Keywords intertwin discrepancy - monochorionic-diamniotic twins - middle cerebral artery -
cerebroplacental ratio - Doppler
Monochorionic-diamniotic (MCDA) twin pregnancies are at a three to five times higher
risk of perinatal morbidity and mortality than dichorionic twins.[1 ] This increase in risk is attributed to a shared placenta and characterized by intertwin
vascular anastomoses which, when unbalanced, leads to complications specific to MCDA
twins.[2 ]
[3 ] These risks include twin-twin transfusion syndrome (TTTS), twin anemia-polycythemia
sequence (TAPS), and selective intrauterine growth restriction (sIUGR).[4 ]
Due to the increased risk of complications, these pregnancies require close surveillance.
However, the evidence for timing and components of monitoring is limited and the recommendations
for surveillance vary between governing bodies.[4 ]
[5 ]
[6 ]
[7 ] The Society for Maternal-Fetal Medicine recommends serial ultrasound surveillance
at every 2 weeks, starting at 16 weeks, to monitor amniotic fluid levels and bladder
filling per guidance from the North American Fetal Therapy Network, but there continues
to be no consensus on the inclusion of umbilical artery (UA) and middle cerebral artery
(MCA) Doppler measurements in the surveillance of MCDA pregnancies.[7 ] Doppler interrogation of the UA and MCA have been shown to play an important role
in antenatal assessment of high-risk pregnancies, decreasing perinatal morbidity and
mortality.[8 ]
[9 ]
[10 ]
[11 ] In addition, the cerebroplacental ratio (CPR) may have value in the assessment of
fetal wellbeing and prediction of adverse neonatal outcomes.[12 ]
[13 ]
[14 ]
[15 ]
[16 ] CPR is a combined measurement of fetal response and placental status and theorized
to be a more sensitive Doppler index for predicting perinatal outcomes.[17 ]
[18 ]
The data on the utility of Doppler measurements in MCDA twins and prediction of adverse
pregnancy outcomes are limited with variable conclusions. Some have demonstrated an
association between abnormal Doppler measurements in monochorionic twins with neonatal
morbidity, preterm delivery, and low birth weight (BW), while others demonstrated
that isolated Doppler abnormalities are commonly observed in monochorionic twins and
are not associated with adverse outcomes.[19 ]
[20 ] Gaziano et al was the first study to evaluate CPR in both monochorionic and dichorionic
twin pregnancies and demonstrated that CPR was superior to the UA and MCA in prediction
of adverse neonatal events.[21 ] Lastly, two retrospective studies have explored the novel utility of intertwin discrepancy
of CPR and MCA-PSV and demonstrated an association with perinatal loss and sIUGR,
respectively.[22 ]
[23 ]
Doppler ultrasonography, specifically intertwin differences of Doppler indices, in
MCDA twin pregnancies requires further exploration to identify optimal methods of
surveillance and subsequent timely interventions for these high-risk pregnancies.
Here, we report our evaluation of the role of intertwin differences in MCA-PSV and
CPR in the surveillance of MCDA pregnancies and association with MCDA-specific complications.
Materials and Methods
We conducted a retrospective cohort study reviewing all MCDA twin pregnancies that
underwent antenatal surveillance over a 10-year period between January 1, 2007, and
February 1, 2017, at a single, high-volume metropolitan perinatal referral center
associated with the Department of Obstetrics and Gynecology at the David Geffen School
of Medicine at the University of California Los Angeles (UCLA). This study was approved
by the UCLA Institutional Review Board (IRB no.: 17–000486) and a waiver of informed
consent was obtained. Women with MCDA twin pregnancies who were scheduled for biweekly
ultrasounds, or as clinically indicated, between 16 and 34 weeks were included. All
ultrasound studies were performed by registered diagnostic sonographers, followed
by a confirmatory scan by a board-certified maternal-fetal medicine specialist. During
each biweekly ultrasound, patients underwent Doppler evaluation of UA and MCA parameters,
along with amniotic fluid and growth assessments per our center's protocol. Patients
were identified through a search function within the clinical ultrasound database.
We performed a multilayer search using dropdown values for number of gestation (“2”),
chorionicity (“monochorionic-diamniotic”), and report comments for appropriate terms
(“twin,” “twins,” and “monochorionic”). Each chart was reviewed individually to ensure
accuracy of chorionicity, and clinical information and ultrasound variables were extracted
from the review of medical records by one obstetrician (T.M.) to ensure uniformity
in coding. Only deidentified information was used.
Pregnancies were dated by measurement of crown-rump length (CRL) of the larger twin
in the first trimester, dates of embryo transfer in in vitro fertilization (IVF) patients,
or by the date of a certain last menstrual period (LMP) in women with regular cycles,
unless there was a discrepancy of more than 5 to 7 days between dating by LMP and
the CRL of the larger twin.[6 ] Chorionicity was determined by the presence of lambda or T signs and number of placentas
at the first ultrasound.[24 ] Exclusion criteria included pregnancies complicated by chromosomal abnormalities
or major structural anomalies and patients who presented after intrauterine fetal
demise (IUFD) before 16 weeks of either twin or after the development of MCDA-twin-specific
complications, including TTTS, TAPS, and sIUGR. Patients with incomplete ultrasound
records or without MCA Doppler measurements were also excluded.
Variables collected included maximum vertical pockets of amniotic fluid in each sac,
estimated fetal weight, UA, and MCA Doppler measurements. The head circumference,
biparietal diameter, abdominal circumference, and femur length were used to calculate
estimated fetal weight via Hadlock's formula.[25 ] UA Doppler measurements were categorized as normal, elevated systolic-to-diastolic
ratio defined as greater than 95th percentile for gestational age, absent-end diastolic
flow, or reverse-end diastolic flow. MCA Doppler measurements were defined as elevated
if peak systolic velocity (PSV) was greater than 1.5 multiples of the median (MoM)
for gestational age.[26 ]
Intertwin MCA-PSV discrepancy (MCA-ΔPSV-MoM ) was defined as the absolute difference of MCA-PSV MoM between the twins. CPR was
calculated as the ratio of MCA PI to UA PI, and intertwin CPR discrepancy (CPR-Δ)
was defined as the absolute difference of CPR between the twins. Measurements were
performed between 14 to 37 weeks. For this study, the MCA-ΔPSV-MoM and CPR-Δ measurements were divided evenly into two groups defined as the <26 weeks
group (14–25 completed weeks) and the ≥26 weeks group (26–37 completed weeks) and
assessed as predictors of adverse pregnancy outcomes. If multiple measurements were
performed, the maximum intertwin discrepancy for MCA and CPR were used for analysis.
The primary outcome of interest for this study was the development of MCDA-specific
complications, including TTTS, TAPS, and sIUGR. TTTS was diagnosed according to Quintero
staging criteria.[27 ] TAPS was defined as MCA-PSV higher than 1.5 MoM for gestational age in one twin
and lower than 0.8 MoM in the other twin.[28 ] This definition is based on our regional fetal surgeon's diagnostic criteria for
TAPS which is required before fetal interventions will be offered. sIUGR was diagnosed
when the estimated fetal weight of one twin was below 10th percentile for the assigned
gestational age.[29 ] Secondary outcomes that were collected included pregnancy and neonatal outcomes.
Pregnancy outcomes included IUFD(s), gestational age at delivery, and mode of delivery.
Neonatal outcomes included average birth weight (BW), BW difference, and NICU admission.
BW difference was calculated as (larger twin BW – smaller twin BW) / larger twin BW × 100%.[30 ]
Fisher's exact test or Chi-square test was used to examine the association between
categorical variables and complication groups, presented as frequency count (%). Continuous
variables were presented as median (interquartile range [IQR]) and compared using
the Wilcoxon's rank-sum test. The association between maximum MCA-ΔPSV-MoM or CPR-Δ at <26 weeks and ≥26 weeks and development of MCDA-specific complications
and other adverse pregnancy or neonatal outcomes were evaluated through simple logistic
regression models and calculation of Pearson's correlation coefficients. Receiver
operating characteristic (ROC) curves were generated to assess the predictive value
of maximum MCA-ΔPSV-MoM and CPR-Δ at <26 weeks and ≥26 weeks, and Youden's index was used to identify their
best cut-off values in the prediction of respective outcomes. p -Values of <0.05 were considered statistically significant. All analyses were performed
using SAS v9.4 (SAS Institute Inc., Cary, NC).
Results
Two hundred and twenty MCDA twin pregnancies were identified. Seventy pregnancies
were excluded due to incomplete clinical data (e.g., single, second-opinion ultrasound
or lack of MCA data prior to development of a standardized protocol), one was excluded
due to unclear chorionicity, three were excluded due to referral after development
of TTTS, and three were excluded because of major fetal structural anomalies. As a
result, 143 MCDA twin pregnancies met inclusion criteria and were included in the
analysis. A total of 1,763 ultrasounds were reviewed with a median of 11 (IQR: 8–14)
ultrasounds performed per patient throughout the gestation. A total of 1,187 MCA and
834 CPR measurements were collected for analysis.
Baseline maternal demographics and clinical characteristics of all MCDA twin pregnancies
and those that developed TTTS, TAPS, or sIUGR are depicted in [Table 1 ]. Maternal age, body mass index (BMI), race, parity, and the presence of maternal
comorbidity did not differ significantly between pregnancies complicated by MCDA-twin-specific
complications. Pregnancies complicated by sIUGR were more likely to have a history
of a prior preterm delivery (p = 0.02) and had a higher proportion of Hispanic ethnicity (p = 0.04). Pregnancies conceived by assisted reproductive technology did not differ
in development of TTTS, TAPS, or sIUGR when compared with those that conceived spontaneously
(p > 0.10).
Table 1
Maternal demographics and characteristics of all MCDA twin pregnancies and those with
MCDA-twin-specific complications
Characteristic
All patients (n = 143)
TTTS (n = 16)
p -Value
TAPS (n = 7)
p -Value
sIUGR (n = 41)
p -Value
Maternal age (y)
Median (IQR)
35.0 (31–38)
34.0 (31.5–37.5)
0.75
36 (33–39)
0.36
34.0 (30–36)
0.07
Body mass index (kg/m2 )
Median (IQR)
26.1 (22.2–28.9, n = 124)
24.5 (21.8–29.4, n = 14)
0.63
28.0 (21.9–28.3, n = 5)
0.84
26.6 (21.9–29.3, n = 34)
0.58
Weight (kg)
Median (IQR)
64.4 (56.7–75.2, n = 131)
60.6 (55.8–75.2, n = 14)
0.86
75.1 (69.9–77.1, n = 6)
0.12
62.8 (56.7–70.5, n =36)
0.18
Ethnicity
Hispanic/Latino
9 (6.3)
1 (6.3)
1.00
0 (0)
1.00
6 (14.6)
0.04
Not Hispanic/Latino
135 (94.4)
15 (93.7)
7 (100)
35 (85.4)
Race
White/more than one race
97 (67.8)
11 (68.8)
0.71
5 (71.4)
0.29
28 (68.3)
0.51
Black/African American
3 (2.1)
0 (0)
0 (0)
0 (0)
Asian or Pacific Islander
28 (19.6)
3 (18.8)
0 (0)
7 (17.1)
Other
12 (8.4)
1 (6.3)
2 (28.6)
4 (9.8)
Unknown
4 (2.8)
1 (6.3)
0 (0)
2 (4.9)
Nulliparous
59 (41.3)
7 (43.8)
1.00
1 (14.3)
0.24
19 (46.3)
0.46
History of preterm delivery
No
140 (97.9)
16 (100)
1.00
7 (100)
1.00
38 (92.7)
0.02
Yes
3 (2.1)
0 (0)
0 (0)
3 (7.3)
Maternal comorbidity
None
122 (85.3)
14 (87.5)
0.69
6 (85.7)
0.41
31 (75.6)
0.11
Chronic hypertension
1 (0.7)
0 (0)
0 (0)
0 (0)
Diabetes mellitus
3 (2.1)
0 (0)
1 (14.3)
2 (4.9)
Asthma
3 (2.1)
1 (6.3)
0 (0)
1 (2.4)
Thyroid disease
6 (4.2)
0 (0)
0 (0)
4 (9.8)
Other
8 (5.6)
1 (6.3)
0 (0)
3 (7.3)
Use of ART
No
97 (67.8)
13 (81.3)
0.27
7 (100)
0.10
29 (70.7)
0.70
Yes
46 (32.2)
3 (18.8)
0 (0)
12 (29.3)
Abbreviations: ART, assisted reproductive technology; IQR, interquartile range; MCDA,
monochorionic-diamniotic; sIUGR, selective intrauterine growth restriction; TAPS,
twin anemia-polycythemia sequences; TTTS, twin-to-twin transfusion syndrome.
Note: Values are presented as n (%) unless otherwise indicated. If values were missing for certain parameters, n is indicated.
Sixteen (11.2%) pregnancies were complicated by TTTS, 7 (4.9%) by TAPS, and 41 (28.7%)
by sIUGR ([Fig. 1 ]). The median gestational age at diagnosis was 22.7 weeks (range: 15.4–30.0), 30.1
weeks (range: 17.9–35.0), and 26.3 weeks (range: 14.9–25.9) for TTTS, TAPS, and sIUGR,
respectively. Of those with TTTS, four (25%) were stage I, six (37.5%) were stage
II, four (25%) were stage III, one (6.3%) was stage IV, and one (6.3%) was stage V.
Nine (56.3%) pregnancies complicated by TTTS underwent laser ablation, and the remaining
seven pregnancies underwent expectant management due to being ineligible for intervention.
Five pregnancies were greater than 26 weeks of gestation at the time of diagnosis
and two were complicated by IUFD of both twins. Of the seven pregnancies complicated
by TAPS, six (85.7%) were spontaneous TAPS and one (14.3%) developed following laser
ablation treatment of TTTS. All but one of the pregnancies complicated by sIUGR was
diagnosed with type-1 sIUGR, and all underwent expectant management with close surveillance.
Fig. 1 Flow diagram of monochorionic-diamniotic twin pregnancies and development of primary
outcomes. MCDA, monochorionic-diamniotic; sIUGR, selective intrauterine growth restriction;
TAPS, twin anemia-polycythemia sequence; TTTS, twin-twin transfusion syndrome.
Pregnancy and neonatal outcomes are summarized in [Table 2 ]. Fourteen patients did not have delivery outcomes available for review due to delivery
outside the system, and two pregnancies were complicated by TTTS resulting in fetal
demise of both twins. As a result, a total of 127 patients with pregnancy and neonatal
outcomes were available for review. Gestational age of delivery was significantly
lower for pregnancies complicated by TTTS (p < 0.01) and sIUGR (p = 0.01) but not for TAPS (p = 0.23). Indication for delivery was also significantly different for pregnancies
complicated by TTTS (p < 0.01) and sIUGR (p < 0.01) but not TAPS (p = 0.46). There was not an increased risk of cesarean delivery for pregnancies with
MCDA-specific complications. The average BW was significantly lower in pregnancies
that were complicated by TTTS (p < 0.01) and sIUGR (p < 0.01) but not for pregnancies complicated by TAPS (p = 0.53). As expected, BW discordance was higher in pregnancies complicated by sIUGR
at 17.7% (IQR: 12.1–24.0, p < 0.01). Pregnancies that developed MCDA-specific complications had more than twice
the NICU admissions of one or both twins compared with respective uncomplicated MCDA
pregnancies. There were a total of four neonatal deaths, three of which were pregnancies
complicated by TTTS.
Table 2
Pregnancy and neonatal outcomes of all MCDA twin pregnancies and those with MCDA-twin-specific
complications
Pregnancy/neonatal outcome
All patients (n = 127)
TTTS (n = 14)
p -Value
TAPS (n = 6)
p -Value
sIUGR (n = 36)
p -Value
Mode of delivery
Cesarean section
105 (82.7)
12 (85.7)
1.00
4 (66.7)
0.30
32 (88.9)
0.59
Vaginal delivery
21 (16.5)
2 (14.3)
2 (33.3)
4 (11.1)
Assisted vaginal delivery
1 (0.01)
0 (0)
0 (0)
0 (0)
Gestational age at birth
Median (IQR)
35.9 (34.0–36.4)
30.7 (28–35)
<0.01
34.7 (34.1–35.7)
0.23
34.9 (33.9–35.9)
0.01
Indication for delivery
Spontaneous labor
38 (29.9)
6 (42.9)
<0.01
2 (33.3)
0.46
8 (22.2)
<0.01
Uncomplicated MCDA twins
36 (28.3)
0 (0)
0 (0)
0 (0)
Complicated MCDA twins
31 (24.4)
4 (28.6)
3 (50.0)
24 (66.7)
NRFHT
8 (6.3)
4 (28.6)
1 (16.7)
3 (8.3)
HTN disease of pregnancy
8 (6.3)
0 (0)
0 (0)
1 (2.8)
Other
6 (4.7)
0 (0)
0 (0)
0 (0)
Birth weight difference (%)
Median (IQR)
9.2 (4.2–16.9), n = 122
10.6 (7.2–13.0), n = 11
0.62
5.3 (3.4–8.0), n = 5
0.14
17.7 (12.3–24.0), n = 35
<0.01
Average birth weight (g)
Median (IQR)
2,237.5 (1,925.1–2,494.8), n = 122
1,675.0 (917.5–1,927.8), n = 11
<0.01
2,092.5 (2,077.5–2,205.0), n = 5
0.53
1,990 (1,692.5–2,193.8), n = 35
<0.01
NICU admission
None
53 (42.7)
3 (21.4)
0.02
2 (33.3)
0.08
6 (17.1)
<0.01
One twin
20 (16.1)
3 (21.4)
1 (16.7)
9 (25.7)
Both twins
51 (41.1)
8 (61.5)
3 (50.0)
20 (57.1)
Length of NICU stay (d)
6 (0–20), n = 124
46 (15–75)
<0.01
13.5 (7–19)
0.21
15 (6–24), n = 35
<0.01
Abbreviations: HTN, hypertensive; IQR, interquartile range; MCDA, monochorionic-diamniotic;
NICU, neonatal intensive care unit; NRFHT, nonreassuring fetal heart rate tracing;
sIUGR, selective intrauterine growth restriction; TAPS, twin anemia-polycythemia sequences;
TTTS, twin-to-twin transfusion syndrome.
Note: Values are presented as n (%) unless otherwise indicated. If values were missing for certain parameters, n is indicated.
Results of the univariate logistic regression model analysis of MCA-ΔPSV-MoM and CPR-Δ are presented in [Table 3 ]. MCA-ΔPSV-MoM at <26 weeks was associated with IUFD (odds ratio [OR] = 18.91, 95% confidence interval
[CI]: 2.11–169.13, p = 0.01,), NICU admission (OR = 91.46, 95% CI: 1.26–301.74, p = 0.03), and TAPS (OR = 21.39, 2.33–196.80, p = 0.01). MCA-ΔPSV-MoM at ≥26 weeks was also associated with TAPS (OR = 769.79, 95% CI: 15.98–999.99, p < 0.01). Intertwin CPR discrepancy at <26 weeks was significantly associated with
the development of TTTS (OR = 2.23, 95% CI: 1.10–4.76, p = 0.03). The average time before TTTS developed and intertwin CPR discordance first
noted was 2 weeks and 1 day, and 80% of the measurements demonstrated a lower CPR
value in the donor and a higher CPR value in the recipient. CPR-Δ at <26 weeks was
also significantly associated with NICU admission of at least one twin (OR = 3.94,
95% CI: 1.31–11.85, p = 0.02).
Table 3
Logistic regression model analysis of intertwin MCA-PSV MoM and CPR difference at
<26 and ≥26 weeks as predictors of complications in MCDA twin pregnancies
Outcome
Intertwin difference with outcome
Intertwin difference without outcome
Odds ratio
95% CI
p -Value
<26 weeks intertwin MCA-PSV MoM difference
TTTS
0.35 ± 0.32
0.28 ± 0.20
3.20
0.48–21.33
0.23
TAPS
0.60 ± 0.55
0.27 ± 0.17
21.39
2.33–196.80
0.01
sIUGR
0.31 ± 0.24
0.28 ± 0.21
1.79
0.34–9.42
0.49
IUFD
0.59 ± 0.63
0.28 ± 0.16
18.91
2.11–169.13
0.01
NICU admission
0.33 ± 0.26
0.23 ± 0.11
19.46
1.26–301.74
0.03
≥26 weeks intertwin MCA-PSV MoM difference
TTTS
0.35 ± 0.18
0.37 ± 0.19
0.88
0.03–24.99
0.94
TAPS
0.72 ± 0.25
0.35 ± 0.17
769.79
15.98–>999.99
<0.01
sIUGR
0.36 ± 0.19
0.37 ± 0.19
0.78
0.09–6.68
0.82
IUFD
0.18
0.37 ± 0.19
0.002
<0.001–314.35
0.31
NICU admission
0.40 ± 0.22
0.33 ± 0.15
6.86
0.70–66.89
0.10
<26 weeks intertwin CPR difference
TTTS
1.21 ± 1.48
0.60 ± 0.50
2.23
1.10–4.76
0.03
TAPS
0.56 ± 0.30
0.68 ± 0.72
1.09
0.39–3.04
0.87
sIUGR
0.76 ± 0.53
0.65 ± 0.77
1.23
0.73–2.05
0.44
IUFD
0.95 ± 1.09
0.64 ± 0.67
0.92
0.30–2.82
0.80
NICU admission
0.81 ± 0.82
0.50 ± 0.40
3.94
1.31–11.85
0.02
≥26 weeks intertwin CPR difference
TTTS
0.78 ± 0.53
1.05 ± 1.01
0.58
0.16–2.14
0.42
TAPS
0.96 ± 0.46
1.03 ± 1.01
1.21
0.66–2.23
0.55
sIUGR
0.94 ± 0.57
1.06 ± 1.09
0.84
0.48–1.46
0.53
IUFD
0.58 ± 0.37
1.04 ± 0.99
0.11
<0.001–32.94
0.44
NICU admission
0.86 ± 0.54
1.20 ± 1.44
0.61
0.34–1.11
0.11
Abbreviations: CI, confidence interval; CPR, cerebroplacental ratio; IUFD, intrauterine
fetal demise; MCA-PSV, middle cerebral artery-peak systolic velocity; MCDA, monochorionic-diamniotic;
MoM, multiple of the median; NICU, neonatal intensive care unit; sIUGR, selective
intrauterine growth restriction; TAPS, twin anemia-polycythemia sequences; TTTS, twin-to-twin
transfusion syndrome.
Note: Values are presented as mean ± standard deviation.
Pearson's correlation coefficient demonstrated a significant correlation between CPR-Δ
at <26 weeks to gestational age at delivery (r = − 0.30, p = 0.002) and average BW (r = − 0.38, p < 0.001). Increasing CPR-Δ at <26 weeks was correlated with earlier gestational age
at delivery and lower average BW, respectively. There was also a moderate association
of increasing CPR-Δ at <26 weeks with nonreassuring fetal testing requiring delivery
(r = 0.39). In contrast, CPR-Δ at ≥26 weeks was not associated with the development
of complications or adverse perinatal outcomes.
ROC curves were developed to assess the predictive performance of MCA-ΔPSV-MoM and CPR-Δ for MCDA-twin-specific complications and other adverse pregnancy and neonatal
outcomes. [Fig. 2 ] presents the ROC curves for MCA-ΔPSV-MoM at <26 weeks for TAPS (area under curve [AUC] = 0.62), IUFD (AUC = 0.61), and NICU
admission (AUC = 0.61) and MCA-ΔPSV-MoM at ≥26 weeks for TAPS (AUC = 0.92). An intertwin MCA PSV MoM discrepancy of 0.61
at <26 weeks would identify TAPS with a sensitivity of 57% and specificity of 98%.
A MCA-ΔPSV-MoM cut-off of 0.27 at <26 weeks would identify pregnancies complicated by IUFD with
sensitivity of 71% and specificity of 61%, and an intertwin MCA PSV MoM discrepancy
of 0.36 at <26 weeks would predict the requirement of NICU admission with a sensitivity
of 34% and specificity of 89%. With an MCA-ΔPSV-MoM cut-off of 0.44 at ≥26 weeks, we would identify pregnancies complicated by TAPS with
a sensitivity of 100% and specificity of 73%.
Fig. 2 Receiver operating characteristic curves for prediction of (A ) TAPS, (B ) IUFD, (C ) NICU admission by intertwin MCA-PSV MoM difference at <26 weeks and (D ) TAPS by intertwin MCA-PSV MoM difference at ≥26 weeks. AUC, area under curve; MCA-PSV;
middle cerebral artery peak systolic velocity; MoM, multiple of the median; NICU,
neonatal intensive care unit; IUFD, intrauterine fetal demise; TAPS, twin anemia-polycythemia
sequence.
Fig. 3 Receiver operating characteristic curves for prediction of (A ) TTTS and (B ) NICU admission by intertwin CPR difference at < 26 weeks. CPR, cerebroplacental
ratio; NICU, neonatal intensive care unit; TTTS, twin-twin transfusion syndrome.
ROC curves for the development of TTTS (AUC = 0.68) and NICU admissions (AUC = 0.67)
by CPR-Δ at <26 weeks are shown in [Fig. 3 ]. With a CPR-Δ cut-off of 0.73 at <26 weeks, we would identify pregnancies complicated
by TTTS with a sensitivity of 67% and a specificity of 73%. Using a CPR-Δ cut-off
of 0.39 at <26 weeks, we would identify pregnancies requiring NICU admission following
delivery with 78 and 55% of sensitivity and specificity, respectively.
Discussion
This study evaluates the utility of intertwin discrepancy of MCA-PSV MoM and CPR in
the surveillance of MCDA twin pregnancies and its association with the development
of MCDA-twin-specific complications and adverse pregnancy outcomes. We identified
that increased intertwin differences in these parameters at various times in gestation
can be associated with the development of complications of MCDA twin gestations and
adverse pregnancy outcomes.
Confirmation that MCA-ΔPSV-MoM at ≥26 weeks is a strong predictor of TAPS is consistent with the current diagnostic
criteria of TAPS.[28 ] A recent study by Tollenaar et al demonstrated that delta MCA PSV > 0.5 MoM had
a greater diagnostic accuracy for predicting TAPS than the traditional individual
MCA PSV cut-off criteria.[31 ] Our study supports their findings that increasing intertwin MCA-ΔPSV-MoM may be predictive of the eventual development of TAPS. However, the MCA-ΔPSV-MoM cut-off value shown to be most predictive of TAPS in our study was 0.44 MoM. This
is lower than traditional diagnostic criteria for TAPS and the one suggested by Tollenaar
et al. Based on our study findings, intertwin MCA-ΔPSV-MoM may provide additional utility in identifying evidence of TAPS prior to meeting the
classic diagnostic criteria and earlier in the process. In addition, the predictive
value of MCA-ΔPSV-MoM for TAPS was significantly higher at ≥26 weeks than at <26 weeks consistent with
the majority of TAPS cases being diagnosed in the late second or third trimester.[32 ] The discrepancy in predictive value of MCA-ΔPSV-MoM at <26 versus ≥26 weeks of TAPS argues for continued surveillance of the MCA throughout
the entirety of the pregnancy.
Multiple studies have demonstrated the value of CPR in the evaluation of singleton
pregnancies for the prediction of adverse perinatal outcomes, particularly in fetal
growth restriction.[13 ]
[14 ]
[15 ]
[16 ]
[17 ]
[18 ] We did not see an association with intertwin CPR difference and development of sIUGR.
A possible explanation for the lack of association with sIUGR is that we did not include
an estimated fetal weight discordance of 25% in the diagnostic criteria for sIUGR
and as a result, the average BW discordance in our cohort was 17.7% with no pair exceeding
24% discordance, likely demonstrating less-severe sIUGR. In addition, all of the pregnancies
except one were complicated by type-1 sIUGR which is associated with a more favorable
outcome. In contrast, we observed a significant association with CPR-Δ at <26 weeks
with NICU admission. Increasing CPR-Δ at < 26 weeks was also correlated with earlier
gestational age at delivery, lower average BW, and development of nonreassuring fetal
status requiring delivery. It is possible that these were confounding factors, as
they are interrelated and can influence the rate of NICU admission. However, prior
studies on singleton gestations of both small for gestational age and appropriate
for gestational age fetuses have also shown that CPR is an independent predictor for
NICU admissions.[14 ]
[15 ] These studies along with our study findings of CPR-Δ at <26 weeks associated with
NICU admission and nonreassuring fetal status requiring delivery may support the claim
that CPR serves as a more sensitive marker for placental insufficiency.
Multiple second trimester ultrasound findings have been demonstrated to be associated
with TTTS.[33 ]
[34 ]
[35 ] Our study is the first to demonstrate an association between intertwin CPR difference
and the development of TTTS. On average, intertwin CPR discordance was identified
2 weeks and 1 day prior to the development of TTTS, and 62.5% (10/16) of pregnancies
complicated by TTTS did not demonstrate an abnormal CPR value by the traditional criteria
of <1. This temporal association of impending TTTS may prompt heightened surveillance.
Although there was a significant association of CPR-Δ at <26 weeks with development
of TTTS, our cohort did not demonstrate significant predictive ability of the measurement.
The assessment in predictive value of CPR-Δ at <26 weeks may have been limited by
the lower number of pregnancies complicated by TTTS and further studies are required
to assess its clinical utility.
Limitations and Strengths
Limitations and Strengths
The primary limitation of this study is its retrospective design. Approximately one-third
of the patients identified as MCDA twins for possible inclusion were one-time second-opinion
evaluations without continued serial surveillance at our center or were evaluated
prior to the inclusion of MCA evaluation into our center's surveillance protocol.
As a result, the number of MCDA twins and specifically those with MCDA-specific complications
that were included in the study for analysis was decreased. Additionally, delivery
outcomes were unavailable for 14 patients due to delivery outside the system, but
they were included in the analysis because both ultrasound and primary outcome data
were available for review. Furthermore, neonatal hemoglobin and hematocrit data were
not included in the analysis and antenatal diagnosis of TAPS could not be confirmed.
Missing data are inherent to the retrospective nature of this study and may have resulted
in a bias. Patients included in the study were identified through the search function
of the clinical ultrasound database which may have led to ascertainment bias. There
may also be a component of selection bias for a high-risk population, given that the
patients selected for this study are from a perinatal referral center.
Overall, our study demonstrates that intertwin MCA-ΔPSV-MoM is associated with TAPS, IUFD, and NICU admission, and intertwin CPR-Δ is associated
with TTTS and NICU admission. We also demonstrate the strong predictive value of MCA-ΔPSV-MoM at ≥26 weeks for TAPS with a cut-off value lower than the current diagnostic criteria
for TAPS. Current recommendations from the Society for Maternal-Fetal Medicine on
management of MCDA twin pregnancies do not include routine surveillance of UA or MCA
Doppler during biweekly ultrasounds, but the findings from this study may suggest
potential utility.[7 ] We recognize that the overall number of complicated MCDA-twin pregnancies is lower
within the study and postnatal confirmation of TAPS was not performed, which makes
it difficult to make robust clinical recommendations from our study. However, the
associations identified in this study brings attention to an alternative method of
assessing fetal status in MCDA twin gestations through intertwin discrepancy of measurements
rather than isolated values.
Conclusion
Based on these study findings, an increase in intertwin MCA and CPR discrepancy may
be associated with adverse pregnancy and neonatal outcomes, including TAPS, TTTS,
IUFD, and NICU admission. This study highlights the utility of assessing intertwin
differences in Doppler indices in the surveillance of MCDA twin pregnancies and their
role in potentially predicting the risk for development of perinatal complications.
Earlier or more accurate identification of such complications may allow for earlier
clinical interventions, including fetal therapy, evaluation for appropriate timing
of delivery, allowing time for antenatal transfer to higher level of care, or ensuring
delivery at a tertiary care center where adequate postnatal interventions are available.
This in turn may improve neonatal outcomes. Prospective trials are required to evaluate
the clinical utility of surveillance of intertwin MCA and CPR differences to identify
pregnancies at risk for development of TTTS or TAPS, allowing for earlier detection
and successful intervention.