S TAGE-BAS ED RES TRICTION
AP P ROACH
TO
THE
MANAGEMENT
OF
FETAL
GROWTH
Francesc Figueras, MD; Eduard Gratacos, MD
Barcelona Center of Maternal-Fetal Medicine and Neonatology (Hospital Clinic and Hospital Sant Joan de Deu), IDIBAPS, University of Barcelona, and Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain
Ad d re s s c o rre s p o n d e n c e to: Eduard Gratacós and Francesc Figueras Maternal-Fetal Medicine Department Hospital Clinic, University of Barcelona Sabino de Arana 1, 08028 Barcelona Spain Telephone: +34 93 227 5600 Fax: +34 (0) 93 227 5605 E-mail: [email protected] S h o rt title: Update on FGR Acknowledgements: the authors express their gratitude to Cerebra Foundation for the Brain Injured Child (Carmarthen, Wales, UK), and Obra Social “la Caixa” (Barcelona, Spain) for the continuous support to our research, which was essential togenerate part of the data here discussed.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/pd.4412 This article is protected by copyright. All rights reserved.
Wh a t's a lre a d y kn own a b o u t this to p ic ? FGR is a m o n g th e o b s te tric a l e n titie s with the g re a te s t va ria tio n in c linic a l p ra ctice, d u e to a c o m bin a tio n o f th e lac k o f s tro n g evid e n c e , th e c o m ple xity o f th e va ria b les re q u ire d for a s s e s s ing fe ta l d e terio ratio n, a n d th e va ria b le ris ks a s s o c ia te d with p re m a turity a t d iffe re nt g e s tatio n al a g e s . Wh a t d o es this s tu d y a d d ? We p ro p o s e a p roto co l th at inte g ra tes c u rre n t e vid e n c e to c la s s ify s ta g e s o f fe tal d e te riora tio n , a n d e s tab lis h e s fo llow-u p inte rva ls a n d o p tim al d e live ry tim in g s , wh ic h m a y fa c ilita te d e c is io n -m a kin g a n d m inim ize va ria b ility in th e c lin ic al m a n a g e m e nt.
This article is protected by copyright. All rights reserved.
ABS TRACT FGR is among the obstetrical entities with the greatest variation in clinical practice. The first clinically relevant step in the management of fetal growth restriction (FGR) is the distinction of “true” FGR, associated with signs of abnormal feto-placental function and poorer perinatal outcome, from small-for-gestational age (SGA) fetuses, which do not present abnormal Doppler and have near normal perinatal outcome. Such distinction should not be only relied on umbilical artery Doppler, since this parameter identifies only severe, early-onset, forms of placental insufficiency. Instead, FGR should be diagnosed in the presence of any of the factors associated with a poorer perinatal outcome, including Doppler cerebroplacental ratio, uterine artery Doppler, a growth centile below the 3rd centile. Upon diagnosis, differentiating into early-onset and late-onset FGR is useful to distinguish two clear phenotypes, with differences in severity, association with preeclampsia, and sequence of fetal deterioration. Finally, management of FGR aims at an optimal balance between minimizing fetal injury or death versus the risks of iatrogenic preterm delivery. We propose a protocol that integrates current evidence to classify stages of fetal deterioration, and establishes follow-up intervals and optimal delivery timings, which may facilitate decision-making and minimize variability in the clinical management.
This article is protected by copyright. All rights reserved.
INTRODUCTION FGR is probably among the obstetrical entities with the greatest variation in clinical practice, in terms of monitoring and recommended gestational age at delivery. This results from a combination of the lack of strong supportive evidence, the complexity of the variables and indices that need to be integrated for assessing fetal deterioration, and the variable risks associated with prematurity at different gestational ages. The first aim in the clinical management of FGR should be to distinguish “true” FGR from constitutional small for gestational age (SGA) fetuses. Once FGR is identified, the second aim should be to ascertain whether there is risk of in utero fetal injury or death. Thus, a first step is to identify within the small fetuses the subset of FGR, because they will have an increased risk of adverse outcome and stillbirth and should be delivered once term is reached. A second step is to identify the presence of any sign suggesting that there is risk of fetal injury or death that may recommend delivery before term. While strong evidence to support firm recommendations for any of these two aims is lacking, a protocol that integrates the best available evidence can help reducing substantially clinical practice variation. In this review we analyze current evidence and suggest a systematic approach to FGR, which entails a proper identification of FGR versus SGA, and a stage-based management protocol which may help reducing clinical variability.
THE IDENTIFICATION OF “FETAL GROWTH “(CONS TITUTIONAL) S MALL FOR GES TATIONAL AGE”
RES TRICTION”
VERS US
Clinical evidence shows that there are, at least, two groups of small fetuses, normally referred to as FGR versus constitutional SGA, also defined as just SGA. FGR is associated with poorer perinatal outcome, abnormal Doppler suggesting fetal adaptation to undernutrition/hypoxia, signs of placental disease and higher risk of preeclampsia. SGA fetuses do not present the above changes and display perinatal outcomes similar to those of normally grown fetuses. It is unknown whether these late-onset SGA fetuses are truly “constitutionally small” or they represent another form of fetal abnormal smallness. However, the distinction between FGR versus SGA is clinically relevant because of the wide consensus that it is reasonable to deliver electively FGR earlier, whereas elective delivery before term offers no benefit in SGA. The diagnosis of FGR is currently performed by means of a combination of Doppler and estimated fetal weight. For 20 years, the Doppler index widely used to distinguish FGR from SGA was abnormal umbilical artery (UA) Doppler. However, UA identifies severe placental disease but fails to pick up instances of mild placental disease, which in reality constitute the majority of cases of FGR [1]. Thus, UA Doppler should always be used in combination integrated in the cerebroplacental ratio (CPR). CPR is calculated by dividing the middle cerebral artery (MCA) Doppler pulsatility index (PI) by the UA Doppler PI. This index correlates better with adverse outcome than UA Doppler alone [2]. Aside from CPR, both the uterine artery Doppler PI (UtA PI) [3, 4] and a very low EFW (6 and 11% in those withBPP>8 [38]. A meta-analysis [39] showed no significant benefit of biophysical profile in high-risk pregnancies. Consequently, whenever Doppler expertise and/or cCTG are available, the incorporation of BPP in management protocols of FGR is questionable.
This article is protected by copyright. All rights reserved.
4.2 EVIDENCES ABOUT TIMING OF DELIVERY IN FGR No treatment has been demonstrated to be of benefit in growth restriction [40-44]. Thus, assessment of fetal well-being and timely delivery remain as the main management strategy. The Growth Restriction Intervention Trial (GRIT) study[13] was a multicentre randomized controlled trial including 548 pregnancies with fetal compromise between 24 and 36 weeks, aimed to compare the effect of delivering early with delaying birth for as long as possible. The study observed that when obstetricians were uncertain about timing of delivery based on umbilical artery Doppler, they were prepared to vary the timing by about 4 days, and although such delay caused some stillbirths, earlier delivery resulted in an almost equal number of additional deaths. Thus, incorporation of UA Doppler allowed delay of delivery by an average of 4 days, at a price of an increased risk of stillbirth, whereas delivery at diagnosis minimized stillbirths at a price of increased risk of neonatal death. Moreover, at 2 years of age, there was a trend towards more disability in the immediate delivery group [12]. One randomized equivalence trial compared the effect of induction of labor or expectant monitoring in women after 37 weeks of gestation with suspected SGA. They found negligible differences in perinatal and neonatal outcomes between induction of labor and expectant monitoring [18, 19]. At two years of age no differences between both strategies were found [45]. Being true that no strategy was found to be preferable, labor induction after 37 weeks has been introduced into many clinical guidelines, under the rationale to prevent those rare but devastating instances of stillbirth. It should also be acknowledged that further studies differentiating true FGR from other causes of SGA not associated with poor perinatal outcome are required. 4.3. A S TAGE-BAS ED P ROTOCOL FOR MANAGING FGR While strong evidence is lacking to support firm recommendations on the timing of delivery, a protocol that integrates the best available evidence can help reducing clinical practice variation. One approach is to group in stages those indices or signs that are associated with similar fetal risks, since they should indicate similar follow up intervals and timing of delivery. Thus, based on the available evidence from the literatura, we suggest to profile several stages, or prognostic groups, which define different management strategies. SGA: Fortnightly Doppler and growth assessment is safe [46] and constitutes standard practice. Labor induction should be recommended at 40 weeks. Stage I FGR [severe smallness or mild placental insufficiency]: Uterine artery, UA or MCA Doppler, or the CPR are abnormal. Available evidence suggests a low risk of fetal deterioration before term. Labor induction beyond 37 weeks is acceptable, but the risk of intrapartum fetal distress is increased [17]. Stage II FGR [severe placental insufficiency]: This stage is defined by UA AEDV (and also probably by reverse AoI). Delivery should be recommended after 34 weeks. The risk of emergent caesarean section at labor induction exceeds 50%, and, therefore, elective caesarean section is a reasonable option. Monitoring twice a week until then
This article is protected by copyright. All rights reserved.
is recommended. Stage III FGR [advanced fetal deterioration, low-suspicion signs of fetal acidosis]: The stage is defined by reverse diastolic flow in the UA (REDV) or DV-PI>95th centile. There is an association with a higher risk of stillbirth and poorer neurological outcome. However, since signs suggesting a very high risk of stillbirth within days are not present yet, it seems reasonable to delay elective delivery to reduce as possible the effects of severe prematurity. We suggest delivery should be recommended by cesarean section after 30 weeks. Monitoring every 24-48 is recommended. Stage IV FGR [high-suspicion of fetal acidosis and high risk of fetal death]: There are spontaneous FHR decelerations, reduced short term variability (
AP P ROACH
TO
THE
MANAGEMENT
OF
FETAL
GROWTH
Francesc Figueras, MD; Eduard Gratacos, MD
Barcelona Center of Maternal-Fetal Medicine and Neonatology (Hospital Clinic and Hospital Sant Joan de Deu), IDIBAPS, University of Barcelona, and Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain
Ad d re s s c o rre s p o n d e n c e to: Eduard Gratacós and Francesc Figueras Maternal-Fetal Medicine Department Hospital Clinic, University of Barcelona Sabino de Arana 1, 08028 Barcelona Spain Telephone: +34 93 227 5600 Fax: +34 (0) 93 227 5605 E-mail: [email protected] S h o rt title: Update on FGR Acknowledgements: the authors express their gratitude to Cerebra Foundation for the Brain Injured Child (Carmarthen, Wales, UK), and Obra Social “la Caixa” (Barcelona, Spain) for the continuous support to our research, which was essential togenerate part of the data here discussed.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/pd.4412 This article is protected by copyright. All rights reserved.
Wh a t's a lre a d y kn own a b o u t this to p ic ? FGR is a m o n g th e o b s te tric a l e n titie s with the g re a te s t va ria tio n in c linic a l p ra ctice, d u e to a c o m bin a tio n o f th e lac k o f s tro n g evid e n c e , th e c o m ple xity o f th e va ria b les re q u ire d for a s s e s s ing fe ta l d e terio ratio n, a n d th e va ria b le ris ks a s s o c ia te d with p re m a turity a t d iffe re nt g e s tatio n al a g e s . Wh a t d o es this s tu d y a d d ? We p ro p o s e a p roto co l th at inte g ra tes c u rre n t e vid e n c e to c la s s ify s ta g e s o f fe tal d e te riora tio n , a n d e s tab lis h e s fo llow-u p inte rva ls a n d o p tim al d e live ry tim in g s , wh ic h m a y fa c ilita te d e c is io n -m a kin g a n d m inim ize va ria b ility in th e c lin ic al m a n a g e m e nt.
This article is protected by copyright. All rights reserved.
ABS TRACT FGR is among the obstetrical entities with the greatest variation in clinical practice. The first clinically relevant step in the management of fetal growth restriction (FGR) is the distinction of “true” FGR, associated with signs of abnormal feto-placental function and poorer perinatal outcome, from small-for-gestational age (SGA) fetuses, which do not present abnormal Doppler and have near normal perinatal outcome. Such distinction should not be only relied on umbilical artery Doppler, since this parameter identifies only severe, early-onset, forms of placental insufficiency. Instead, FGR should be diagnosed in the presence of any of the factors associated with a poorer perinatal outcome, including Doppler cerebroplacental ratio, uterine artery Doppler, a growth centile below the 3rd centile. Upon diagnosis, differentiating into early-onset and late-onset FGR is useful to distinguish two clear phenotypes, with differences in severity, association with preeclampsia, and sequence of fetal deterioration. Finally, management of FGR aims at an optimal balance between minimizing fetal injury or death versus the risks of iatrogenic preterm delivery. We propose a protocol that integrates current evidence to classify stages of fetal deterioration, and establishes follow-up intervals and optimal delivery timings, which may facilitate decision-making and minimize variability in the clinical management.
This article is protected by copyright. All rights reserved.
INTRODUCTION FGR is probably among the obstetrical entities with the greatest variation in clinical practice, in terms of monitoring and recommended gestational age at delivery. This results from a combination of the lack of strong supportive evidence, the complexity of the variables and indices that need to be integrated for assessing fetal deterioration, and the variable risks associated with prematurity at different gestational ages. The first aim in the clinical management of FGR should be to distinguish “true” FGR from constitutional small for gestational age (SGA) fetuses. Once FGR is identified, the second aim should be to ascertain whether there is risk of in utero fetal injury or death. Thus, a first step is to identify within the small fetuses the subset of FGR, because they will have an increased risk of adverse outcome and stillbirth and should be delivered once term is reached. A second step is to identify the presence of any sign suggesting that there is risk of fetal injury or death that may recommend delivery before term. While strong evidence to support firm recommendations for any of these two aims is lacking, a protocol that integrates the best available evidence can help reducing substantially clinical practice variation. In this review we analyze current evidence and suggest a systematic approach to FGR, which entails a proper identification of FGR versus SGA, and a stage-based management protocol which may help reducing clinical variability.
THE IDENTIFICATION OF “FETAL GROWTH “(CONS TITUTIONAL) S MALL FOR GES TATIONAL AGE”
RES TRICTION”
VERS US
Clinical evidence shows that there are, at least, two groups of small fetuses, normally referred to as FGR versus constitutional SGA, also defined as just SGA. FGR is associated with poorer perinatal outcome, abnormal Doppler suggesting fetal adaptation to undernutrition/hypoxia, signs of placental disease and higher risk of preeclampsia. SGA fetuses do not present the above changes and display perinatal outcomes similar to those of normally grown fetuses. It is unknown whether these late-onset SGA fetuses are truly “constitutionally small” or they represent another form of fetal abnormal smallness. However, the distinction between FGR versus SGA is clinically relevant because of the wide consensus that it is reasonable to deliver electively FGR earlier, whereas elective delivery before term offers no benefit in SGA. The diagnosis of FGR is currently performed by means of a combination of Doppler and estimated fetal weight. For 20 years, the Doppler index widely used to distinguish FGR from SGA was abnormal umbilical artery (UA) Doppler. However, UA identifies severe placental disease but fails to pick up instances of mild placental disease, which in reality constitute the majority of cases of FGR [1]. Thus, UA Doppler should always be used in combination integrated in the cerebroplacental ratio (CPR). CPR is calculated by dividing the middle cerebral artery (MCA) Doppler pulsatility index (PI) by the UA Doppler PI. This index correlates better with adverse outcome than UA Doppler alone [2]. Aside from CPR, both the uterine artery Doppler PI (UtA PI) [3, 4] and a very low EFW (6 and 11% in those withBPP>8 [38]. A meta-analysis [39] showed no significant benefit of biophysical profile in high-risk pregnancies. Consequently, whenever Doppler expertise and/or cCTG are available, the incorporation of BPP in management protocols of FGR is questionable.
This article is protected by copyright. All rights reserved.
4.2 EVIDENCES ABOUT TIMING OF DELIVERY IN FGR No treatment has been demonstrated to be of benefit in growth restriction [40-44]. Thus, assessment of fetal well-being and timely delivery remain as the main management strategy. The Growth Restriction Intervention Trial (GRIT) study[13] was a multicentre randomized controlled trial including 548 pregnancies with fetal compromise between 24 and 36 weeks, aimed to compare the effect of delivering early with delaying birth for as long as possible. The study observed that when obstetricians were uncertain about timing of delivery based on umbilical artery Doppler, they were prepared to vary the timing by about 4 days, and although such delay caused some stillbirths, earlier delivery resulted in an almost equal number of additional deaths. Thus, incorporation of UA Doppler allowed delay of delivery by an average of 4 days, at a price of an increased risk of stillbirth, whereas delivery at diagnosis minimized stillbirths at a price of increased risk of neonatal death. Moreover, at 2 years of age, there was a trend towards more disability in the immediate delivery group [12]. One randomized equivalence trial compared the effect of induction of labor or expectant monitoring in women after 37 weeks of gestation with suspected SGA. They found negligible differences in perinatal and neonatal outcomes between induction of labor and expectant monitoring [18, 19]. At two years of age no differences between both strategies were found [45]. Being true that no strategy was found to be preferable, labor induction after 37 weeks has been introduced into many clinical guidelines, under the rationale to prevent those rare but devastating instances of stillbirth. It should also be acknowledged that further studies differentiating true FGR from other causes of SGA not associated with poor perinatal outcome are required. 4.3. A S TAGE-BAS ED P ROTOCOL FOR MANAGING FGR While strong evidence is lacking to support firm recommendations on the timing of delivery, a protocol that integrates the best available evidence can help reducing clinical practice variation. One approach is to group in stages those indices or signs that are associated with similar fetal risks, since they should indicate similar follow up intervals and timing of delivery. Thus, based on the available evidence from the literatura, we suggest to profile several stages, or prognostic groups, which define different management strategies. SGA: Fortnightly Doppler and growth assessment is safe [46] and constitutes standard practice. Labor induction should be recommended at 40 weeks. Stage I FGR [severe smallness or mild placental insufficiency]: Uterine artery, UA or MCA Doppler, or the CPR are abnormal. Available evidence suggests a low risk of fetal deterioration before term. Labor induction beyond 37 weeks is acceptable, but the risk of intrapartum fetal distress is increased [17]. Stage II FGR [severe placental insufficiency]: This stage is defined by UA AEDV (and also probably by reverse AoI). Delivery should be recommended after 34 weeks. The risk of emergent caesarean section at labor induction exceeds 50%, and, therefore, elective caesarean section is a reasonable option. Monitoring twice a week until then
This article is protected by copyright. All rights reserved.
is recommended. Stage III FGR [advanced fetal deterioration, low-suspicion signs of fetal acidosis]: The stage is defined by reverse diastolic flow in the UA (REDV) or DV-PI>95th centile. There is an association with a higher risk of stillbirth and poorer neurological outcome. However, since signs suggesting a very high risk of stillbirth within days are not present yet, it seems reasonable to delay elective delivery to reduce as possible the effects of severe prematurity. We suggest delivery should be recommended by cesarean section after 30 weeks. Monitoring every 24-48 is recommended. Stage IV FGR [high-suspicion of fetal acidosis and high risk of fetal death]: There are spontaneous FHR decelerations, reduced short term variability (
