Main text
Introduction
Twin-to-twin transfusion syndrome (TTTS) affects approximately 10-15%
of monochorionic diamniotic twin pregnancies (MCDA). 1Fetoscopic laser surgery (FLS) has become the standard treatment for
managing these pregnancies. 2 Despite the apparent
success of FLS, spontaneous preterm birth (sPTB) remains to be a major
complication and a challenge that determines perinatal morbidity and
survival, 3,4 with a reported gestational age (GA) at
delivery of 31 to 33 weeks of gestation. 5,6 sPTB
accounts for almost 48% of these deliveries 7 which
has been largely related to preterm labor and preterm prelabor rupture
of membranes (PPROM) with occurrence to as high as 53% in some reports.5,8,9 Up to date, effective PTB preventative measures
in this population are lacking.
Indomethacin, a non-specific cyclooxygenase (COX) inhibitor, is a
commonly used tocolytic agent. The three proposed mechanisms of action
include COX blockage, uterine calcium efflux blockage, which reduces
uterine resting tone, and the hydrophobic effect on cervical matrix
metalloproteinases (MMP), which prevents further softening and
shortening. 10,11 Long-term indomethacin therapy (LIT)
(>48 hours, and not beyond 32 weeks gestation) used under
strict follow-up guidelines has shown effectiveness in stabilizing
cervical length (CL) in dichorionic diamniotic twin (DCDA) pregnancies
with a short cervix. 12 The safety of LIT in the
setting of the short cervix in singleton pregnancies has been
demonstrated in a cohort study which showed no significant differences
in fetal and neonatal complications compared to a matched control group.13
The hypothesis of our study was that LIT prolongs pregnancy and reduces
the risk for sPTB in the setting of TTTS treated with FLS.
Materials and Methods
This was a retrospective cohort study of prospectively collected data of
consecutive TTTS cases that underwent FLS at two fetal treatment centers
between 2012 and 2018. The study was approved by the institutional
review boards of both participating institutions (University of
Maryland, Baltimore [UMB], MD and Baylor College of Medicine
[BCM], Houston, TX). The study results are reported according to the
Strengthening the Reporting of Observational Studies in Epidemiology
(STROBE) guidelines for cohort studies. 14
Preoperative evaluation and
management
Patients referred for evaluation of TTTS, underwent comprehensive
ultrasound examination, including biometry measurements with Doppler
studies for the diagnosis and staging of TTTS based on the Quintero
system, 15 performed by registered diagnostic medical
sonographers supervised by experienced fetal medicine specialists. All
cases with TTTS Stage II or higher were offered surgical intervention,
as were Stage-I cases if they presented with a short cervix of less than
25 mm or symptomatic polyhydramnios. Patients undergoing FLS at UMB were
started on the LIT protocol (see below in the LIT protocol section for
details).
Operative procedure
FLS was performed using a single port fetoscope under either local
anesthetic in conjunction with intravenous sedation or regional
anesthesia. The entry technique used was either the Seldinger or sharp
trocar method. The placental vascular equator was identified, and a
diode laser used to ablate all intertwin vascular anastomoses using
selective or sequential selective method followed by equatorial
dichorionization ’Solomon technique’ 16 if technically
feasible. When needed, amnioinfusion was performed to improve
visualization. If amniodrainage was necessary, it was performed
following the coagulation phase of the procedure.
Postoperative evaluation and
management
Patients remained in the hospital for a minimum of 24 hours. Daily
ultrasound exams were performed while patients remained in the hospital.
After discharge, patients were either followed with weekly scans by the
fetal center if feasible or returned to the referring provider with
recommended follow-up care per institutional protocol. The decision for
delivery was based on the referring physician’s assessment. Information
about pregnancy outcomes was collected prospectively either from the
patients or the referring physicians as a part of follow-up care.
LIT protocol
LIT was administered as a standard regimen using oral indomethacin of
100 mg loading dose, then 50 mg every 6 hours for up to 48 hours,
followed by a maintenance dose of 25 mg every 6 hours thereafter. The
minimum duration was 48 hours and not beyond 32 weeks gestation. LIT
ultrasound surveillance included weekly evaluation of the maximum
vertical pocket (MVP) and Doppler flow studies (ductus arteriosus
[DA], ductus venosus, and atrioventricular valves). These weekly
scans were continued as long as patients were still using indomethacin.
LIT was stopped if 1. The patient was returned to the referring
provider, where performing the weekly LIT ultrasound surveillance was
not feasible, knowing that cervical length was stable. This category is
referred to as ”stable clinical status” throughout the paper, 2. LIT
complications, including DA constriction, defined as the DA peak
systolic velocity exceeded the 95th percentile for GA,
and/or the DA pulsatility index (PI) was <
5th percentile for GA, or oligohydramnios defined as
MVP of less than 2 cm, 3. PPROM, and 4. Reaching 32 weeks gestation.13
Study groups and outcome
measures
LIT in the setting of TTTS treated with FLS was used routinely after FLS
in one of the participating institutions (UMB), while TTTS cases from
the second institution (BCM) did not receive LIT. Exclusion criteria
included triplet gestations, pregnancies that underwent cervical
cerclage placement, postoperative complications that resulted in dual
twin demise, obstetrical and medical indicated deliveries at less than
32 weeks gestation (did not encounter PTL or PPROM), and patients with
missing records. Collected data included preoperative, operative, and
postoperative variables, delivery information, and perinatal survival.
Preoperative variables included maternal characteristics (age, parity,
race, previous PTB, BMI), TTTS stage using the Quintero criteria, CL
(measured transvaginally), recipient’s MVP, presence of anterior
placenta, and presence of selective fetal growth restriction (sFGR).
Operative variables included GA at FLS, size of trocar outer sheath in
mm, number of anastomoses ablated, whether or not complete
dichorionization was performed, the occurrence of chorioamnion membrane
separation (CAS), and septostomy (intertwin membrane disruption).
Postoperative variables included GA at delivery, live births, and
neonatal survival. The primary outcome measure was GA at delivery.
Secondary outcome measures included FLS-to-delivery interval, live
births, and neonatal survival.
Statistical analysis
Study data were deidentified and imported into the statistical software.
Results are reported as mean ± standard deviation (SD), median
(interquartile range [IQR]), or number (percentage). Normal
distribution was determined by Shapiro-Wilk test. Categorical variables
were compared using the Pearson’s chi-square or Fisher’s exact test.
Continuous variables were compared using an unpaired t -test for
normally distributed data or the Wilcoxon rank-sum test for not normally
distributed data. Pearson correlation was used to assess linear
correlation between two continuous variables.
Log-binomial regression was used to directly estimate relative risks
(RRs) of PTB, very PTB, and extremely PTB. Significant variables in
bivariate analysis were incorporated into a log-binominal regression
model to determine which factors were independent risk factors of the
primary outcome (PTB) and estimate adjusted RR. The number needed to
treat (NNT) was calculated using pooled absolute risk reduction for PTD.
A secondary analysis was performed to evaluate FLS-to-delivery duration.
Kaplan–Meier curve was used to visualize the FLS-to-delivery survival
function for each group, and equality of survival functions between
groups was tested using the log-rank test. Cox regression analysis was
used to estimate hazard ratios (HRs) for FLS-to-delivery survival.
Multivariate stepwise backward Cox regression was used to identify
significant independent maternal characteristics, pre-operative
variables, and operative variables that predict FLS-to-delivery survival
and estimate adjusted HR.
Trocar outer sheath diameter and total number of anastomoses were
categorized into quartiles, age was categorized into <35 and
≥35 (advanced maternal age), BMI was categorized into <25
(underweight or normal), 25 – 30 (overweight), and ≥30 (obese), parity
was categorized into 0, 1, and 2 or more, MVP was categorized into
<8 (oligohydramnios or normal), 8 – 12 (polyhydramnios), ≥12
(severe polyhydramnios), and GA at FLS was categorized into
<18 weeks, 18 – 24 weeks, and ≥24 weeks in log-binomial and
Cox regression models to allow non-linear relationships. The
p- value <0.05 was considered statistically significant.
Statistical analysis was performed using the Stata 16
software.17
Results
A total of 557 FLS procedures were performed during the study period. In
this study, a total of 146 pregnancies were excluded. (Figure 1) The
distribution of the excluded pregnancies was similar between the two
centers (Table 1). After applying the exclusion criteria, 411
pregnancies were included in the final analysis; of those, 180
pregnancies received LIT (43.8%) and 231 did not (56.2%).
Maternal characteristics and preoperative
variables
There were no statistically significant differences in maternal age,
prior PTB, sFGR, CL <25 mm, presence of anterior placenta, and
Quintero staging between the two groups (Table 2). Preoperative
significant differences between groups were race, of which 69.3% were
white in the LIT group vs. 54.5% in the non-LIT group
(p<0.001), BMI with the median of 23.95 (IQR: 21 – 29.4) in
the LIT group vs. 28.2 (IQR: 25.4 – 34.2) in the non-LIT group
(p<0.001), parity with the median of 1 (IQR: 0 – 1) in the
LIT group vs. 1 (IQR: 0 – 2) in the non-LIT group
(p<0.001), and recipient MVP with the median of 11 (IQR: 9.3
– 13.3) in the LIT group vs. 10.1 (IQR 8.5 – 12.45) in the
non-LIT group (p=0.006) (Table 2).
Operative variables
Median GA at the time of FLS was 20.4 weeks which was similar between
groups. The use of Solomon technique and CAS did not differ
significantly between groups. Trocar outer sheath diameter was different
between groups (median of 3.33 mm [IQR: 3.33 – 4] in the LIT groupvs. 3.2 mm [IQR: 3.1 – 3.8] in the non-LIT group,
p<0.001), total number of anastomoses were higher in the LIT
group (median of 13 [IQR: 10 – 18] vs. 11 [IQR: 8 – 13],
p<0.001), and occurrence of postoperative septostomy was more
common in the non-LIT group (24.8% vs. 6.1%, p<0.001) (Table
3).
Postoperative variables
Gestational age at delivery was significantly different between the
groups with median GA at delivery of 33.6 weeks (IQR: 31.2 – 35.3) in
the LIT groups vs. 31.1 weeks (IQR: 28.57 – 34) in the non-LIT
group (P <0.001). PTB < 26 weeks (1.1% in the
LIT group vs. 6.1% in the non-LIT group), extreme PTB
< 28 weeks (5.6% in the LIT group vs. 15.2% in the
non-LIT group), PTB < 32 weeks (27.8% in the LIT groupvs. 54.1% in the non-LIT), and PTB < 34 weeks (50.6%
in the LIT group vs. 73.6% in the non-LIT) were all
significantly higher in the non-LIT group (p=0.010, p=0.002,
p<0.001, and p<0.001, respectively), Figure 2. FLS
to delivery duration was significantly higher in the LIT group than in
the non-LIT group with the median of 90 days (IQR: 70.35 – 108.85)vs. 76 days (IQR: 49 – 98), respectively (p<0.001)
(Table 4).
The risk of PTB prior to 34, 32, 28, and 26 weeks was significantly
lower in the LIT group compared to the non-LIT group (RR=0.69, 0.51,
0.37, and 0.18, respectively). Multivariate regression analysis showed
race, BMI, parity, MVP, trocar outer sheath diameter, total number of
anastomoses, and septostomy, are not associated with PTB while
indomethacin use is a protective factor against PTB. (Table 5) The
number needed to treat (NNT) with LIT to prevent one PTB<32
weeks gestation was 4 (95% CI: 3.82 to 3.94), and to prevent one
PTB<34 weeks was 5 (95% CI: 4.32 to 5.12).
Kaplan-Meier curve showed a significantly longer FLS-to-delivery
duration in the LIT group compared to the non-LIT group (Log-rank test
for equality of survival functions: p<0.001, Figure 3).
Multivariate stepwise backward Cox regression showed CL <
25mm, GA at intervention, LIT, and CAS were independent predictors of
FLS-to-delivery survival. (Table 6) LIT remained a statistically
significant predictor for longer FLS-to-delivery survival, even after
adjusting for CL < 25mm, GA at intervention, and CAS (adjusted
HR: 0.68, 95% CI: 0.55 – 0.83).
There were no significant differences in live birth rates between the
two groups. Neonatal survival (>28 days) of at least one
newborn was increased in the LIT group compared to the non-LIT group
(98.9% vs. 95.7%), although this increase was not statistically
significant (p=0.05). (Table 4)
LIT group
characteristics
A total of 180 pregnancies received LIT in the cohort (43.8%). Median
GA at the start of LIT was 20.4 weeks (IQR: 18.4 – 22.3), and at the
stop was 24.4 weeks (IQR: 22.2 – 26.6), with a median duration of 21
days (IQR: 15.4 – 33.95). Reasons to stop LIT in descending order were:
stable clinical status (149 cases, 83%), 32 weeks gestation (13 cases,
7%), PPROM (13 cases, 7%), and fetal complications (4 cases, 2%).
Fetal complications included 3 fetuses (1.5%) with constriction of DA
and one fetus (0.5%) with oligohydramnios (Table 7). All four cases of
fetal complications were resolved after stopping LIT. The neonatal
intensive care unit (NICU) chart review showed that the patient with
resolved oligohydramnios fetus delivered at 30 weeks and the newborn had
only prematurity-related respiratory distress syndrome (RDS). The three
patients with resolved DA constriction fetuses were delivered at 32.4
weeks, 33.6 weeks, and 34.1 weeks. The first two newborns had RDS and
bronchopulmonary dysplasia (BPD), while the third newborn had no
complications. None of them required surgical intervention. All four
were discharged home in stable condition. PPROM rate in the LIT cohort
was 28.2% (n=49) with a mean GA at PPROM of 29.6 weeks (IQR: 27.5 –
31.3). There was a moderate positive correlation, both between the
duration of LIT and duration of FLS-to-PPROM (r=0.48, p=0.002) and
between the duration of LIT and duration of FLS-to-delivery (r=0.33,
p<0.001).
Discussion
This is the first study to evaluate the efficacy of LIT in prolonging
pregnancy and reducing the risk of sPTB in the setting of TTTS treated
with FLS. The main findings of the study were that the LIT group had a
significantly longer pregnancy with a median of 2 weeks, longer
FLS-to-delivery interval with a median of 2 weeks, 31% reduction in
risk of PTB (GA less than 34 weeks), 52% reduction in risk of very PTB
(GA less than 32 weeks), and 67% and 84% reduction in risk of extreme
PTB (GA less than 28 and 26 weeks, respectively), and higher neonatal
survival compared to the non-LIT group. Cox regression analysis showed
that LIT is a significant predictor for prolongation of pregnancy
following FLS, even after adjustment for CL, GA at FLS, and chorioamnion
separation. The NNT with LIT to prevent one PTB<32 weeks
gestation was 4, and to prevent one PTB<34 weeks was 5.
PTB has been a major determinant for outcomes after FLS, with
significant risk factors including PPROM, short preoperative CL,
intraoperative amnioinfusion, and an increased number of anastomoses.7,18 Other reported risk factors include septostomy19-22 and chorioamnion separation.23-26 In our study, the multivariate regression
analysis showed that none of these factors were significant independent
predictors for PTB while LIT was the only significant independent
protective factor in preventing PTB. Early gestational age at
intervention (<18 weeks), on the other hand, has not been
found to increase the risk for PTB in this population27, similarly to what our study showed.
The most common etiology for PTB is spontaneous PTB in 48 percent of
patients. 18 Effective PTB prevention measures in
multiple gestations, in general, and in MCDA complicated with TTTS
undergoing FLS, in specific, have not yet been defined. In multiple
gestation with a normal or short cervix, interventions such as other
forms of tocolytics, cerclage, progesterone, pessary, routine
hospitalization, or bed rest have not been proven to prolong pregnancy
or improve neonatal morbidity and mortality. 10,28-40In the setting of TTTS treated with FLS with short preoperative CL,
cervical cerclage did not prolong pregnancy in a retrospective,
multicenter cohort study. 41 Our study showed that LIT
use significantly increased the FLS-to-delivery interval regardless of
the length of the cervix and gestational age of the surgery.
The efficacy of short-term antenatal indomethacin use is well reported
in the literature. In singleton pregnancies in the setting of preterm
labor, a 2015 metanalysis of two randomized trials showed indomethacin
compared to placebo was significantly effective in reducing the risk of
delivery within 48 hours of initiation. 42 In the
setting of exam-indicated cerclage, indomethacin along with antibiotics
significantly prolonged pregnancy for more than 28 days.43 In twin pregnancies, a retrospective matched
case-control study previously reported that LIT stabilizes cervical
length in DCDA twin gestations with short CL. 12 It is
important to emphasize that our study demonstrated that LIT reduces the
risk of extreme prematurity by 67% and 84% (GA less than 28 and 26
weeks, respectively).
PPROM has been reported to be as high as 53% after FLS.5,8,9 In PPROM generally, sequence of events modulates
metalloproteinases (MMPs) expression, secretion, and activation by local
and infiltrating cells synchronously with myometrial and cervical
changes. This leads to the progressive loss of the mechanical properties
and tensile strength of the amniotic membranes and eventually to their
rupture. 44-49 Similar cascade of events has been
shown in amniotic membranes following FLS. 50 In our
study, longer duration of LIT use was associated with longer
FLS-to-delivery interval. This effect of LIT has significant rationale
given that indomethacin has multiple vectors of impact, including
tocolysis, uterine relaxation, biochemical cervical stabilization, and
hydrophobic effect on MMPs. 11
In terms of indomethacin safety, data on fetal effects have been
conflicting, with the main concerns being oligohydramnios and
constriction of ductus arteriosus, both of which have been shown to
resolve within 48 hours of stopping the medication.51,52 Neonatal effects associated with antenatal use
of indomethacin have also been controversial, mostly related to the
prematurity associated adverse events aside from the use of
indomethacin. In a meta-analysis including randomized trials, there were
no statistically significant differences in adverse events between cases
with indomethacin use and controls 53 while a
systematic review of case-control pairs that were not matched for GA or
birth weight showed an increase in neonatal morbidity.54 Other reported fetal and neonatal outcome data are
mainly in the form of case reports and case series.55-62 Turan et al. investigated the safety of LIT in a
matched case-control analysis considering the effects of GA and birth
weight on neonatal morbidities. That study showed no significant
increase in neither fetal nor neonatal complications in cases underwent
LIT. 13 In the current study, there were only four
indomethacin-related fetal complications, including one oligohydramnios
and three DA constrictions. All four resolved after stopping LIT, and
all four newborns were discharged home in stable condition.
Our study has several strengths. To the best of our knowledge, this is
the first study reporting on the effect of LIT in prolonging pregnancy
and reducing the risk of sPTB in monochorionic pregnancies complicated
by TTTS that required FLS. The study was conducted in two experienced,
high volume fetal centers. The data were collected from all consecutive
patients who underwent FLS which minimizes the selection bias. The data
were collected prospectively as an ongoing process, which reduces
recollection bias and missing data. The establishment of a vigorous,
standardized LIT protocol allowed for uniformly proper follow-up of
these patients. The sample size was large enough to assess the effect of
the most relevant risk factors in a regression model.
We acknowledge the limitations of our study, including the retrospective
nature of the study. The study was conducted in two different centers;
therefore, different institutional practices or techniques might have
impacted the outcomes despite following similar procedural indications
and follow-up protocols between the two participating institutions.
Other limitations include the lack of neonatal outcomes comparisons
between the groups aside from perinatal survival.
In conclusion, in the setting of TTTS treated with FLS, LIT; defined as
indomethacin use for more than 48 hours and not beyond 32 weeks
gestation; was significantly effective in prolonging pregnancy with a
median of 2 weeks and reducing the risk of PTB particularly the risk of
extreme prematurity, which has the highest impact on neonatal outcomes.
Future prospective randomized trials are required to confirm our
findings and investigate the effect of LIT in other clinical settings
such as in patients with short cervical length.
Disclosure of
interests
None declared. Completed disclosure of interests forms are available to
view online as supporting information.
Contribution to
authorship
HJM and OMT conceived the study and designed the protocol. HJM and NP
collected the data. HJM wrote the first draft of the paper. OMT and HT
were involved in the statistical analysis and drafting the results. EK,
JE, AS, AN, RD, MB, MC, and CH were all involved in critical analysis of
the data. All authors contributed significantly to critical revisions of
successive drafts of the manuscript. HJM and OMT are the guarantors of
the review.
Funding
None.
Acknowledgements
The authors would like to thank all the staff and workers of the fetal
care center at the University of Maryland and Baylor college of Medicine
for their hard work and dedication to deliver the best care for our
patients.