Keywords
monochorionic triplets - triplet outcomes based on chorionicity - dichorionic triplets
- diamniotic - monochorionic twin pair in triplet gestation - triplet gestation outcomes
The incidence of multiple gestations has risen significantly over several decades.
This is primarily due to the increased use of fertility drugs for ovulation induction,
superovulation, and assisted reproductive technologies (ARTs), such as in vitro fertilization
(IVF). In 1960, before the commercial availability of drugs for the treatment of infertility,
there were approximately 4.3 million births in the United States, with 1,244 triplets
and higher-order multiples. In 2011, the total number of births was slightly lower
(3.9 million), but there were 5,417 triplets and higher-order multiples.[1] Approximately 20% of higher-order multiple births are naturally conceived, 39 to
67% are related to ovulation induction/superovulation, and 13 to 44% are associated
with ART.
Multiple gestations are at significantly increased risk of fetal, neonatal, and maternal
complications, as well as complete pregnancy loss, when compared with singleton pregnancies.
In a recent review, the risk of delivery < 32 weeks of gestation for singleton, twin,
triplet, and quadruplet pregnancies was 2, 8, 26, and > 95%, respectively.[2]
Most IVF centers in the United States look to balance success along with limiting
higher-order multiples.[3] However, even with the transfer of two embryos, there appears to be an increasing
number of triplet gestations with a monochorionic (MC) twin pair.[4] This occurs when one of the transferred embryos splits into a twin pair that shares
a placenta. The monochorionic twin pairs suffer additional risks of growth discordance
and twin-twin transfusion syndrome (TTTS), as compared with dichorionic (DC) twin
gestations.[5] This translates into even earlier preterm delivery rates and increased morbidity,
mortality, and long-term sequelae of prematurity.[6]
[7]
Studies evaluating triplet pregnancy outcomes in relation to chorionicity have been
few and may not reflect contemporary antenatal and neonatal care.[8]
[9]
[10] We aimed to compare perinatal and neonatal outcomes in triplet gestations based
on placental chorionicity in a contemporary cohort. We hypothesized that triplets
containing a DC or MC placenta continue to have increased morbidity and mortality
compared with a trichorionic (TC) triplet gestation.
Methods
This was a retrospective cohort study of triplet gestations delivered at ≥ 20 weeks
at a tertiary care hospital from 2009 to 2015. Data were abstracted through the hospital
and outpatient office electronic medical records. A total of 42 sets of triplets were
found to be eligible for analysis, of which 26 were TC, 14 DC, and 2 MC. The DC and
MC gestations were combined into one group (DC + MC, n = 16) for the comparisons. All gestations were triamniotic. This study was approved
by the Advocate Institutional Review Board and a waiver of consent was obtained.
The primary outcome was composite neonatal morbidity and mortality, including respiratory
distress syndrome (RDS), intraventricular hemorrhage (IVH), necrotizing enterocolitis
(NEC), < 10th percentile birth weight, and death.
We relied on a convenience sample size of eligible neonates who met the study eligibility
criteria. Descriptive statistics for continuous variables are reported as mean ± standard
deviation (SD), while count and percent are reported for all categorical variables.
Comparative analysis between the TC versus DC + MC groups were compared using independent
Student t-tests or Wilcoxon Rank sum tests for the continuous variables, and Pearson chi-square
or Fisher's exact test for the categorical variables as applicable. All analyses were
performed using SPSS for Windows, version 22.0 (SPSS Inc., Chicago, IL). A two-tailed
p level of 0.05 was considered statistically significant in all analyses.
Results
Maternal baseline characteristics were comparable as outlined in [Table 1]. Except for race and body mass index (BMI), with more patients in the TC group being
of non-Hispanic/white or Asian/Pacific Islander descent (p = 0.04) and having higher BMIs (p = 0.02), no other differences were noted.
Table 1
Maternal baseline characteristics
|
Variable
|
Total
n = 42
|
Trichorionic
Triamniotic
n = 26
|
Dichorionic + monochorionic
Triamniotic
n = 16
|
p Value
|
|
Maternal age (y), mean ( ± SD)
|
33.4 ( ± 4.43)
|
33.5 ( ± 4.7)
|
33.3 ( ± 4.1)
|
0.85
|
|
Mode of conception, n (%)
|
|
|
|
|
|
Spontaneous
Ovulation induction
Assisted (IVF, IUI)
|
5 (11.9)
2 (4.8)
35 (83.3)
|
4 (15.4)
2 (7.7)
20 (76.9)
|
1(6.3)
0
15 (93.8)
|
0.63
0.52
0.22
|
|
Race, n (%)
|
|
|
|
|
|
Non-Hispanic/white
Black
Hispanic
Asian/Pacific Islander
|
35 (83.3)
2 (4.8)
1 (2.4)
4 (9.5)
|
24 (92.3)
2 (7.7)
0
0
|
11 (68.8)
0
1 (6.3)
4 (25.0)
|
0.04[a]
0.52
0.38
0.02[a]
|
|
Nulliparous, n (%)
|
19 (45.2)
|
11 (42.3)
|
8 (50.0)
|
0.63
|
|
Body mass index (kg/m2), mean ( ± SD)
|
32.6 ( ± 7.2)
|
34.3 ( ± 8.1)
|
29.69 ( ± 4.5)
|
0.02[a]
|
|
Previous preterm delivery, n (%)
|
3 (7.1)
|
2 (7.7)
|
1 (6.3)
|
1.00
|
Abbreviations: IUI, intrauterine insemination; IVF, in vitro fertilization; SD, standard
deviation.
a
p < 0.05.
All patients were managed by the maternal-fetal medicine service with a standardized
protocol for fetal surveillance based on chorionicity. There were no significant differences
in pregnancy complications ([Table 2]), including the presence of a shortened cervix, cerclage placement, use of tocolytics,
premature rupture of membranes, pregnancy-induced hypertension, gestational diabetes,
or TTTS. Significantly more patients in the combined DC + MC group received vaginal
progesterone (43.8 vs. 11.5%, p = 0.03). An increased risk of intrauterine growth restriction (IUGR) was noted in
the DC + MC group (25 vs. 3.8%); however, the difference was not statistically significant
given the small number of patients (p = 0.06).
Table 2
Prenatal management and complications
|
Variable
|
Total
n = 42
|
Trichorionic
Triamniotic
n = 26
|
Dichorionic + monochorionic
Triamniotic
n = 16
|
p Value
|
|
Short cervix, n (%)
|
3 (7.1)
|
2 (7.7)
|
1 (6.3)
|
1.00
|
|
GA diagnosis, mean ( ± SD)
|
21.8 ( ± 1.9)
|
21.3 ( ± 2.1)
|
23.0 ( ± 0.1)
|
0.56
|
|
Cerclage, n (%)
|
6 (14.3)
|
4 (15.4)
|
2 (12.5)
|
1.00
|
|
Tocolytic therapy, n (%)
|
24 (57.1)
|
13 (50.0)
|
11 (68.8)
|
0.23
|
|
Vaginal progesterone, n (%)
|
10 (23.8)
|
3 (11.5)
|
7 (43.8)
|
0.03[a]
|
|
Corticosteroids, n (%)
|
|
|
|
|
|
1 course
2 courses
|
19 (45.2)
11 (26.2)
|
11 (42.3)
5 (19.2)
|
8 (50.0)
6 (37.5)
|
0.75
0.28
|
|
IUGR, n (%)
|
5 (11.9)
|
1 (3.8)
|
4 (25.0)
|
0.06
|
|
PROM, n (%)
|
13 (31.0)
|
10 (38.5)
|
3 (18.8)
|
0.30
|
|
PIH, n (%)
|
13 (31.0)
|
9 (34.6)
|
4 (25.0)
|
0.73
|
|
Gestational DM, n (%)
|
4 (9.5)
|
3 (11.5)
|
1 (6.3)
|
1.00
|
|
TTTS, n (%)
|
2 (4.8)
|
0
|
2 (12.5)
|
0.14
|
Abbreviations: DM, diabetes mellitus; GA, gestational age; IUGR, intrauterine growth
retardation; PIH, prolactin inhibitory hormone; PROM, premature rupture of membranes;
SD, standard deviation; TTTS, twin-twin transfusion syndrome.
a
p < 0.05.
No statistically significant differences were noted for the recorded pregnancy outcomes
between the groups (all p values > 0.05; [Table 3]). The risk of preterm delivery was higher between 28 and 32 weeks in the DC + MC
group (37.5 vs. 11.5%), but not statistically significant (p = 0.06). TTTS (n = 2, 12.5%) was noted only in the DC + MC group.
Table 3
Pregnancy outcomes
|
Variable
|
Total
n = 42
|
Trichorionic
Triamniotic
n = 26
|
Dichorionic + monochorionic
Triamniotic
n = 16
|
p Value
|
|
GA at delivery, n (%)
|
|
|
|
|
|
32–37 wk
28–32 wk
< 28 wk
|
28 (66.7)
9 (21.4)
5 (11.9)
|
20 (76.9)
3 (11.5)
3 (11.5)
|
8 (50.0)
6 (37.5)
2 (12.5)
|
0.10
0.06
1.00
|
|
Delivery, n (%)
|
|
|
|
|
|
Spontaneous labor
Induction
Medical indication
|
24 (57.1)
7 (16.7)
11 (26.2)
|
17 (65.4)
5 (19.2)
4 (15.4)
|
7 (43.8)
2 (12.5)
7 (43.8)
|
0.21
0.69
0.09
|
|
PPH, n (%)
|
6 (14.3)
|
5 (19.2)
|
1 (6.3)
|
0.38
|
|
Blood transfusion, n (%)
|
7 (16.7)
|
7 (26.9)
|
0
|
NA
|
Abbreviations: GA, gestational age; NA, not applicable; PPH, postpartum hemorrhage.
Most neonatal outcomes were comparable between the groups ([Table 4]). However, a significant decrease in birth weight was noted in the DC + MC group,
especially for neonates B and C (p = 0.03 and 0.01, respectively). Similar results were noted for neonates B and C when
they were categorized into < 10th percentile birth weight (p = 0.04). Also, neonates C in the DC + MC group were statistically more likely to
have low APGAR (American Pediatric Gross Assessment Record) scores compared with the
neonates in the TC group (8.9 vs. 8.4, p = 0.05). Both neonatal deaths were noted in triplet C.
Table 4
Neonatal outcomes
|
Variable
|
Total
n = 42
|
Trichorionic
Triamniotic
n = 26
|
Dichorionic + monochorionic
Triamniotic
n = 16
|
p Value
|
|
Low APGAR (< 7) at 5 minute, mean ( ± SD)
|
|
|
|
|
|
Neonate A
Neonate B
Neonate C
|
8.7 ( ± 0.6)
8.8 ( ± 0.5)
8.7 ( ± 0.6)
|
8.8 ( ± 0.4)
8.9 ( ± 0.3)
8.9 ( ± 0.3)
|
8.4 ( ± 0.8)
8.6 ( ± 0.7)
8.4 ( ± 0.7)
|
0.09
0.07
0.05[a]
|
|
Congenital malformations, n (%)
|
3 (7.1)
|
2 (7.7)
|
1 (6.3)
|
1.00
|
|
NICU admission, n (%)
|
|
|
|
|
|
Neonate A
Neonate B
Neonate C
|
7 (16.7)
9 (21.4)
8 (19.0)
|
5 (19.2)
4 (15.4)
3 (11.5)
|
2 (12.5)
5 (31.3)
5 (31.3)
|
0.40
0.72
0.45
|
|
LOS (d), mean ( ± SD)
|
9.64 ( ± 9.9)
|
8.29 ( ± 7.8)
|
12 ( ± 12.3)
|
0.28
|
|
> 30% discordance, n (%)
|
5 (11.9)
|
3 (11.5)
|
2 (12.5)
|
1.00
|
|
RDS, n (%)
|
|
|
|
|
|
Neonate A
Neonate B
Neonate C
|
24 (57.1)
27 (64.3)
25 (59.5)
|
13 (50.0)
18 (69.2)
15 (57.7)
|
11 (68.8)
9 (56.3)
10 (62.5)
|
0.20
1.00
0.74
|
|
IVH grades 3 and 4, n (%)
|
|
|
|
|
|
Neonate A
Neonate B
Neonate C
|
0
0
2 (4.8)
|
0
0
1 (3.8)
|
0
0
1 (6.3)
|
NA
NA
1.00
|
|
NEC, n (%)
|
|
|
|
|
|
Neonate A
Neonate B
Neonate C
|
3 (7.1)
0
1 (2.4)
|
1(3.8)
0
0
|
2 (12.5)
0
1 (6.3)
|
0.54
NA
0.37
|
|
Death, n (%)
|
|
|
|
|
|
Neonate A
Neonate B
Neonate C
|
0
0
3 (7.1)
|
0
0
1 (3.8)
|
0
0
2 (12.5)
|
NA
NA
0.54
|
|
< 10th percentile birth weight, n (%)
|
|
|
|
|
|
Neonate A
Neonate B
Neonate C
|
10 (23.8)
5 (11.9)
5 (11.9)
|
6 (23.1)
1 (3.8)
1 (3.8)
|
4 (25.0)
4 (25.0)
4 (25.0)
|
0.72
0.04[a]
0.04[a]
|
|
Birth weight (g), mean ( ± SD)
|
|
|
|
|
|
Neonate A
Neonate B
Neonate C
|
1,644.6 ( ± 557.7)
1,715.1 ( ± 503.4)
1,694.3 ( ± 520.9)
|
1,717.89 ( ± 579.4)
1,844.2 ( ± 508.6)
1,846.9 ( ± 483.6)
|
1,508.5 ( ± 506.8)
1,475.4 ( ± 409.4)
1,446.3 ( ± 496.2)
|
0.26
0.03[a]
0.01[a]
|
|
Composite morbidity (M) and mortality (M), n (%)[b]
|
105 (83.3)
|
57 (73.1)
|
48 (100)
|
<0.01[c]
|
Abbreviations: APGAR, American Pediatric Gross Assessment Record; IVH, intraventricular
hemorrhage; LOS, length of stay; NA, not applicable; NEC, necrotizing enterocolitis;
NICU, neonatal intensive care unit; RDS, respiratory distress syndrome; SD, standard
deviation.
a
p ≤ 0.05.
b Composite M&M = RDS, IVH, NEC, < 10th percentile birth weight, death.
c
p < 0.01.
There was a significant difference in the composite morbidity and mortality between
the groups, and all DC + MC gestations suffered some morbidity. Two neonatal deaths
were from complications of prematurity (RDS, IVH, NEC). One of the pregnancies was
complicated by TTTS in an MC gestation with delivery at 26 weeks and neonatal death
at day 9 of life, whereas the other was a TC gestation complicated by spontaneous
preterm delivery at 25 weeks and neonatal death on day 2 of life. The other case of
TTTS in our cohort delivered at 29 weeks. Finally, the overall survival to discharge
home in this contemporary cohort of triplets was 39/42 (92.9%).
Discussion
This study results suggest that all DC and MC gestations in this cohort suffered some
morbidity or mortality. Our results are consistent with prior studies showing that
a triplet gestation that is fully MC or has an MC twin pair is at higher risk of complications
than a triplet gestation that is TC.[4]
[5] Because of the increased rate of complications associated with MC gestations, determination
of chorionicity by late first-trimester or early second-trimester ultrasound is imperative
for counseling and management with multifetal gestation.
One of the most important factors in the increased risk of neonatal morbidity and
mortality associated with triplet gestations is the development of TTTS. The only
two cases of TTTS in our study were in DC + MC gestations, and the rate of 12.5% observed
is similar to that noted in MC twins. Interestingly, a recent study noted a lower
than expected rate of TTTS in DC triplets (3/51, 5.8%).[11] The authors stated that it was unclear whether DC triplet pregnancies are inherently
at less risk for developing TTTS as compared with MC twins. They went on to speculate
that the presence of the third gestational sac may act as a buffer, reducing pressure
on the chorionic plate when hydramnios is present, thereby decreasing the risk of
developing TTTS, similar to the mechanisms postulated by which amnioreduction may
improve TTTS.
The recent decrease in the rate of multiple gestations is the result of a reduction
in the number of embryos transferred with each cycle of IVF, and an increase in the
number of multiple pregnancy reduction procedures being performed. The ARTs that have
the most significant effect on the increase in multifetal gestations are IVF and ovarian
hyperstimulation with gonadotropins. Even with the transfer of two embryos, there
appears to be an increasing number of triplet gestations with an MC twin pair.[4] Further research is needed to elucidate the risk factors and ARTs that increase
the risk of monozygotic twinning.
Limitations of this study include the retrospective nature and relatively small sample
size. More specifically, because of its retrospective nature, the study is limited
in terms of data availability and accuracy, while the potential for statistical errors
such as a type 2 error (“false negative”) due to the relatively small sample size
is possible. Although future studies utilizing larger groups of prospectively enrolled
patients are needed, it is important to note that this study represents a real-world
experience of a large referral and tertiary care center in the northwest suburbs of
Illinois. Although this study was underpowered to show a difference in mortality and
individual morbidities between the groups, all DC and MC gestations suffered some
morbidity or mortality.
It is important to note that neonatal morbidity and mortality in nonanomalous fetuses
are due primarily to prematurity issues, and this is particularly evident in multiple
gestations. Twenty-five percent of all DC or MC triplet gestations in our cohort had
IUGR. These pregnancies are frequently delivered early for fetal indications. The
management of growth disorders in triplets needs to be evaluated further to determine
whether earlier delivery is needed, or if close observation is feasible to decrease
iatrogenic prematurity.
