone as an additional

SEPTEMBER 2015 American Journal of Obstetrics amp Gynecology 439

ajogorg Letters to the Editors