Pharmacological Interventions for the Prevention of Fetal Growth Restriction

BMJ Open: first published as 10.1136/bmjopen-2019-029467 on 26 July 2019. Downloaded from PEER REVIEW HISTORY

BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form (http://bmjopen.bmj.com/site/about/resources/checklist.pdf) and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below.

ARTICLE DETAILS

TITLE (PROVISIONAL) Pharmacological interventions for the prevention of foetal growth restriction: protocol for a systematic review and network meta- analysis. AUTHORS Bettiol, Alessandra; Lombardi, Niccolò; Crescioli, Giada; Avagliano, Laura; Mugelli, Alessandro; Ravaldi, Claudia; Vannacci, Alfredo

VERSION 1 – REVIEW

REVIEWER Gordijn SJ University Medical Center Groningen, Groningen, The Netherlands REVIEW RETURNED 17-Feb-2019

GENERAL COMMENTS This is a very useful review that may aid the progression of a therapeutic intervention for FGR.

In the manuscript the distinction between SGA and FGR is not sufficiently addressed. For example in the Methods line 10: do we want to treat SGA? Not in my opinion, we want to treat the fetus at

risk. please look at our Delphi procedure that defined FGR (true http://bmjopen.bmj.com/ fetus at risk Gordijn et al UOG 2016). Furthermore in the methods line 46 birthweight for gestational age? Can a baby be growth restricted (growth restriction in the newborn(GRN)) when delivered with a birthweight above p10? Please specify how to loot at the issue

FGR is not reaching the own growth potential (specify 'own' in L7

Abstract and L 7 introduction) on September 26, 2021 by guest. Protected copyright.

Abstract L8: management is balance between maturation and starvation?

Methods L43: SGA or FGR? L 59 please specify

p9 L27: hypoxia? asphyxia?

Furthermore I would advice to also look at placental lesions (maybe even divide per lesion).. The lesion determines whether a therapy will work or not...

REVIEWER Anna David University College London, UK REVIEW RETURNED 03-Mar-2019

BMJ Open: first published as 10.1136/bmjopen-2019-029467 on 26 July 2019. Downloaded from GENERAL COMMENTS Thank you for asking me to review this protocol. It is a great idea to to do this but it needs more careful thought particularly how the authors plan to assess definition of FGR in the papers they review. The assessment of quality in the studies that are identified will be particularly important. Further definitions are needed before going ahead with the searches.

How is FGR to be defined? Very important that they use a properly accepted definition to assess the validity of papers in the search. For example they could use the definitions put forward by Gordjin in her Delphi consensus paper.

What other causes of FGR will the authors check for exclusion in the search papers? e.g. virus infection, aneuploidy, fetal structural anomaly?

What do the authors mean by clinically diagnosed risk of FGR? Does this mean a clinician thinks they are likely to get it in the papers that come up in the search?

Their primary end point is FGR but perhaps the treatments might not prevent FGR (however they are defining it) but may delay delivery or improve neonatal outcome. The authors need to think more carefully about their outcome measures. Why not gestational age at delivery or delay in delivery.

In terms of interventions they should also consider IGF1 and IGF2 infusion, PDE type 3 inhibitors for FGR. Correction it is hydrogen sulphide not sulphite.

For safety the authors also need to consider fetal Adverse Events as well as maternal and neonatal AEs. MedDRA now has a group of fetal AEs defined specifically for use in clinical trials. The http://bmjopen.bmj.com/ authors may find that many trials or studies have not defined AEs in a satisfactory way but this in itself would be an interesting finding.

VERSION 1 – AUTHOR RESPONSE on September 26, 2021 by guest. Protected copyright.

Reviewer(s)' Comments to Author:

Reviewer: 1 Reviewer Name: Sanne J Gordijn Institution and Country: University Medical Center Groningen, Groningen, The Netherlands Please state any competing interests or state ‘None declared’: none

Please leave your comments for the authors below

This is a very useful review that may aid the progression of a therapeutic intervention for FGR.

BMJ Open: first published as 10.1136/bmjopen-2019-029467 on 26 July 2019. Downloaded from Reviewer #1, Comment 1-In the manuscript the distinction between SGA and FGR is not sufficiently addressed. For example in the Methods line 10: do we want to treat SGA? Not in my opinion, we want to treat the fetus at risk. please look at our Delphi procedure that defined FGR (true fetus at risk Gordijn et al UOG 2016). Furthermore in the methods line 46 birthweight for gestational age? Can a baby be growth restricted (growth restriction in the newborn(GRN)) when delivered with a birthweight above p10? Please specify how to loot at the issue

 Response to Comment 1: We thank the reviewer for this precious comment and for the literature support. We better distinguished the definitions of FGR and SGA in the Introduction, as follow: “Foetal growth restriction (FGR), also known as intrauterine growth restriction (IUGR), includes different conditions in which a foetus fails to reach its own growth potential. For many years, the most common parameter used to measure FGR was small for gestational age (SGA) [1] , although the two terms are not synonymous. Recently, an international clinical consensus was obtained about the definition of FGR [2], therefore works aimed to study the risk of growth-related adverse fetal outcome should focus on true FGR. Namely, SGA is usually defined by a fetal size <10th centile for a population or customized standard [1]. However, this definition includes also a proportion of constitutionally small but health foetuses, while excluding a group of foetuses with biometry >10th percentile but not meeting their own growth potential. On the other hand, the concept of FGR applies only to non-healthy foetuses, that failed to reach their growth potential and thus are at increased risk of adverse outcomes [2]. According to the definition identified through a Delphi consensus procedure [2], early FGR (i.e., at gestational age <32 weeks), in the absence of congenital anomalies, is defined by fetal abdominal circumference (AC)/ estimated fetal weight (EFW)<3rd centile or umbiliac artery(UA) absent end-diastolic flow (AEDF), or by the co-presence of AC (EFW<10th centile and uterine arterly (utA) pulsatility index (PI)>95th centile, alone or in combination with UA- PI>95th centile. On the other hand, late FGR (i.e., at gestational age of 32 weeks of more), is defined, in the absence of congenital anomalies, by AC/EFW<3rd centile or by the co- http://bmjopen.bmj.com/ presence of at least two parameters among i) AC/EFW<10th centile, ii) AC/EFW crossing centiles>2 quartiles on growth centiles, or iii) cerebroplacental ratio (CPR)<5th centile or UA- PI>95th centile.” (page 4)

We also uniformed the use of the word FGR rather than of SGA throughout the manuscript.

on September 26, 2021 by guest. Protected copyright. Reviewer #1, Comment 2- FGR is not reaching the own growth potential (specify 'own' in L7 Abstract and L 7 introduction)

 Response to Comment 2: We corrected the definition of FGR, as suggested: “Foetal growth restriction (FGR) includes different conditions in which a foetus fails to reach the own full growth, […]” (Abstract, page 2, lines 2-3). “Foetal growth restriction (FGR), also known as intrauterine growth restriction (IUGR), includes different conditions in which a foetus fails to reach its own growth potential.” (Introduction, page 4, lines 2-3).

Reviewer #1, Comment 3-Abstract L8: management is balance between maturation and starvation?

 Response to Comment 3: We clarified this sentence, as follow: “The management of FGR is based on the prolongation of pregnancy long enough for foetal organs to mature, while preventing starvation”. (Abstract, page 2, line 4).

BMJ Open: first published as 10.1136/bmjopen-2019-029467 on 26 July 2019. Downloaded from

Reviewer #1, Comment 4: Methods; L43: SGA or FGR?

 Response to Comment 4: We agree with the reviewer in recognizing that the words SGA and FGR were improperly used as synonyms. We revised the manuscript accordingly, and better distinguished between SGA and FGR.

Reviewer #1, Comment 5: L 59 please specify

 Response to Comment 5: As suggested, we specified the included antiplatelet agents, as follow: “Other antiplatelet agents (including ditazole, cloricromen, clopidogrel, ticlopidine, dipyridamole, carbasalate, epoprostenol, indobufen, iloprost, aloxiprin, eptifibatide, tirofiban, triflusal, beraprost, treprostinil, prasugrel, cilostazol, ticagrelor, cangrelor, vorapaxar, and selexipa)” (Page 7). Namely, the term “other” referred to the fact that Acetylsalicylic acid was listed above, thus was not included in this list of antiplatelet agents.

Reviewer #1, Comment 6: p9 L27: hypoxia? asphyxia?

 Response to Comment 6: As suggested, we improved our search strategy by adding these two terms in the list of conditions to be searched (Supplementary Material 1).

Reviewer #1, Comment 57: Furthermore I would advice to also look at placental lesions (maybe even divide per lesion).. The lesion determines whether a therapy will work or not...

 Response to Comment 7: We thank the Reviewer for this suggestion, that we appreciated.

We think that it is methodologically difficult to synthetize the outcome “placental lesions” http://bmjopen.bmj.com/ through a meta-analytic approach, though this outcome is of great clinical worth. Thus, we planned to retrieve all data related to placental lesions from the evaluated studies, and to narratively summarize them in the Results. Accordingly, we revised the “Outcomes” section (“In studies reporting the primary outcome, also data related to placental lesions (i.e., fetal and maternal vascular malperfusion) will be retrieved [18].” (Page 8)), as well as the “Outcomes and prioritization ” section (“Placental characteristics will be considered out of the total number of cases for whom placental evaluation was available, focusing on villous branching abnormalities and maternal decidual arteriopathy.” (Page 12)). on September 26, 2021 by guest. Protected copyright.

Reviewer: 2 Reviewer Name: Anna David Institution and Country: University College London, UK Please state any competing interests or state ‘None declared’: I am a shareholder in Magnus Growth, a company that is aiming to take a therapy for fetal growth restriction into the clinic.

Please leave your comments for the authors below

Reviewer #2, Comment 1: Thank you for asking me to review this protocol. It is a great idea to to do this but it needs more careful thought particularly how the authors plan to assess definition of FGR in

BMJ Open: first published as 10.1136/bmjopen-2019-029467 on 26 July 2019. Downloaded from the papers they review. The assessment of quality in the studies that are identified will be particularly important. Further definitions are needed before going ahead with the searches.

 Response to Comment 1: We fully agree with the reviewer in recognizing the importance of a careful assessment of quality of included studies. To better address this issue, we planned to perform a second sensitivity analysis, limiting the analysis to only high-quality clinical trials. We implemented the section “Subgroup and sensitivity analyses”, accordingly: “If possible, a second sensitivity analysis will be performed including only high-quality clinical trials.” (Page 15).

Concerning the definition of FGR in papers, we better specified that “As the definition of FGR is based on biometric measures not always reported in details in published studies, we will accept the diagnosis of FGR provided by the authors of the studies.” (Section “Outcomes”, page 8)

Reviewer #2, Comment 2: How is FGR to be defined? Very important that they use a properly accepted definition to assess the validity of papers in the search. For example they could use the definitions put forward by Gordjin in her Delphi consensus paper.

 Response to Comment 2: We thank the reviewer for this precious comment and for the literature support. We better distinguished the definitions of FGR and SGA in the Introduction, as follow: “Foetal growth restriction (FGR), also known as intrauterine growth restriction (IUGR), includes different conditions in which a foetus fails to reach its own growth potential. For many years, the most common parameter used to measure FGR was small for gestational age (SGA) [1] , although the two terms are not synonymous. Recently, an

international clinical consensus was obtained about the definition of FGR [2], therefore works http://bmjopen.bmj.com/ aimed to study the risk of growth-related adverse fetal outcome should focus on true FGR. Namely, SGA is usually defined by a fetal size <10th centile for a population or customized standard [1]. However, this definition includes also a proportion of constitutionally small but health foetuses, while excluding a group of foetuses with biometry >10th percentile but not meeting their own growth potential. On the other hand, the concept of FGR applies only to non-healthy foetuses, that failed to reach their growth potential and thus are at increased risk of adverse outcomes [2]. According to the definition identified through a Delphi consensus procedure [2], early FGR on September 26, 2021 by guest. Protected copyright. (i.e., at gestational age <32 weeks), in the absence of congenital anomalies, is defined by fetal abdominal circumference (AC)/ estimated fetal weight (EFW)<3rd centile or umbiliac artery(UA) absent end-diastolic flow (AEDF), or by the co-presence of AC (EFW<10th centile and uterine arterly (utA) pulsatility index (PI)>95th centile, alone or in combination with UA- PI>95th centile. On the other hand, late FGR (i.e., at gestational age of 32 weeks of more), is defined, in the absence of congenital anomalies, by AC/EFW<3rd centile or by the co- presence of at least two parameters among i) AC/EFW<10th centile, ii) AC/EFW crossing centiles>2 quartiles on growth centiles, or iii) cerebroplacental ratio (CPR)<5th centile or UA- PI>95th centile.” (page 4)

Reviewer #2, Comment 3: What other causes of FGR will the authors check for exclusion in the search papers? e.g. virus infection, aneuploidy, fetal structural anomaly?

BMJ Open: first published as 10.1136/bmjopen-2019-029467 on 26 July 2019. Downloaded from  Response to Comment 3: As suggested by the reviewer, we implemented the paragraph “Participants” by revising the Exclusion criteria, as follow: “No restriction on maternal age will be applied. We will exclude studies performed on women with or carrying foetuses with congenital anomalies, including abnormal karyotype and/or genetic anomalies, and malformations. We will also exclude studies on women with intrauterine infections and or with history of drug or alcohol abuse. No other restriction on maternal clinical conditions will be applied.” (page 6-7)

Reviewer #2, Comment 4: What do the authors mean by clinically diagnosed risk of FGR? Does this mean a clinician thinks they are likely to get it in the papers that come up in the search?

 Response to Comment 4: We agree with the reviewer in recognizing that this point was unclear. We improved the Inclusion criteria in the paragraph “Participants”, as follow: “We will include studies performed on gestating women at diagnosed risk of FGR, including [16]: o history of late pregnancy loss or FGR o history of recurrent pregnancy loss (define by 3 or more consecutive first trimester spontaneous abortions) o hypertensive diseases o pre-eclampsia (in the current or previous pregnancies) o diabetes mellitus o congenital cyanotic heart diseases o restrictive pneumopathies o severe renal diseases o autoimmune diseases o hereditary or acquired thrombophilia o severe anaemia http://bmjopen.bmj.com/ Other risk factors for FGR reported by the clinicians as present in the cohort of women in the retrieved studies, will be evaluated case by case for possible inclusion.” (page 6).

Reviewer #2, Comment 5: Their primary end point is FGR but perhaps the treatments might not

prevent FGR (however they are defining it) but may delay delivery or improve neonatal outcome. The on September 26, 2021 by guest. Protected copyright. authors need to think more carefully about their outcome measures. Why not gestational age at delivery or delay in delivery.

 Response to Comment 5: We thank the reviewer for this precious comment, and we fully agree in recognizing that FGR is not an exhaustive outcome to compare the efficacy of the different interventions. However, as the primary objective of this NetMA is to compare the efficacy of different treatments in terms of FGR prevention, we preferred not to modify our primary outcome. However, in order to account also for other outcomes related to the treatment efficacy, we revised the secondary efficacy outcomes, considering preterm birth, foetal and neonatal death, and neonatal complications, as follow: “In studies evaluating the above mentioned primary outcome, also the following secondary efficacy outcomes will be considered (when reported): o Preterm birth, defined as a delivery before completing 37 weeks of gestation. o Foetal or neonatal death, including the events related to early or late pregnancy loss, and perinatal and early neonatal death [17]. o Neonatal complications, including necrotizing enterocolitis (NEC), respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), intraventricular haemorrhage

BMJ Open: first published as 10.1136/bmjopen-2019-029467 on 26 July 2019. Downloaded from (IVH), retinopathy of prematurity (ROP), periventricular leucomalakia (PVL), and other conditions related to the abnormal growth and reported in the considered studies.” (page 8).

On the other hand, we preferred to exclude the previously reported secondary outcomes “pre- eclampsia” and “placental abruption”, thus better focusing on the foetal and neonatal outcomes rather than on the maternal ones.

Reviewer #2, Comment 6: In terms of interventions they should also consider IGF1 and IGF2 infusion, PDE type 3 inhibitors for FGR.

 Response to Comment 6: As suggested, we included also IGF1 and 2 and PDE type 3 inhibitors in the list of evaluated interventions. We implemented the search string, accordingly (see Supplementary Material 1).

Reviewer #2, Comment 7: Correction it is hydrogen sulphide not sulphite.  Response to Comment 7: We corrected the orthographic mistake.

Reviewer #2, Comment 8: For safety the authors also need to consider fetal Adverse Events as well as maternal and neonatal AEs. MedDRA now has a group of fetal AEs defined specifically for use in clinical trials. The authors may find that many trials or studies have not defined AEs in a satisfactory way but this in itself would be an interesting finding.  Response to Comment 8: We thank the reviewer for this comment; as suggested, we included in our definition of safety outcomes also adverse events experienced by foetuses.

http://bmjopen.bmj.com/

VERSION 2 – REVIEW

REVIEWER Gordijn SJ University Medical Center Groningen REVIEW RETURNED 11-Apr-2019

on September 26, 2021 by guest. Protected copyright. GENERAL COMMENTS good luck with this project. Some minor textual issues in the text (umbilical)

REVIEWER Anna David University College London, UK I hold shares in a company that is aiming to develop a treatment for fetal growth restriction REVIEW RETURNED 15-Apr-2019

GENERAL COMMENTS Thank you for asking me to review again. All my comments have been addressed but just two minor issues remain: My comment 3: The authors say that they “will exclude studies performed on women with or carrying foetuses with congenital anomalies, including abnormal karyotype and/or genetic anomalies, and malformations. We will also exclude studies on women with intrauterine infections and or with history of drug or

BMJ Open: first published as 10.1136/bmjopen-2019-029467 on 26 July 2019. Downloaded from alcohol abuse.” Probably they mean that they will include studies where these women have been excluded from analysis.

My comment 5: the authors say they will “exclude the previously reported secondary outcomes “pre-eclampsia” and “placental abruption”, thus better focusing on the foetal and neonatal outcomes rather than on the maternal ones.” There is generally insufficient consideration of maternal outcomes in obstetric drug studies so I would suggest that the authors leave in these maternal outcomes. Indeed I would prefer that they expand them, as maternal health is a primary safety outcome in new drug trials.

VERSION 2 – AUTHOR RESPONSE Reviewer(s)' Comments to Author:

Reviewer: 1 Reviewer Name: Gordijn SJ Institution and Country: University Medical Center Groningen

Please state any competing interests or state ‘None declared’: none declared

Please leave your comments for the authors below

Reviewer #1, Comment 1

Good luck with this project. Some minor textual issues in the text (umbilical). http://bmjopen.bmj.com/

 Response to Comment 1: We revised the text and corrected the orthographical mistakes.

Reviewer: 2 Reviewer Name: Anna David Institution and Country: University College London, UK on September 26, 2021 by guest. Protected copyright. Please state any competing interests or state ‘None declared’: I hold shares in a company that is aiming to develop a treatment for fetal growth restriction.

Please leave your comments for the authors below

Reviewer #2, Comment 1: Thank you for asking me to review again. All my comments have been addressed but just two minor issues remain: My comment 3: The authors say that they “will exclude studies performed on women with or carrying foetuses with congenital anomalies, including abnormal karyotype and/or genetic anomalies, and malformations. We will also exclude studies on women with intrauterine infections and or with history of drug or alcohol abuse.” Probably they mean that they will include studies where these women have been excluded from analysis.

 Response to Comment 1: We agree with the Reviewer in recognizing that this sentence might be misunderstood. In our systematic review and network meta-analysis, we plan to include only studies that did not include women with the above mentioned characteristics (with or carrying foetuses with congenital anomalies, including abnormal karyotype and/or

BMJ Open: first published as 10.1136/bmjopen-2019-029467 on 26 July 2019. Downloaded from genetic anomalies, and malformations; with intrauterine infections and or with history of drug or alcohol abuse). We revised the period to make it clearer and more reader-friendly, as follow: “We will include only studies performed on women without or not carrying foetuses with congenital anomalies, including abnormal karyotype and/or genetic anomalies, and malformations. We will include only studies performed on women without intrauterine infections and or without history of drug or alcohol abuse.”.

Reviewer #2, Comment 2: My comment 5: the authors say they will “exclude the previously reported secondary outcomes “pre-eclampsia” and “placental abruption”, thus better focusing on the foetal and neonatal outcomes rather than on the maternal ones.” There is generally insufficient consideration of maternal outcomes in obstetric drug studies so I would suggest that the authors leave in these maternal outcomes. Indeed, I would prefer that they expand them, as maternal health is a primary safety outcome in new drug trials.

Response to Comment 2: We agree with the Reviewer in recognizing the importance of considering maternal health outcomes, as a relevant issue for choosing the most appropriate therapeutic approach. However, considering that our systematic review and network meta-analysis is primarily focused on fetal and neonatal outcomes, a meta-analytic approach of maternal outcomes falls behind our aims. Nevertheless, given the importance of maternal endpoints in this therapeutic area, we plan to descriptively evaluate all reported maternal adverse events (such as pre-eclampsia and placental abruption). We therefore implemented the “Outcomes” section, as follow: “In addition, in studies reporting the primary outcome, all maternal adverse events (such as pre-eclampsia, placental abruption, exc.) will be evaluated.” (page 9). We also implemented the “Outcomes and prioritisation” section (“Similarly, maternal adverse events (such as pre-eclampsia, placental abruption, exc.) will be the number of women experiencing any event out of the total number of treated patients”. (page 11)), and the “Data synthesis” section (“For http://bmjopen.bmj.com/ safety outcomes, no quantitative synthesis will be performed, and the proportions of each reported adverse event will be described at study level. Similarly, all reported maternal adverse events will be described, and no quantitative analysis will be performed.” (page 12)), accordingly.