Perinatal Outcomes of Monochorionic Twin Pregnancies with Selective Fetal Growth Restriction According to Umbilical Artery Dopplers and Fetal intervention: a Systematic Review and Meta-analysis

doi:10.21203/rs.3.rs-3783393/v1

Download PDF

Research Article

Perinatal Outcomes of Monochorionic Twin Pregnancies with Selective Fetal Growth Restriction According to Umbilical Artery Dopplers and Fetal intervention: a Systematic Review and Meta-analysis

https://doi.org/10.21203/rs.3.rs-3783393/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Objective

To investigate perinatal outcomes of monochorionic twins complicated by selective fetal growth restriction (sFGR) classified according to umbilical artery (UA) Doppler and type of management including expectant management, fetoscopic laser therapy, and selective reduction of the smaller twin.

Methods

A systematic search was performed in 3 databases until June 2022. The primary outcome was mortality including intrauterine fetal demise (IUFD), neonatal death (NND), and perinatal death (PND), and secondary outcomes were gestational age at birth, birthweight, and neonatal outcomes including survival free from neurological complications (intact survival). Meta-analyses of proportions were used to analyze the extracted data.

Results

27 studies encompassing 354 monochorionic twin pregnancies with type I sFGR, 421 type II sFGR, and 475 type III sFGR were included. In pregnancies with type I sFGR managed expectantly, the smaller twin IUFD occurred in 2% (95% CI 1–6), NND in 2% (95% CI 0–50), while 96% (95% CI 88–99) survived without neurological compromise. In pregnancies with type I sFGR managed with laser, smaller twin IUFD occurred in 12% (95% CI 4–25). In type II sFGR managed expectantly, smaller twin IUFD occurred in 18% (95% CI 1–30), NND in 17% (95% CI 1–26), and 38% (95% CI 22–56) survived without neurological compromise. In pregnancies with type II sFGR managed with laser, smaller twin IUFD occurred in 55% (95% CI 48–63), and 42% (95% CI 3–54) survived without neurological compromise. In type III sFGR managed expectantly, smaller twin IUFD occurred in 16% (95% CI 11–23), NND in 5% (95% CI 3–8), and 62% (95% CI 32–86) survived without neurological compromise. With laser, the smaller twin IUFD occurred in 16% (95% CI 11–23), PND in 63% (95% CI 37–84), and 80% (95% CI 44–97) survived without neurological compromise.

Conclusion

Type I sFGR has low risk of IUFD with expectant management. Type III sFGR had higher morbidity and mortality with laser therapy compared to expectant management. Type II sFGR treated with laser therapy had higher mortality but somehow lower morbidity compared to those managed expectantly, with scarce outcomes data following selective reduction.

monochorionic twin

fetal growth restriction

fetoscopy

laser

systematic review

meta-analysis

Meta-analysis shows that type I selective fetal growth restriction (sFGR) is characterized by good perinatal outcomes with expectant management, which represents the most reasonable management strategy for most of these cases. Pregnancies complicated by Type II sFGR treated with fetoscopic laser ablation had higher mortality, but lower morbidity compared to those managed expectantly, supporting the use of fetal therapy at gestations remote from neonatal viability. Type III sFGR had both high morbidity and mortality when managed by laser compared to expectant management although studies investigating laser were very limited. There is scarce data on the outcome following selective reduction.

Selective fetal growth restriction (sFGR) complicates 7–14% of monochorionic (MC) twin pregnancies¹. This pathology is associated with increased morbidity including brain injury and mortality, particularly of the smaller twin². The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) guidelines defines sFGR in MC twin pregnancies when the estimated fetal weight (EFW) of one twin is < 10th centile and EFW discordance is ≥ 25%.³ An expert consensus using the Delphi procedure, aimed at unifying the diagnosis of sFGR, has since been published.⁴

There are few classifications for sFGR in the literature, most commonly used is the one by Gratacos et al. in which it classifies sFGR into three types by type of UA Doppler end-diastolic flow (EDF) in the smaller twin, including type I which is positive EDF, type II which is persistently absent EDF, and type III which is intermittent absent/reversed (IAREDF)⁵.

One particular complication in the risk of sudden demise or profound hypotension in one twin causing death or neurological injury in the co-twin. In a previous systematic review we have reported that the perinatal survival in MC twin pregnancies complicated Type I sFGR is 97%, but survival in types II and III is around 50% and 80%, respectively⁶. Current management options include expectant management or fetal intervention via either fetoscopic laser photocoagulation (FLP) or selective reduction (SR) of the smaller twin. SR favors the outcome of the larger twin⁷, while FLP can achieve survival of both twins in select cases at the cost of a higher risk of mortality of the smaller twin and cerebral injury of the larger co-twin.⁸

The development of standardized diagnostic criteria and national guidance on surveillance protocols has the potential to improve the diagnosis and surveillance of sFGR. The optimal antenatal management of sFGR continues to pose a conundrum. Data on the outcomes of these pregnancies have been recently published including 12 additional eligible studies^9–20 since our last systematic review by Townsend et al 2019.⁶ Therefore, we aimed to systematically update the evidence on the perinatal outcomes, including morbidity and mortality, of these pregnancies classified according to UA Doppler waveform and type of management including FLP, expectant management, and SR.

Our study was designed based on the latest version of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)²¹. The protocol for this study was designed and prepared beforehand and submitted to PROSPERO (Registration code CRD42023427335).

Search strategy

A Systematic search of literature was conducted in three databases Embase, Scopus, and PubMed from 2000 to June 2022. Two co-authors (A.S and D.R) performed the search and the screening process independently and conflicts were resolved by a third senior author (H.J.M). A combination of relevant keywords and MeSH terms was used to create the search strategy: “fetal growth retardation” [MeSH] AND “monochorion”. A detailed summary of the search strategy is available in supplementary materials Table S1.

Eligibility criteria

The eligibility criteria were defined using PICO framework: (P) Population: MC twin pregnancies with sFGR. (I) Intervention: SR, expectant management, or FLP. (C) Comparison: types of sFGR. (O) Outcome: perinatal outcomes. Eligible studies are those that had in their material and methods sFGR classification according to the pattern of UA Dopplers. Studies that included pregnancies with concomitant rather than progression to twin to twin transfusion syndrome (TTTS) were excluded. Congenital anomalies of the fetus, and high-order pregnancies were excluded. Studies with less than three cases, review articles, letters to editors, and studies in non-English language were also excluded.

Data extraction and outcome measures

A standardized sheet was prepared for the data extraction with the following study characteristics: name of the first author, year of study, time, type of sFGR, type of management, number of cases undergoing FLP, expectant management, or SR. The primary outcome was mortality, including intrauterine fetal demise (IUFD) (smaller twin fetal demise, larger twin fetal demise, and single fetal demise referring to either smaller or larger twin), neonatal death (NND), and perinatal death (PND). Secondary outcomes included gestational age (GA) at birth, preterm birth (PTB), admission to neonatal intensive care unit (NICU), respiratory distress syndrome (RDS), retinopathy of prematurity (ROP), neonatal sepsis, periventricular leukomalacia (PVL), interventricular hemorrhage (IVH), and intact survival was defined as survival without neurological injury by 28 days of life.⁶ If data were reported for the smaller and larger twin separately, the outcomes of these twins were also entered into the sheet. Two authors (A.S and D.R) extracted the data based on the study characteristics and any disagreement was resolved through discussion with a third author (H.J.M).

Quality Assessment

Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of included cohort or case control studies and risk of bias. NOS comprises "participant selection”, “comparability of study groups” and “assessment of outcome or exposure". A score above 7 is considered as high quality ²². No studies were excluded based on quality assessment results.

Data synthesis and Statistical Analysis

Meta-analysis of proportions and their corresponding 95% confidence intervals were generated for variables reported in at least 2 studies. The Mantel-Hazel method was used. The median and interquartile range values were converted to mean and standard deviation using the Wan formula.²³ Outcomes were pooled based on the type of sFGR classified according to the pattern of UA EDF (Gratacos classification) and based on management strategy including FLP, expectant management, and SR. Heterogeneity of the included studies was assessed graphically and statistically by Higgins I² test. The weight given to each study was decided according to the inverse variance method to minimize the imprecision of the pooled effect estimate. Owing to the anticipated heterogeneity of included studies, the random effect model was used for pooling the effect sizes and their 95% CI was consequently calculated. To test the overall significance of the random model, z-test was performed. Potential publication bias was graphically assessed by creating funnel plots for each of the groups. R (R Foundation for Statistical Computing, Vienna, Austria) and RStudio (RStudio, Inc., Boston, MA) were used for cleaning the data, statistical analysis, and creating the forest and funnel plots.

Study characteristics

As shown in PRISMA flow chart (Fig. 1), a total of 1688 articles were retrieved from three databases. Of those articles, 654 were excluded for duplication. The remaining 1034 studies were screened for eligibility. Title and abstract screening resulted in 61 potentially eligible studies. After a full-text assessment was performed, total of twenty-seven studies encompassing 3868 MC twin pregnancies complicated by sFGR were included. Among the 3868 MC twin pregnancies included in the present systematic review, 530 were type I, 1105 were type II, and 995 were type III sFGR. Exclusion reasons following full text assessment are outlined in the PRISMA flow chart.

Study characteristics are presented in Table 1. Studies were published between 2004 and 2021. Six studies were from Spain, 4 from Japan, 3 from USA, 2 from each of UK, Brazil, Israel, France, China, Italy, 1 from Russia, and 1 multinational. One study was RCT²⁴ and the rest were cohorts. 7 cohort studies were prospective and 20 were retrospective. Further details regarding inclusion/exclusion criteria, sFGR type, management strategies, and reported outcomes per each study are in Table 1.

Table 1

Study characteristics of the included studies in the systematic review
Author	Year of publication	Study period	Country	Institute	Study design	Inclusion criteria	Exclusion criteria	Total Sample size	sFGR type and sample size	sFGR diagnostic criteria	Management type and sample size	Reported outcomes	NOS score
Shinar³⁴	2020	2008–2019	1. Canada 2. China 3. Belgium 4. The Netherlands 5. Israel 6. Switzerland	Multicentric (9) 1. Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada 2. Shanghai First Maternity and Infant Hospital of Tongji University, Shanghai, China 3. University Hospitals Leuven, Leuven, Belgium 4. Leiden University Medical Center, Leiden, The Netherlands 5. Chaim Sheba Medical Center, Tel Hashomer, Tel Aviv University, Tel Aviv, Israel 6. University of Bern, Bern, Switzerland 7. Lausanne University Hospital, Lausanne, Switzerland 8. Erasmus MC University Medical Center, Rotterdam, The Netherlands 9. Health Sciences Centre, University of Toronto, Toronto ON, Canada	Retrospective	MCDA twin pregnancies complicated by Type-III sFGR	1. Higher-order multiple gestations 2. Pregnancies with major fetal anomalies 3. TTTS, TRAP, TAPS	328	Type III	EFW < 10th centile with EFW discordance > 25th centile	SR in 18 cases, Expectant management in 310 cases	GA, PTB, Birth weight, RDS, ROP, PVL, Neonatal sepsis, IUFD, NND.	7
Monaghan³⁵	2018	2000–2015	United Kingdom	St. George's Hospital, London, UK	Retrospective	MCDA twin pregnancies diagnosed with sFGR between 16 weeks gestation and birth, conducted at the Fetal Medicine Unit at St George's hospital.	Pregnancies complicated by fetal abnormality, aneuploidy, genetic syndromes, or those with missing pregnancy outcome data were excluded from the analysis.	65	Type I and (n = 43), Type II (n = 22)	EFW < 10th centile with EFW discordance > 25th centile	FLP in 14 cases	IIUFD, NND, GA at birth	8
Abellana³⁶	2007	2001–2005	Spain	Multicentric (2) 1. Vall d’Hebron University Hospital, Universitat Autonoma de Barcelona 2. University of Barcelona and Centre for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain	Prospective	MCDA twin pregnancies with sFGR referred in their 2 centers	TTTS	80	Type I and II (n = 40), and III (n = 40)	EFW < 10th centile	SR in 37 cases		8
Aquino³⁷	2021	2010–2018	Brazil	Multicentric (2) 1. Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil 2. Clínica Perinatal, Rio de Janeiro, Brazil	Retrospective	MCDA twin pregnancies with sFGR managed expectantly, delivered between 2010 and 2018 at their 2 referral centers	1. TTTS, except for spontaneous resolution of Quintero I. TAPS, congenital anomalies, aneuploidies, and genetic syndromes diagnosed during prenatal care or after birth. Dual FGR cases and patients delivered in outside institutions were also excluded from the analysis.	75	Type I (n = 67), II (n = 5), and III (n = 3)	EFW of one twin < 3rd centile or in the presence of at least two out of four contributory parameters: EFW < 10th centile, AC < 10th centile, EFW discordance of ≥ 25%, and umbilical artery pulsatility index > 95th centile	Expectant management in 75 cases	PTB, Birthweight, RDS, ROP, Neonatal sepsis, IUFD, NND, PND	8
Batsry³⁸	2021	2012–2018	Israel	The Sheba Medical Center, Tel Hashomer, Israel	Retrospective	MCDA twin pregnancies diagnosed with sFGR before 24 weeks of gestation and managed at a single tertiary referral center.	MCDA twin pregnancies with TTTS or TAPS and pregnancies with fetal anomalies, as well as chromosomal or genetic abnormalities.	148	Type I (n = 29), II (n = 22), and III (n = 9)	EFW < 10th centile with EFW discordance > 25 centile	Expectant Management in 60 cases	PTB, Birthweight, NND, Intact Survival, PND	8
Chmait³⁹	2020	2006–2018	USA	Kech school of medicine, University of southern California, CA	Prospective	MCDA twin pregnancies undergoing fetal treatment for sFGR type II at the center between 2006 and 2018 were studied.		45	Type II	EFW < 10th centile	SR in 9 cases, FLP in 45 cases	Birthweight, IUFD, GA, NND, PND	8
Chon⁴⁰	2019	2006–2017	USA	Keck School of Medicine, University of Southern California, Los Angeles, CA, USA	Retrospective	MCDA twin pregnancies with sFGR type III.	Patients with both twins having EFW < 10th percentile	39	Type II (n = 17) and Type III (n = 22)	EFW < 10th centile	Expectant management in 15 cases, FLP in 1 case	IUFD	8
Colmant⁴¹	2021	2011–2016	France	Hôpital Necker Enfants Malades, AP-HP, Paris, France	Retrospective	MCDA twin pregnancies referred for sFGR with permanent AREDF in the UA, defined as type II and gestational age at diagnosis < 27 weeks	Co-existing TTTS and morphological or chromosomal abnormalities detected prenatally.	346	Type II	EFW < 10th centile or AC < 5th centile	Expectant management in 45 cases, FLP in 13 cases, SR in 50 cases	Birthweight, IUFD, TOP, NND, PND, live birth	7
Cordero⁴²	2015	Unknown (6 years but not specific period)	Spain	Hospital Clinic of Barcelona	Retrospective	MCDA twin pregnancies with sFGR type II or III during a 6-year period at Hospital Clinic of Barcelona.	TTTS or associated abnormalities detected prior to surgery	180	Type II (n = 41) and type III (n = 49)	EFW < 10th centile or AC < 10th centile with EFW discordance > 25 centile	SR in 90 cases	PTB, Birthweight	8
Gratacos⁴³	2004	Unknown (2 years but not specific period)	Spain	Multicentric 1. University Hospital Vall d’Hebron, Barcelona, Spain 2. University Hospital Gasthuisberg, Leuven, Belgium	Prospective	MCDA twin pregnancies with sFGR.	TTTS	146	Type I, II (n = 20), and type III (n = 22)	EFW < 10th centile in one twin	Expectant management in 42 cases	Birthweight, IVH, Abnormal brain imaging findings, IUFD.	7
Gratacos⁵	2007	Unknown (3.5 years but not specific period)	Spain	Multicentric 1. University Hospital Vall d’Hebron, Barcelona, Spain 2. University Hospital Gasthuisberg, Leuven, Belgium	Prospective	MCDA twin pregnancies with sFGR.	TTTS	402	Type I (n = 39), II (n = 30) and III (n = 65)	EFW < 10th centile in one twin	FLP in 134 cases	Birthweight, IVH, abnormal brain imaging findings, IUFD	8
Gratacos⁴⁴	2008	2003–2006	Spain	Multicentric 1. University Hospital Vall d’Hebron, Barcelona, Spain 2. University Hospital Gasthuisberg, Leuven, Belgium 3. Hospital Clinic, University of Barcelona, 4. Hospital Gregorio Marañon 5. Universidad Complutense de Madrid, Madrid	Retrospective	MCDA twin pregnancies with sFGR.	TTTS	294	Type III	EFW < 10th centile in one twin	Expectant management in 31 cases, FLP in 18 cases	Birthweight, IVH, IUFD	7
Ishii⁴⁵	2010	2001–2009	Japan	Multicentric (4) 1. Seirei Hamamatsu General Hospital, Hamamatsu, Japan 2. National Center for Child Health and Development, Tokyo, Japan 3. Nagara Medical Center, Gifu, Japan 4. Perinatal Care Center, Yamaguchi University Hospital, Ube, Japan	Retrospective	MCDA twin pregnancies with sFGR.	TTTS or fetal malformations	606	Type I (n = 31), II (n = 55), and III (n = 15)	EFW < 10th centile in one twin	Expectant management in 101cases	Birthweight, IUFD, NND	7
Ishii⁴⁶	2015	2012–2014	Japan	Multicentric (4) 1. Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan 2. Tokuyama Central Hospital, Shunan, Japan 3. National Center for Child Health and Development, Tokyo, Japan 4. Seirei Hamamatsu General Hospital, Hamamatsu, Japan	Prospective	MCDA twin pregnancies with sFGR.	TTTS or fetal malformations	10	Type II and III	EFW < 10th centile in one twin	FLP in 10 cases	PTB, Birthweight, IVH, PVL, IUFD, TOP, NND, PND, Intact Survival	8
Ishii⁴⁷	2018	2012–2016	Japan	Multicentric (5) 1. Osaka Women’s and Children Hospital, Izumi, Japan 2. National Center for Child Health and Development, Tokyo, Japan 3. Seirei Hamamatsu General Hospital, Hamamatsu, Japan 4. Toho University Omori Medical Center, Tokyo, Japan 5. Kawasaki Medical University, Okayama, Japan	Retrospective	MCDA twin pregnancies with sFGR.	TTTS or fetal malformations	104	Type II (n = 42) and III (n = 10)	EFW < 10th centile in one twin	FLP in 52 cases	PTB, Birthweight, IVH, PVL, IUFD, TOP, NND, PND, Intact survival, Total live birth	8
Koch⁴⁸	2017	2008–2015	France	Multicentric (2) 1. The University Hospitals of Strasbourg (level 2 maternity unit) 2. The Hospital de Hautepierre (level 3 maternity unit)	Retrospective	MCDA twin pregnancies with sFGR.	TTTS or fetal malformations	30	Type I (n = 16), II (n = 9), and III (n = 5)	EFW < 10th centile in one twin	FLP in 5 cases, Expectant management in 16 cases	Birthweight, IUFD, NND, PND	7
Miyadahira⁴⁹	2018	2007–2016	Brazil	São Paulo University (USP) Medical School and at the Heart Hospital, São Paulo, Brazil	Retrospective	MCDA twin pregnancies with sFGR.	TTTS, TAPS, or fetal malformations	67	Type II (n = 36) and III (n = 31)	EFW < 10th centile or AC < 10th centile with EFW discordance > 25th centile	FLP in 30 cases, Expectant management in 28 cases	PTB, Birthweight, IVH, IUFD, NND. PND	8
Peeva⁵⁰	2015	1992–2014	UK	King’s College Hospital, London, UK	Retrospective	MCDA twin pregnancies with type II sFGR.	TTTS	142	Type II	AC < 5th centile and EFW discrepancy > 25th centile or > 22 weeks EFW EFW < 5th centile and EFW discrepancy > 25th centile	FLP in 133 cases	PND	8
Peng⁵¹	2016	2008–2014	China	Hospital of Sun Yat-sen University, Guangzhou, China	Retrospective	Selective reduction that was performed for complicated MCDA twin pregnancies		16	Type I (n = 3), II and III (n = 13)	EFW < 2nd centile in one twin	SR in 4 cases	PND	8
Quintero⁵²	2019	-	USA	"Multicentric (2) 1. Children’s Hospital Los Angeles University Center for Excellence in Developmental Disabilities, University of Southern California, Los Angeles, CA, USA 2. Florida International University, Herbert Wertheim School of Medicine, Miami, FL, USA"	Prospective	MCDA twin pregnancies with type II sFGR.	Major congenital anomalies, families who refused the neurodevelopmental assessment and examination of their children, families unable to complete the measures in English or Spanish, and families who the research team was unable to contact after making reasonable efforts to contact them.	20	Type II	EFW < 10th centile in one twin	FLP in 14 cases, Expectant management in 6 cases	PTD, Birthweight, IVH, IUFD, NND, PND, Intact survival	7
Visentin⁵³	2013	2008–2011	Italy	University of Padua, Padua, Italy	Prospective	MCDA twin pregnancies with sFGR.	TTTS, TAPS, fetal reduction, or demise during pregnancy	14	Type II	EFW < 10th centile in one twin	Expectant management in 21 cases	NICU admission, ROP, IVH, PVL, Neonatal sepsis, IUFD, NND, PND	7
Wang⁵⁴	2017	2011–2015	China	Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021 China	Retrospective	MCDA twin pregnancies undergoing SR		4	Type II	Not specified	SR	Birthweight, IUFD, NND, PND	8
Weisz⁵⁵	2011	2004–2008	Israel	Sheba Medical Center, Tel-Hashomer, Israel	Prospective	MCDA twin pregnancies with sFGR.	TTTS or fetal malformations	37	Type I (n = 19), II and III (n = 18)	EFW < 10th centile in one twin	Expectant management in 37 cases	Birthweight, RDS, PVL, PTB, IVH, Neonatal sepsis, abnormal brain imaging findings, IUFD, PND, NND	8
Rustico⁵⁶	2017	2004–2012	Italy	"The Vittore Buzzi Children’s Hospital, University of Milan in Italy"	Retrospective	MCDA twin pregnancies complicated by sFGR,	TTTS, TAPS	280	Type I (n = 65), II (n = 62) and III (n = 14)	EFW < 10th centile in one twin OR EFW discrepancy > 25th centile	Expectant management in 14o cases	Birthweight, IUFD, NND, PND	8
Sukhwani⁵⁷	2021	2012–2018	Spain	"Fetal Medicine Unit of La Paz Hospital. Medical Faculty of Autónoma University, Madrid, Spain"	Retrospective	MCDA twin pregnancies with sFGR.	TTTS	135	Type I (n = 25), II (n = 5), and III (n = 25)	EFW < 10th centile in one twin and EFW discrepancy > 25th centile	Expectant management in 18 cases, SR in 12 cases	NICU, PVL, PND	7
Ishii⁵⁸	2009	2001–2008	Japan	Multicentric (3) 1. Seirei Hamamatsu General Hospital, Hamamatsu 2. National Nagara Medical Center, Gifu 3. Yamaguchi University Hospital, Ube, Japan	Retrospective	MCDA twin pregnancies with sFGR.	TTTS or fetal malformations	63	Type I (23), II (27), and III (n = 13)	EFW < 10th centile in one twin	Expectant management in 63 cases	IUFD, NND, PND, Intact survival both twins	8
Kostyukov¹⁵	2020	2014–2019	Russia	National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Moscow.	Retrospective	MCDA twin pregnancies with sFGR.	TTTS, TAPS, or fetal malformations	192	Type I (n = 67), II (n = 20), and III (n = 9)	EFW < 10th centile or AC < 10th centile and EFW discrepancy > 25th centile	Expectant management in 96 cases	NICU, ROP, IUFD	8
MCDA: monochorionic diamniotic, sFGR: selective fetal growth restriction, EFW: estimated fetal weight, TTTS: twin-to-twin transfusion syndrome, TAPS: twin anemia polycythemia sequence, TRAP: twin reversed arterial perfusion sequence, FLP: fetoscopic laser photocoagulation, SR: selective reduction, NICU: neonatal intensive care unit, PT: preterm birth, GA: gestational age, IUFD: intrauterine fetal demise, NND: neonatal death, PND: perinatal death, RDS: respiratory distress syndrome, ROP: retinopathy of prematurity, IVH: interventricular hemorrhage, PVL: periventricular leukomalacia

Type I sFGR morbidity and mortality outcomes by type of management

There were 8 studies reporting the outcomes following expectant management while one study reported the outcomes following FLP (Table 2).

Table 2

Pooled proportions of outcomes in type I selective fetal growth restriction according to the management optionType I sFGRTable 2. Pooled proportions of outcomes in type I selective fetal growth restriction according to the management option

	Fetoscopic Laser Coagulation				Expectant Management				Selective Reduction
Variable	Studies (n)	n/N or N	Overall OR (95% CI) or MD (95% CI)	I²	Studies (n)	n/N or N	Overall OR (95% CI) or MD (95% CI)	I²	Studies (n)	n/N or N	Overall OR (95% CI) or MD (95% CI)	I²
GA at Birth	1 ³⁵	3	33.61 (30.21, 37.40)	-	8 ^{15, 37, 38, 48, 55–58}	311	34.17 (33.7, 34.64)	72%	-	-	-	-
Birthweight of Smaller Twin	-	-	-	-	6 ^{15, 37, 48, 55–57}	259	1605.51 (1421.86, 1812.9)	96%	-	-	-	-
Birthweight of Larger Twin					6 ^{15, 37, 48, 55–57}	259	2130.52 (2062.66, 2200.62)	37%
Birthweight Discordance					2^{37, 38}	96	21.17 (14.89, 30.09)	94%
NICU Admission					2 ^{15, 57}	126/168	0.69 (0.4, 0.88)	94%
RDS					2^{37, 55}	5/172	0.03 (0, 0.18)	83%
ROP					3 ^{15, 37}	4/441	0.01 (0, 0.02)	0
Neonatal Sepsis					2 ^{37, 55}	31/172	0.1 (0.02, 0.38)	81%
Single IUFD					4 ^{38, 45, 55, 58}	3/141	0.02 (0.01, 0.06)	0
Single IUFD in Smaller Twin	1³⁵	5/43	0.12 (0.04, 0.25)	-	4^{48, 55, 56, 58}	2/123	0.02 (0, 0.06)	0
Single IUFD in Larger Twin	1 ³⁵	2/43	0.05 (0.01, 0.16)	-	3 ^{48, 55, 58}	1/58	0.02 (0, 0.11)	0
Double IUFD					3^{15, 38, 56}	2/158	0.01 (0, 0.09)	0
NND either Twins	1³⁵	1/43	0.02 (0, 0.12)	-	7^{15, 37, 38, 48, 55, 56, 58}	15/534	0.01 (0, 0.05)	31%
NND Smaller Twin					3 ^{48, 56, 58}	8/103	0.02 (0. 0.52)	0
NND Larger Twin					3 ^{48, 56, 58}	4/103	0.04 (0.01, 0.1)	0
Overall PD					7 ^{37, 38, 48, 55–58}	27/444	0.01 (0, 0.08)	59%
PD Smaller Twin					3 ^{48, 56, 58}	17/104	0.07 (0.01, 0.3)	42%
PD Larger Twin					3^{48, 56, 58}	9/104	0.08 (0.02, 0.26)	0
Intact survival Larger Twin					1 ⁵⁸	22/23	0.96 (0.78, 1)	-
Intact survival Smaller Twin					1 ⁵⁸	21/23	0.91 (0.72, 0.99)	-
Intact survival Both Twins					2 ^{38, 58}	69/72	0.96 (0.88, 0.99)	0
sFGR: selective fetal growth restriction, NICU: neonatal intensive care unit, PT: preterm birth, GA: gestational age, IUFD: intrauterine fetal demise, NND: neonatal death, PND: perinatal death, RDS: respiratory distress syndrome, ROP: retinopathy of prematurity, IVH: interventricular hemorrhage, PVL: periventricular leukomalacia

For those managed expectantly, GA at birth was 34.17 (95% CI 33.7, 34.64) weeks’ gestation, RDS in 3% (95% CI 0, 18), ROP in 1% (95% CI 0, 2), and neonatal sepsis in 1% (95% CI 2, 38).

Single fetal demise, double fetal demise, fetal demise of the smaller twin, and fetal demise of the larger twin were 2% (95% CI 1, 6); 1% (95% CI 0, 9), 2% (95% CI 0, 6), and 2% (95% CI 0, 11), respectively. NND of either twin, of the smaller twin, and of the larger twin were 1%, (95% CI 0, 5); 2% (95% CI 0, 5), and 4% (95% CI 1, 10), respectively. PND of both twins, smaller, and larger twin were 1% (95% CI 0, 8), 7% (9% CI 1, 30), and 8% (9% CI 2, 26), respectively.

Intact survival of both twins, smaller twin, and larger twin were 96% (95% CI 88, 99), 91% (95% CI 72, 99), and 96% (95% CI 78, 100), respectively.

Type II sFGR morbidity and mortality outcomes by type of management

There were 9 studies of FLP, 6 studies of expectant management, and 4 studies of SR (Table 3). GA at birth was comparable between FLP and expectant management at 31.88 (95% CI 30.78, 33.02) and 30.38 (95% CI 29.29, 31.52) weeks, respectively, while it was more advanced in the SR group 35.17 weeks (95% CI 33.38, 37.05). RDS and ROP occurred in 39% (95% CI 25, 56) and 7% (95% CI 3, 15) in expectant management. IVH in both twins or the smaller twin were higher in expectant management (9% (95% CI 3, 23) and 22% (95% CI 6, 58), respectively) compared to the FLP group (1% (95% CI 0, 4) and 6% (95% CI 1, 31), respectively). PVL was 48% (95% CI 29, 68) in those managed expectantly.

Table 3

Pooled proportions of outcomes in type II selective fetal growth restriction according to the management option
Type II sFGR
	Fetoscopic Laser Coagulation				Expectant Management				Selective Reduction
Variable	Studies (n)	n/N or N	Overall OR (95% CI) or MD (95% CI)	I²	Studies (n)	n/N or N	Overall OR (95% CI) or MD (95% CI)	I²	Studies (n)	n/N or N	Overall OR (95% CI) or MD (95% CI)	I²
GA at Birth	6 ^{35, 39, 41, 47, 49, 52}	151	31.88 (30.78, 33.02)	69%	9 ^{15, 37, 38, 40, 41, 49, 56, 58}	270	30.38 (29.29, 31.52)	88%	4 ^{39, 41, 42, 54}	103	35.17 (33.38, 37.05)	88%
Birthweight of Both Twins	1 ⁴⁹	30	1732 (1512.23, 1983.71)	-	1 ⁴⁹	6	1310 (766.32, 2239.42)	-	3 ^{39, 42, 54}	53	2673.15 (2224.61, 3212.14)	69%
Birthweight of Smaller Twin	4 ^{41, 47, 49, 52}	99	928.92 (733.81, 1175.91)	99%	6 ^{15, 37, 41, 49, 52, 56}	144	868.47 (627.14, 1202.66)	96%	2^{39, 41}	59	1758.47 (1228.76, 2516.52)	86%
Birthweight of Larger Twin	4 ^{41, 47, 49, 52}	99	1803.03 (1519.03, 2140.14)	80%	6 ^{15, 37, 41, 49, 52, 56}	144	1556.78 (1174.09, 2064.19)	95%	1³⁹	9	2077 (1636.39, 2636.24)	-
Birthweight Discordance					2 ^{37, 38}	27	32.2 (26.4, 39.53)	44%
NICU Admission					2^{15, 53}	56/63	0.97 (0.25, 1)	0
RDS					2 ^{37, 53}	15/38	0.39 (0.25, 0.56)	0
ROP					3 ^{15, 37, 53}	5/73	0.07 (0.03, 0.15)	0
IVH Both Twins	3 ^{47, 49, 52}	1/153	0.01 (0, 0.04)	0	5 ^{37, 38, 49, 52, 53}	7/76	0.09 (0.03, 0.23)	0
IVH Smaller Twin	2 ^{49, 52}	1/18	0.06 (0.01, 0.31)	0	2 ^{49, 52}	2/9	0.22 (0.06, 0.58)	0
IVH Larger Twin					2 ^{49, 52}	2/7	0.29 (0.07, 0.67)	0
PVL					1⁵³	13/27	0.48 (0.29, 0.68)	-
Neonatal Sepsis					4^{37, 53}	15/66	0.24 (0.04, 0.68)	79%
Single IUFD	4 ^{40, 47, 49, 52}	58/174	0.33 (0.27, 0.41)	0	3 ^{15, 37, 41}	15/120	0.13 (0.08, 0.2)	0
Single IUFD in Smaller Twin	6 ^{35, 39, 41, 47, 49, 52}	92/166	0.55 (0.48, 0.63)	31%	5 ^{41, 49, 52, 56, 58}	25/146	0.18 (0.1, 0.3)	53%
Single IUFD in Larger Twin	6 ^{35, 39, 41, 47, 49, 52}	17/134	0.12 (0.05, 0.24)	80%	4^{41, 49, 52, 58}	10/84	0.09 (0.02, 0.33)	11%	2 ^{41, 42}	6/91	0.07 (0.03, 0.14)	0
Double IUFD					3^{15, 38, 56}	10/104	0.1 (0.05, 0.17)	0
Live Birth Both Twins	2^{41, 47}	63/97	0.65 (0.55, 0.74)	0
Live Birth Smaller Twin	1 ⁴⁷	15/42	0.36 (0.22, 0.52)	-
Live Birth Larger Twin	1⁴⁷	40/42	0.95 (0.84, 0.99)	-
NND Either Twins	6^{35, 39, 41, 47, 49, 52}	15/234	0.05 (0.02, 0.13)	47%	9 ^{15, 37, 38, 41, 49, 52, 53, 56, 58}	41/369	0.1 (0.05, 0.19)	57%	2 ^{39, 54}	1/12	0.08 (0.01, 0.41)	0
NND Smaller Twin					4 ^{49, 52, 56, 58}	15/90	0.17 (0.1, 0.26)	42%
NND Larger Twin	4 ^{39, 47, 49, 52}	4/125	0.03 (0.01, 0.08)	0	4 ^{49, 52, 56, 58}	11/94	0.12 (0.07, 0.2)	14%
Overall PD	6^{39, 41, 47, 49, 50, 52}	273/572	0.49 (0.38, 0.61)	80%	9 ^{37, 38, 41, 49, 52, 53, 56, 58}	112/352	0.23 (0.11, 0.43)	60%	2 ^{41, 54}	60/103	0.58 (0.49, 0.67)	0
PD Smaller Twin	6^{39, 41, 47, 49, 50, 52}	163/286	0.52 (0.22, 0.81)	66%	6^{41, 49, 52, 56, 58}	68/146	0.5 (0.24, 0.76)	74%
PD Larger Twin	6 ^{39, 41, 47, 49, 50, 52}	110/286	0.44 (0.16, 0.77)	91%	6^{41, 49, 52, 56, 58}	41/146	0.28 (0.21, 0.36)	0
Intact Survival Both Twins	2 ^{47, 52}	69/101	0.73 (0.48, 0.88)	70%	3^{38, 52, 58}	48/83	0.67 (0.42, 0.85)	74%
Intact survival Larger Twin	2^{47, 52}	50/54	0.93 (0.82, 0.97)	0	2 ^{52, 58}	20/32	0.74 (0.14, 0.98)	0
Intact survival Smaller Twin	2^{47, 52}	19/46	0.42 (0.3, 0.54)	0	2 ^{52, 58}	11/29	0.38 (0.22, 0.56)	0
sFGR: selective fetal growth restriction, NICU: neonatal intensive care unit, PT: preterm birth, GA: gestational age, IUFD: intrauterine fetal demise, NND: neonatal death, PND: perinatal death, RDS: respiratory distress syndrome, ROP: retinopathy of prematurity, IVH: interventricular hemorrhage, PVL: periventricular leukomalacia

Single fetal demise, demise of smaller, or larger twin were higher in the FLP group (33% (95% CI 27, 41), 55% (95% CI 48, 63), and 12% (95% CI 5, 24), respectively) compared to expectant management (13% (95% CI 8, 20), 18% (95% CI 10, 30), and 9% (95% 2, 33), respectively). Demise of the co-twin in the group undergoing SR was 7% (95% CI 3, 14). Similarly, NND and PND were higher in the FLP group (5% (95% CI 2, 13) and 49% (95% CI 38, 61), respectively) compared to expectant management (1% (95% CI 5, 19) and 23% (95% CI 11, 43), respectively).

Intact survival of both twins or the smaller twin appeared to be somehow higher in the FLP group (73% (95% CI 48, 88) and 42% (95% CI 3, 54), respectively) compared to expectant management (67% (95% CI 42, 85) and 38% (9% CI 22, 56), respectively).

Type III sFGR morbidity and mortality by type of management

There were 3 studies of FLP, 9 studies of expectant management, and 3 studies of SR (Table 4).

Table 4

Pooled proportions of outcomes in type III selective fetal growth restriction according to the management option
Type III sFGR
	Fetoscopic Laser Coagulation				Expectant Management				Selective Reduction
Variable	Studies (n)	n/N or N	Overall OR (95% CI) or MD (95% CI)	I²	Studies (n)	n/N or N	Overall OR (95% CI) or MD (95% CI)	I²	Studies (n)	n/N or N	Overall OR (95% CI) or MD (95% CI)	I²
GA at Birth	3 ^{44, 47, 49}	37	32.11 (30.46, 33.85)	69%	9 ^{15, 34, 37, 38, 43, 44, 49, 56, 58}	432	31.36 (30.75, 31.97)	75%	3^{34, 36, 42}	71	33.46 (30.06, 37.26)	95%
Birthweight of Both Twins	1⁴⁹	9	1608.12 (1513.27, 1907.8)	-	3^{34, 49}	642	1640.96 (1431.29, 1881.34)	96%	2 ^{34, 42}	67	2551.82 (2359.97, 2759.26)	0
Birthweight of Smaller Twin	3^{44, 47, 49}	37	933.45 (802.29, 1086.05)	47%	6 ^{15, 34, 37, 44, 49, 56}	388	1206.64 (1165, 1249.76)	0	1³⁶	4	898.3 (766.87, 1052.25)	-
Birthweight of Larger Twin	3^{44, 47, 49}	37	2052.92 (1878.3, 2243.77)	0	6 ^{15, 34, 37, 44, 49, 56}	388	1780.46 (1726.81, 1835.77)	0	1 ³⁶	4	1747 (1573.03, 1940.21)	-
Birthweight Discordance					2^{37, 38}	12	28.16 (23.51, 33.73)	0
NICU Admission					1 ¹⁵	12/12	97 (0.74, 99)	-
RDS					3^{34, 37}	289/612	0.47 (0.43, 0.51)	46%
ROP					3 ^{15, 34, 37}	17/605	0.03 (0.02, 0.04)	54%
IVH Both Twins	3^{44, 47, 49}	3/55	0.05 (0.02, 0.16)	0	4 ^{34, 43, 44, 49}	18/652	0.03 (0.02, 0.04)	3%
IVH Smaller Twin	2 ^{44, 49}	3/11	0.27 (0.09, 0.59)	0	4^{34, 43, 44, 49}	6/302	0.02 (0.01, 0.04)	18%
IVH Larger Twin					4 ^{34, 43, 44, 49}	12/350	0.03 (0.02, 0.06)	0
PVL	2 ^{44, 47}	2/43	0.05 (0.01, 0.17)	0	2^{34, 44}	11/585	0.03 (0.01, 0.09)	87%
Neonatal Sepsis					2 ^{34, 37}	48/593	0.25 (0.03, 0.76)	92%
Single IUFD	2^{47, 49}	8/38	0.2 (0.08, 0.42)	64%	6 ^{15, 34, 37, 39, 43, 44}	44/497	0.14 (0.1, 0.2)	50%	2 ^{42, 54}	2/50	0.27 (0, 1)	0
Single IUFD in Smaller Twin	3^{44, 47, 49}	18/37	0.45 (0.23, 0.69)	61%	6 ^{39, 43, 44, 49, 56, 58}	24/149	0.16 (0.11, 0.23)	0
Single IUFD in Larger Twin	3 ^{44, 47, 49}	3/37	0.08 (0.03, 0.22)	0	5 ^{39, 43, 44, 49, 58}	9/136	0.07 (0.03, 0.13)	0
Double IUFD					5 ^{15, 34, 38, 39, 56}	29/410	0.1 (0.05, 0.19)	72%
Live Birth both Twins	1⁴⁷	18/20	0.9 (0.68, 0.99)	-
Live Birth Smaller Twin	1 ⁴⁷	8/10	0.8 (0.44, 0.97)	-
Live Birth Larger Twin	1 ⁴⁷	10/10	1 (0.69, 1)	-
NND Either Twin					8^{15, 34, 37–39, 49, 56, 58}	27/753	0.04 (0.02, 0.05)	14%
NND Smaller Twin					5 ^{34, 39, 49, 56, 58}	19/365	0.05 (0.03, 0.08)	0
NND Larger Twin					5 ^{34, 39, 49, 56, 58}	15/406	0.04 (0.01, 0.17)	82%
Overall PD	2^{47, 49}	24/38	0.67 (0.2, 0.95)	90%	6 ^{37–39, 49, 56, 58}	34/210	0.16 (0.12, 0.22)	0	2^{36, 54}	16/81	0.2 (0.12, 0.3)	0
PD Smaller Twin	2 ^{47, 49}	12/19	0.63 (0.37, 0.84)	58%	4^{39, 49, 56, 58}	20/96	0.21 (0.14, 0.3)	2%
PD Larger Twin	2 ^{47, 49}	12/19	0.87 (0.01, 1)	0	4^{39, 49, 56, 58}	10/96	0.1 (0.06, 0.18)	0
Intact survival Larger Twin	1⁴⁷	10/10	1 (0.69, 1)	-	1 ⁵⁸	5/13	0.38 (0.14, 0.68)	-
Intact survival Smaller Twin	1⁴⁷	8/10	0.8 (0.44, 0.97)	-	1 ⁵⁸	8/13	0.62 (0.32, 0.86)	-
Intact Survival Both Twins	1 ⁴⁷	18/20	0.9 (0.68, 0.99)	-	2 ^{38, 58}	22/38	0.58 (0.43, 0.72)	50%
sFGR: selective fetal growth restriction, NICU: neonatal intensive care unit, PT: preterm birth, GA: gestational age, IUFD: intrauterine fetal demise, NND: neonatal death, PND: perinatal death, RDS: respiratory distress syndrome, ROP: retinopathy of prematurity, IVH: interventricular hemorrhage, PVL: periventricular leukomalacia

Mean GA at birth was comparable between the three groups: 32.11 weeks (95% CI 30.46, 33.85) in FLP group, 31.36 weeks (95% CI 30.75, 31.97) in expectant management, and 33.46 weeks (95% CI 30.06, 37.26) in SR group. RDS and ROP were 47% (95% CI 43, 51) and 3%, (95% CI 2, 4) in expectant management. IVH in both twins or the smaller twin were higher in the FLP group (5% (95% CI 2, 16) and 27% (95% CI 9, 59), respectively) compared to expectant management (3% (95% CI 2, 4) and 2% (95% CI 1, 4), respectively).

Single fetal demise and demise of the smaller twin were higher in the FLP group (20% (95% CI 8, 42) and 45% (95% CI 23, 69), respectively) compared to expectant management (14% (95% CI 10, 20) and 16% (95% CI 11, 23), respectively). Fetal demise of the larger twin was comparable between FLP and expectant management. PND of both twins, smaller twin, and larger twin were higher in the FLP group (67% (95% CI 2, 95), 63% (95% CI 37, 84), and 87% (95% CI 20, 90), respectively) compared to expectant management (16% (95% CI 12, 22), 21% (95% CI 14, 30), and 10% (95% CI 6, 18), respectively). There was only one study that assessed intact survival in the FLP group and one study in expectant management. In pregnancies that underwent SR, co-twin demise and PND were 27% (95% CI 0, 65) and 20% (95% CI 12, 30), respectively.

Publication bias and risk of bias assessment

There was no evidence of small study effects for any outcome. Risk of bias using NOS for cohort and case control showed a minimum score of 7 (total score in Table 1, details of scoring in Table S2).

Comment

Principal findings

In this systematic review and meta-analysis, we have shown that twin pregnancies with type I sFGR have a favorable prognosis with expectant management representing the most reasonable management option. Patients with type II sFGR have a higher rate of mortality and lower morbidity, particularly neurological morbidity when managed by FLP compared to expectant management. Type III sFGR had both higher mortality and morbidity when managed by laser compared to expectant management.

Results in the context of what is known.

Our current meta-analysis showed that the FLP is associated with a higher rate of mortality, particularly of the growth-restricted fetus, and better neurodevelopmental outcomes of the surviving fetus in type II sFGR. This finding could be explained by understanding pathophysiology of the sFGR and the effect of fetal interventions. It is speculated that the sFGR results from the unbalanced sharing of the placenta between twins and that there is a positive correlation between the severity of an unequal placental territory and birthweight discordance²⁵. Likewise, it is reported that the placental territory discordance ratio was lower in sFGR I than in sFGR II and III²⁶. Accordingly, it is hypothesized that in severe cases, the separation of the placenta after the FLP could leave the growth-restricted twin with even smaller placental territory, inadequate to supply its demands, and potentially increase the risk of its demise.

In addition to the unequal placental sharing, vascular anastomosis significantly influences the natural history of the twin pregnancies with sFGR²⁵. Two major types of anastomoses have been described in complicated MC twin pregnancies. First, the unidirectional arterio-venous (AV) anastomoses resulting in abnormal transfusion from the donor to recipient twin. Second, the arterio-arterial (AA) or venovenous (VV) anastomoses, a lower resistance circulation system with a potentially bidirectional flow. The number and caliber of AA anastomoses are shown to be higher in sFGR III than in sFGR I and II^{26, 27}. In pregnancies with sFGR, AA anastomosis could possibly compensate for the underlying abnormality by directing blood from the larger twin to the hypovolemic growth-restricted fetus²⁵. Accordingly, ablating vascular anastomosis by FLP abolishes the compensatory circulation to the growth-restricted twin and may explain the higher rate of IUD.

The compensatory blood flow from the larger twin to the smaller twin through AA anastomosis could also have a potential detrimental effect in the case of acute feto-fetal transfusion, where the demise of the growth-restricted fetus results in its circulatory collapse and concomitant sudden blood shifting from the larger twin, which could increase the risk of its demise²⁵. Accordingly, selective reduction of the growth-restricted twin could prevent this event by preventing the sudden circulatory shift. This reason could potentially explain the finding that the co-twin survival rate after SR is higher compared to the group of twin pregnancies that were managed expectantly.

In this meta-analysis, we have shown that type I sFGR was favorable with expectant management. Buca et al. have shown in their meta-analysis that sFGR type I delivered at later gestational ages and have a low risk of deterioration ². In addition, these patients have a lower neurodevelopmental morbidity and perinatal mortality rate than sFGR II and III². However, deterioration of fetal status occurred in more than half of the patients with sFGR II, and nearly one out of four of sFGR type II pregnancies experienced adverse perinatal outcomes². Twin pregnancies with sFGR type III have a similar placental discordance ratio to sFGR type I and lower birthweight discordance than sFGR type II. However, the higher number of AA anastomoses in type II and III sFGR increases the risk of unpredictable acute feto-fetal transfusion, which could explain the high rate of neurological injury in those managed expectantly²⁸. Altogether, pregnancies with sFGR type I have more stable course and better outcomes than sFGR II and III, and the adverse effects of fetal interventions outweigh their potential advantages. However, the underlying pathophysiology of sFGR II and III is more severe, therefore potentially benefiting from an active fetal intervention to improve the prognosis of the larger twin.

In our review, we observed excess morbidity and mortality in type III sFGR that were managed with laser. Given the more published studies for type III since our last review, this is a new finding compared to our last published review that showed higher mortality but not morbidity with FLP compared expectant management while acknowledging that survival and neurological morbidity are competing outcomes which might have inflected the results seen in FLP vs expectant management.⁶ Technical challenges faced in these pregnancies could potentially explain these results. Proximate cord insertion is frequently encountered in twin pregnancies with type III sFGR²⁹. Angiovascular architecture in MC placentas with proximate cord insertions could either preclude the procedure completely or result in incomplete laser surgery³⁰. Post-laser residual anastomoses are common as dye studies have shown.³¹ Additionally, proximate cords are frequently connected with large size AA anastomoses rendering coagulation difficult or even impossible.³²

Clinical and Research Implications

If active fetal intervention is chosen, SR is a reasonable choice in view of the significant technical difficulties and surgical complications which can be encountered when performing FLP in these pregnancies. This is a challenging recommendation and not feasible where termination is not an option either because of the legal limits or the parents’ wishes. There is then a role for laser therapy and further studies are needed to clarify case selection and the relative risks of laser compared to other options.

Strengths and Limitations

The strength of this review is the comprehensive search of the literature and evaluation of the perinatal outcomes of monochorionic twin pregnancies complicated by sFGR categorized according to the UA Doppler waveform and their management plan. The limitations of this study are largely related to the small number of included cases and the heterogeneity among the studies. Only papers published in English were included which might have created selection bias. The management protocol varied among centers including GA at treatment, selection criteria for treatment, and different surgical expertise among different centers. Moreover, there were no studies reporting head-to-head comparison of management plans. Accordingly, the conclusion was based on comparing the pooled proportions of perinatal outcomes between the three management groups. Outcomes including survival and neurological morbidity are competing outcomes which might have affected results of FLP vs expectant management and while the definition for intact survival was similar among included studies which is free of neurological complications by 28 days of life, this does not reflect on longer term neurological injury. Studies evaluating outcomes following selective reduction per type of sFGR are limited with small sample size, thus limiting drawing conclusions. Finally, some of the variables that we intended to collect and stratify were only reported by small number of studies which limited our ability to include them in the analysis.

The literature lacks robust evidence to guide the best management approach in monochorionic twin pregnancies complicated by sFGR types II and III. Pregnancies with type I sFGR have good prognosis with expectant management and close monitoring. Those with sFGR types II and III have a considerable risk of demise of the smaller twin and neurological impairment of the larger co-twin. Accordingly, active fetal interventions might improve the intact survival of the larger twin. Prospective large multicenter studies using unified diagnostic criteria and management protocols, with long-term follow-up are needed to provide better evidence on how best to manage these complex pregnancies. The feasibility of a randomized trial of expectant management versus active fetal intervention in early-onset sFGR is currently addressed in a multicenter prospective study (the FERN study).³³

- Ethics approval and consent to participate: not obtained given that study is systematic review

- Consent for publication: not obtained given that study is systematic review

- Availability of data and materials: The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

- Funding: N/A

- Acknowledgment: Authors acknowledge the role and efforts of all the authors of included articles as well as the participants in these articles.

Author Contribution

H.J.M: Study design and methodology, manuscript preparationA.J. and M.H: statistical analysisF.A: manuscript preparationA.S and D.R: abstract screen, full text review, and data collectionA.K: Expert review process

Authors report no conflicts of interest

Valsky DV, Eixarch E, Martinez JM, E G. Selective intrauterine growth restriction in monochorionic diamniotic twin pregnancies. Prenat Diagn 2010; 30.
Buca D, Pagani G, Rizzo G, Familiari A, Flacco ME, Manzoli L, Liberati M, Fanfani F, Scambia G, D'Antonio F. Outcome of monochorionic twin pregnancy with selective intrauterine growth restriction according to umbilical artery Doppler flow pattern of smaller twin: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2017; 50: 559-568.
Khalil A, Rodgers M, Baschat A, Bhide A, Gratacos E, Hecher K, Kilby MD, Lewi L, Nicolaides KH, Oepkes D, Raine-Fenning N, Reed K, Salomon LJ, Sotiriadis A, Thilaganathan B, Ville Y. ISUOG Practice Guidelines: role of ultrasound in twin pregnancy. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology 2016; 47.
Khalil A, Beune I, Hecher K, Wynia K, Ganzevoort W, Reed K, Lewi L, Oepkes D, Gratacos E, Thilaganathan B, Gordijn SJ. Consensus definition and essential reporting parameters of selective fetal growth restriction in twin pregnancy: a Delphi procedure. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology 2019; 53.
Gratacós E, Lewi L, Muñoz B, Acosta-Rojas R, Hernandez-Andrade E, Martinez JM, Carreras E, Deprest J. A classification system for selective intrauterine growth restriction in monochorionic pregnancies according to umbilical artery Doppler flow in the smaller twin. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology 2007; 30.
Townsend R, D'Antonio F, Sileo FG, Kumbay H, Thilaganathan B, Khalil A. Perinatal outcome of monochorionic twin pregnancy complicated by selective fetal growth restriction according to management: systematic review and meta-analysis. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology 2019; 53.
Parra-Cordero M, Bennasar M, Martinez JM, Eixarch E, Torres X, Gratacos E. Cord Occlusion in Monochorionic Twins with Early Selective Intrauterine Growth Restriction and Abnormal Umbilical Artery Doppler: A Consecutive Series of 90 Cases. Fetal Diagn Ther 2016; 39: 186-191.
Chalouhi GE, Marangoni MA, Quibel T, Deloison B, Benzina N, Essaoui M, Al Ibrahim A, Stirnemann JJ, Salomon LJ, Ville Y. Active management of selective intrauterine growth restriction with abnormal Doppler in monochorionic diamniotic twin pregnancies diagnosed in the second trimester of pregnancy. Prenat Diagn 2013; 33: 109-115.
Aquino C, Rodrigues Baiao AE, de Carvalho PRN. Perinatal Outcome of Selective Intrauterine Growth Restriction in Monochorionic Twins: Evaluation of a Retrospective Cohort in a Developing Country. Twin Res Hum Genet 2021; 24: 37-41.
Batsry L, Matatyahu N, Avnet H, Weisz B, Lipitz S, Mazaki-Tovi S, Yinon Y. Perinatal outcome of monochorionic diamniotic twin pregnancy complicated by selective intrauterine growth restriction according to umbilical artery Doppler flow pattern: single-center study using strict fetal surveillance protocol. Ultrasound Obstet Gynecol 2021; 57: 748-755.
Chmait RH, Chon AH, Korst LM, Stephen Y, Llanes A, Ouzounian JG. Selective intrauterine growth restriction (SIUGR) type II: proposed subclassification to guide surgical management. J Matern Fetal Neonatal Med 2022; 35: 1184-1191.
Chon AH, Ma SY, Korst LM, Chmait HR, Purnell ME, Chmait RH. Antenatal course of referred monochorionic diamniotic twins complicated by selective intrauterine growth restriction (SIUGR) type III. J Matern Fetal Neonatal Med 2021; 34: 3867-3873.
Colmant C, Lapillonne A, Stirnemann J, Belaroussi I, Leroy-Terquem E, Kermovant-Duchemin E, Bussieres L, Ville Y. Impact of different prenatal management strategies in short- and long-term outcomes in monochorionic twin pregnancies with selective intrauterine growth restriction and abnormal flow velocity waveforms in the umbilical artery Doppler: a retrospective observational study of 108 cases. BJOG : an international journal of obstetrics and gynaecology 2021; 128.
Ishii K, Wada S, Takano M, Nakata M, Murakoshi T, Sago H. Survival Rate without Brain Abnormalities on Postnatal Ultrasonography among Monochorionic Twins after Fetoscopic Laser Photocoagulation for Selective Intrauterine Growth Restriction with Concomitant Oligohydramnios. Fetal Diagn Ther 2019; 45: 21-27.
Kostyukov K.V. GKA. Perinatal outcomes of monochorionic multiple pregnancies with selective intrauterine growth restriction. Akusherstvo i ginekologiia 2020; 6_2020: 50-58.
Monaghan C, Kalafat E, Binder J, Thilaganathan B, Khalil A. Prediction of adverse pregnancy outcome in monochorionic diamniotic twin pregnancy complicated by selective fetal growth restriction. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology 2019; 53.
Miyadahira MY, Brizot ML, Carvalho MHB, Biancolin SE, Machado RCA, Krebs VLJ, Francisco RPV, Peralta CFA. Type II and III Selective Fetal Growth Restriction: Perinatal Outcomes of Expectant Management and Laser Ablation of Placental Vessels. Clinics (Sao Paulo, Brazil) 2018; 73.
Quintero R, Kontopoulos E, Williams ME, Sloop J, Vanderbilt D, Chmait RH. Neurodevelopmental outcome of monochorionic twins with selective intrauterine growth restriction (SIUGR) type II: laser versus expectant management. J Matern Fetal Neonatal Med 2021; 34: 1513-1521.
Shinar S, Xing W, Pruthi V, Jianping C, Slaghekke F, Groene S, Lopriore E, Lewi L, Couck I, Yinon Y, Batsry L, Raio L, Amylidi-Mohr S, Baud D, Kneuss F, Dekoninck P, Moscou J, Barrett J, Melamed N, Ryan G, Sun L, Van Mieghem T. Outcome of monochorionic twin pregnancy complicated by Type-III selective intrauterine growth restriction. Ultrasound Obstet Gynecol 2021; 57: 126-133.
Sukhwani M, Antolin E, Herrero B, Rodriguez R, de la Calle M, Lopez F, Bartha JL. Management and perinatal outcome of selective intrauterine growth restriction in monochorionic pregnancies. J Matern Fetal Neonatal Med 2021; 34: 3838-3843.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Bmj 2021; 372.
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010; 25.
Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 2014; 14: 1-13.
Quintero RA, Bornick PW, Morales WJ, Allen MH. Selective photocoagulation of communicating vessels in the treatment of monochorionic twins with selective growth retardation. Am J Obstet Gynecol 2001; 185.
Valsky DV, Eixarch E, Martinez JM, Crispi F, Gratacós E. Selective intrauterine growth restriction in monochorionic twins: pathophysiology, diagnostic approach and management dilemmas. Semin Fetal Neonatal Med 2010; 15.
Wang X, Li L, Yuan P, Zhao Y, Wei Y. Placental characteristics in different types of selective fetal growth restriction in monochorionic diamniotic twins. Acta Obstet Gynecol Scand 2021; 100: 1688-1693.
Groene SG, Tollenaar LSA, Slaghekke F, Middeldorp JM, Haak M, Oepkes D, Lopriore E. Placental characteristics in monochorionic twins with selective intrauterine growth restriction in relation to the umbilical artery Doppler classification. Placenta 2018; 71: 1-5.
Ishii K, Murakoshi T, Takahashi Y, Shinno T, Matsushita M, Naruse H, Torii Y, Sumie M, Nakata M. Perinatal outcome of monochorionic twins with selective intrauterine growth restriction and different types of umbilical artery Doppler under expectant management. Fetal Diagn Ther 2009; 26: 157-161.
Couck I, Deprest J, Lewi L. How to Better Distinguish between Type II and III Selective Fetal Growth Restriction in Monochorionic Twin Pregnancies? Fetal Diagn Ther 2022; 49.
Mustafa HJ, Tadbiri H, Pedersen N, Harman C, Turan OM. Proximate Cord Insertion in Twin-to-Twin Transfusion Syndrome: Case Series and PRISMA Compliant Systematic Review and Meta-Analysis. Fetal Diagn Ther 2022; 49.
Zhao DP, Peeters SH, Middeldorp JM, Klumper FJ, Duan T, Oepkes D, Lopriore E. Monochorionic placentas with proximate umbilical cord insertions: definition, prevalence and angio-architecture. Placenta 2015; 36.
Gandhi M, Papanna R, Moise K, Popek E, Johnson A, Moise KJ. Treatment of twin-twin transfusion syndrome with proximate umbilical cord insertions. Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine 2011; 30.
FERN: Intervention or Expectant Management for Early Onset Selective Fetal Growth Restriction in Monochorionic Twin Pregnancy - Institute of Life Course and Medical Sciences - University of Liverpool. https://www.liverpool.ac.uk/life-course-and-medical-sciences/research/groups/fern-study/.].
Shinar S, Xing W, Pruthi V, Jianping C, Slaghekke F, Groene S, Lopriore E, Lewi L, Couck I, Yinon YJUio, gynecology. Outcome of monochorionic twin pregnancy complicated by Type‐III selective intrauterine growth restriction. 2021; 57: 126-133.
Monaghan C, Kalafat E, Binder J, Thilaganathan B, Khalil AJUiO, Gynecology. Prediction of adverse pregnancy outcome in monochorionic diamniotic twin pregnancy complicated by selective fetal growth restriction. 2019; 53: 200-207.
Muñoz‐Abellana B, Hernandez‐Andrade E, Figueroa‐Diesel H, Ferrer Q, Acosta‐Rojas R, Cabero L, Gratacos EJUiO, Obstetrics GTOJotISoUi, Gynecology. Hypertrophic cardiomyopathy‐like changes in monochorionic twin pregnancies with selective intrauterine growth restriction and intermittent absent/reversed end‐diastolic flow in the umbilical artery. 2007; 30: 977-982.
Aquino C, Baião AER, de Carvalho PRNJTR, Genetics H. Perinatal Outcome of Selective Intrauterine Growth Restriction in Monochorionic Twins: Evaluation of a Retrospective Cohort in a Developing Country. 2021; 24: 37-41.
Batsry L, Matatyahu N, Avnet H, Weisz B, Lipitz S, Mazaki‐Tovi S, Yinon YJUiO, Gynecology. Perinatal outcome of monochorionic diamniotic twin pregnancy complicated by selective intrauterine growth restriction according to umbilical artery Doppler flow pattern: single‐center study using strict fetal surveillance protocol. 2021; 57: 748-755.
Chmait RH, Chon AH, Korst LM, Stephen Y, Llanes A, Ouzounian JGJTJoM-F, Medicine N. Selective intrauterine growth restriction (SIUGR) type II: proposed subclassification to guide surgical management. 2022; 35: 1184-1191.
Chon AH, Ma SY, Korst LM, Chmait HR, Purnell ME, Chmait RHJTJoM-F, Medicine N. Antenatal course of referred monochorionic diamniotic twins complicated by selective intrauterine growth restriction (SIUGR) type III. 2021; 34: 3867-3873.
Colmant C, Lapillonne A, Stirnemann J, Belaroussi I, Leroy‐Terquem E, Kermovant‐Duchemin E, Bussieres L, Ville YJBAIJoO, Gynaecology. Impact of different prenatal management strategies in short‐and long‐term outcomes in monochorionic twin pregnancies with selective intrauterine growth restriction and abnormal flow velocity waveforms in the umbilical artery Doppler: a retrospective observational study of 108 cases. 2021; 128: 401-409.
Parra-Cordero M, Bennasar M, Martínez JM, Eixarch E, Torres X, Gratacós EJFD, Therapy. Cord occlusion in monochorionic twins with early selective intrauterine growth restriction and abnormal umbilical artery Doppler: a consecutive series of 90 cases. 2016; 39: 186-191.
Gratacos E, Carreras E, Becker J, Lewi L, Enriquez G, Perapoch J, Higueras T, Cabero L, Deprest JJUiO, Obstetrics GTOJotISoUi, Gynecology. Prevalence of neurological damage in monochorionic twins with selective intrauterine growth restriction and intermittent absent or reversed end‐diastolic umbilical artery flow. 2004; 24: 159-163.
Gratacós E, Antolin E, Lewi L, Martínez J, Hernandez‐Andrade E, Acosta‐Rojas R, Enríquez G, Cabero L, Deprest JJUiO, Obstetrics GTOJotISoUi, Gynecology. Monochorionic twins with selective intrauterine growth restriction and intermittent absent or reversed end‐diastolic flow (Type III): feasibility and perinatal outcome of fetoscopic placental laser coagulation. 2008; 31: 669-675.
Ishii K, Murakoshi T, Hayashi S, Saito M, Sago H, Takahashi Y, Sumie M, Nakata M, Matsushita M, Shinno TJUio, gynecology. Ultrasound predictors of mortality in monochorionic twins with selective intrauterine growth restriction. 2011; 37: 22-26.
Ishii K, Nakata M, Wada S, Murakoshi T, Sago HJJoO, Research G. Feasibility and preliminary outcomes of fetoscopic laser photocoagulation for monochorionic twin gestation with selective intrauterine growth restriction accompanied by severe oligohydramnios. 2015; 41: 1732-1737.
Ishii K, Wada S, Takano M, Nakata M, Murakoshi T, Sago HJFD, Therapy. Survival rate without brain abnormalities on postnatal ultrasonography among monochorionic twins after fetoscopic laser photocoagulation for selective intrauterine growth restriction with concomitant oligohydramnios. 2019; 45: 21-27.
Koch A, Favre R, Viville B, Fritz G, Kohler M, Guerra F, Lecointre L, Gaudineau A, Langer B, Weingertner A-SJJogo, reproduction h. Expectant management and laser photocoagulation in isolated selective intra-uterine growth restriction: A single-center series. 2017; 46: 731-736.
Miyadahira MY, Brizot MdL, Carvalho MHBd, Biancolin SE, Machado RdCA, Krebs VLJ, Francisco RPV, Peralta CFAJC. Type II and III selective fetal growth restriction: perinatal outcomes of expectant management and laser ablation of placental vessels. 2018; 73.
Peeva G, Bower S, Orosz L, Chaveeva P, Akolekar R, Nicolaides KH. Endoscopic Placental Laser Coagulation in Monochorionic Diamniotic Twins with Type II Selective Fetal Growth Restriction. Fetal Diagn Ther 2015; 38.
Peng R, Xie H-N, Lin M-F, Yang J-B, Zhou Y, Chen H-Q, Zhu Y-XJG, Investigation O. Clinical outcomes after selective fetal reduction of complicated monochorionic twins with radiofrequency ablation and bipolar cord coagulation. 2016; 81: 552-558.
Quintero R, Kontopoulos E, Williams ME, Sloop J, Vanderbilt D, Chmait RHJTJoM-F, Medicine N. Neurodevelopmental outcome of monochorionic twins with selective intrauterine growth restriction (SIUGR) type II: laser versus expectant management. 2021; 34: 1513-1521.
Visentin S, Macchi V, Grumolato F, Porzionato A, De Caro R, Cosmi EJJopm. Expectant management in type II selective intrauterine growth restriction and abnormal chord insertion in monochorionic twins. 2013; 41: 309-316.
Wang H-M, Li H-Y, Wang X-T, Wang Y-Y, Li L, Liang B, Wang J, Song JJTJoO, Gynecology. Radiofrequency ablation for selective reduction in complex monochorionic multiple pregnancies: A case series. 2017; 56: 740-744.
Weisz B, Hogen L, Yinon Y, Gindes L, Shrim A, Simchen M, Schiff E, Lipitz SJTR, Genetics H. Perinatal outcome of monochorionic twins with selective IUGR compared with uncomplicated monochorionic twins. 2011; 14: 457-462.
Rustico M, Consonni D, Lanna M, Faiola S, Schena V, Scelsa B, Introvini P, Righini A, Parazzini C, Lista GJUiO, Gynecology. Selective intrauterine growth restriction in monochorionic twins: changing patterns in umbilical artery Doppler flow and outcomes. 2017; 49: 387-393.
Sukhwani M, Antolín E, Herrero B, Rodríguez R, de la Calle M, López F, Bartha JLJTJoM-F, Medicine N. Management and perinatal outcome of selective intrauterine growth restriction in monochorionic pregnancies. 2021; 34: 3838-3843.
Ishii K, Murakoshi T, Takahashi Y, Shinno T, Matsushita M, Naruse H, Torii Y, Sumie M, Nakata MJFd, therapy. Perinatal outcome of monochorionic twins with selective intrauterine growth restriction and different types of umbilical artery Doppler under expectant management. 2009; 26: 157-161.

No competing interests reported.

SupplementarymaterialsFGRmx.docx

Download PDF

Reviews received at journal
03 Jul, 2024
Reviewers agreed at journal
01 Jul, 2024
Reviewers agreed at journal
26 Jun, 2024
Reviewers agreed at journal
03 Jun, 2024
Reviews received at journal
06 Mar, 2024
Reviewers agreed at journal
06 Mar, 2024
Reviews received at journal
26 Feb, 2024
Reviewers agreed at journal
17 Feb, 2024
Reviewers agreed at journal
31 Jan, 2024
Reviewers agreed at journal
19 Jan, 2024
Reviewers invited by journal
31 Dec, 2023
Editor assigned by journal
31 Dec, 2023
Editor invited by journal
30 Dec, 2023
Submission checks completed at journal
30 Dec, 2023
First submitted to journal
20 Dec, 2023

You are reading this latest preprint version

Perinatal Outcomes of Monochorionic Twin Pregnancies with Selective Fetal Growth Restriction According to Umbilical Artery Dopplers and Fetal intervention: a Systematic Review and Meta-analysis

Status:

Version 1

Abstract

Objective

Methods

Results

Conclusion

Figures

Key message

Introduction

Material and Methods

Search strategy

Eligibility criteria

Data extraction and outcome measures

Quality Assessment

Data synthesis and Statistical Analysis

Results

Study characteristics

Type I sFGR morbidity and mortality outcomes by type of management

Type II sFGR morbidity and mortality outcomes by type of management

Type III sFGR morbidity and mortality by type of management

Publication bias and risk of bias assessment

Comment

Principal findings

Clinical and Research Implications

Strengths and Limitations

Conclusions

Declarations

Author Contribution

References

Additional Declarations

Supplementary Files

Status:

Version 1