Twin-twin transfusion syndrome (TTTS) occurs at a frequency of 8%–10% in monochorionic twin pregnancies [1, 9, 15], and the majority of those cases are diagnosed during the second trimester . In the last two decades, the overall prognosis of TTTS cases diagnosed before 26 weeks of gestation has dramatically improved by the introduction of fetoscopic laser photocoagulation (FLP) for placental communicating vessels [18–20]. Recently, several studies have shown that FLP for cases with TTTS after 26 weeks of gestation resulted in outcomes equal to, or superior to, those undergoing conventional treatment strategies [3, 14, 26]. However, there have been only a few studies focused on the clinical features of TTTS developing after 28 weeks of gestation [3, 10, 14, 26], and it is currently unclear which management option minimizes adverse outcomes.
The aim of this study was to describe the incidence and clinical features of TTTS onset during the third trimester. To clarify the natural course of the cases, we performed a single-center cohort study and limited it to the cases managed at our center throughout pregnancy.
This was a retrospective cohort study performed at a tertiary perinatal care center in Japan, providing fetal treatment, including around 30 fetoscopic laser therapies per year. We conducted a retrospective chart review of all monochorionic diamniotic (MD) pregnancies managed from the first trimester onward that delivered at our center between January 2009 and December 2012. The cases with single or double fetal demise before 14 weeks of gestation, fetuses with major anomalies, and twin reversed arterial perfusion sequence (TRAPs) were excluded.
The diagnosis of monochorionicity and the decision of an accurate gestational age were made at first trimester by ultrasound examination. Serial sonographic examinations were performed until delivery at least every 2 weeks to evaluate fetal growth and amniotic fluid volume. Doppler measurements of the umbilical artery and the ductus venous (DV) were performed at 18–19 weeks of gestation, and additional Doppler evaluations were done at the attending physician’s discretion when impaired fetal growth or discordant amniotic fluid volume between twins were found. Inpatient management was initiated only for obstetrical indications. The diagnosis of TTTS was based on the sonographic criteria of polyhydramnios with amniotic fluid volume (AFP) of 8 cm or greater in the recipient fetus and oligohydramnios with AFP of 2 cm or less in the donor fetus. Staging of the disease was done according to the Quintero’s staging system . We examined the prevalence of TTTS during the second and third trimesters.
Concerning cases with TTTS onset during the third trimester, we reviewed maternal demographics as well as the clinical course of these pregnancies. The data of neonatal clinical course, including the need of intratracheal intubation, the administration of catecholamine, transfusion, and neurological findings at 1 month and 6 months of life were also documented. Furthermore, placental findings were reviewed to investigate the features of placental anastomoses evaluated by a color dye injection test.
Initially included in the study were 152 MD twin pregnancies; subsequently, nine cases (three cases with TRAPs, two with spontaneous abortion before 14 weeks of gestation, and four with major anomalies) were excluded (Figure 1). A total of 143 sets of MD twin pregnancies met our criteria and were analyzed. Table 1 shows baseline characteristic of this population. TTTS occurred in 15 cases (10%), 10 cases (6%) diagnosed during the second trimester, and five cases (4%) during the third trimester. Among 10 TTTS cases during the second trimester, eight cases underwent FLP, one underwent a cesarean section to transition to neonatal treatment, and one was a pregnancy termination.
|No. of pregnancies, n||143|
|Maternal age, median (range)||31 (18–42)|
|Primipara, n (%)||78 (55)|
|Spontaneous conception, n (%)||120 (85)|
|Ovulation induction, n (%)||10 (7)|
|IVF/ICSI, n (%)||13 (9)|
|Delivery <22 weeks of gestation, n (%)||8 (6)|
|Termination of pregnancy||2|
|IUFD, n (%)||9 (7)|
|Single IUFD, n||5|
|Both IUFD, n||4|
|TTTS, n (%)||15 (11)|
|Diagnosed <28 weeks of gestation||10|
|Diagnosed >28 weeks of gestation||5|
The five cases with TTTS during the third trimester are summarized in Table 2. Gestational age at TTTS diagnosis ranged from 31+2 to 35+5 weeks. Two cases were Quintero’s stage I and the other three were stage III or IV. Two cases (cases 1 and 3) were inpatients due to threatened preterm labor (TPL) followed by the diagnosis of TTTS. In case 1, amniotic fluid discordance expanded to meet the TTTS criteria; this occurred 2 days after the ultrasonographic evaluation, which revealed isolated oligohydramnios at 31+0 weeks of gestation. In case 3, estimated amniotic volume of both twins was noted to be normal at 33+2 weeks of gestation, however, the patient complained of uterine contractions. Severe polyhydramnios and oligohydramnios with a pericardial effusion and ascites in the recipient fetus were demonstrated 3 days later.
|Age||Parity||GA (w)||Quintero stage||Comments|
|1||33||0||31+2||I||Inpatient due to TPL from 27 weeks of gestation|
Amniotic fluid discordance was detected at 31 weeks by chance
|2||29||0||31+4||IIIRaa||Outpatient as uncomplicated MD twin until 30 weeks without amniotic fluid discordance|
Abdominal distension was started a couple of days before the date of TTTS diagnosis
|3||30||1||33+5||IV||Inpatient due to TPL from 28 weeks|
Amniotic fluid discordance was detected at 33 weeks by chance
|4||22||0||34+5||IV||Outpatient as uncomplicated MD twin until 33 weeks without amniotic fluid discordance|
Abdominal distension was started a couple of days before the date of TTTS diagnosis
|5||33||0||35+5||I||Outpatient as selective IUGR type I until 34 weeks without amniotic fluid discordance|
Abdominal distension was started a couple of days before the date of TTTS diagnosis
The other three cases (cases 2, 4, and 5) were managed as outpatients without obstetrical complications. All three women presented at our outpatient department and complained of abdominal distension, which began a few days before the diagnosis of TTTS. In case 2, sonographic evaluation exhibited TTTS with reversal of DV flow in the recipient twin despite normal sonographic findings 9 days before the diagnosis of TTTS. In case 4, polyhydramnios, pleural effusion, and ascites in the recipient twin together with anhydramnios in the donor twin were found at an examination 7 days after the previous scan in which the amniotic fluid volume was noted to be normal. In case 5, amniotic fluid volume was found to be normal in both twins 14 days before the patient was diagnosed at 33+5 weeks with TTTS.
All cases underwent cesarean section immediately after diagnosis of TTTS without any fetal intervention, and subsequently, neonatal care was initiated by neonatologists. Neonatal and placental findings of the five cases are presented in Table 3. All five recipient neonates and two donor neonates required intratracheal intubation. Four out of five recipients required administration of catecholamine, whereas no donors required this therapy. Two recipient neonates required fresh frozen plasma transfusions to sustain hemodynamic status; one donor required red cell concentrate due to severe anemia. There was neither neonatal death nor abnormal neurological findings at the first month and 6 months after birth.
|GA (weeks)||Quintero stage||Birth weight (g)||Hb (g/dL)||Comments||AAA||AVA||VVA|
|Fetus||Intratracheal intubation||Catecholamine||Transfusion||Neurological findings|
|at 1 month||at 6 months|
|1||31+2||I||1602||20.0||Recipient||Day 0–1||Day 0–2||No||Normal||Normal||Yes||Yes||No|
|2||31+4||IIIRa||1794||20.5||Recipient||Day 0–3||Day 0–2||FFP: day 0–2||Normal||Normal||Yes||Yes||No|
|1158||10.0||Donor||Day 0–3||No||RCC: day 1–3||Normal||Normal|
|3||33+5||IV||2376||14.0||Recipient||Day 0–7||No||FFP: day 3–4||Normal||Normal||No||Yes||No|
|4||34+5||IV||2270||13.9||Recipient||Day 0–1||Day 0–4||No||Normal||Normal||No||Yes||No|
|5||35+5||I||2152||20.4||Recipient||Day 0–4||Day 1–5||No||Normal||Normal||Yes||Yes||No|
In regard to placental findings, arterioarterial anastomoses (AAA) were detected in three cases (cases 1, 2, and 5), and arteriovenous anastomoses were detected in all cases, however, venovenous anastomoses were not found in any case.
The prevalence of TTTS onset after 28 weeks of gestation was 4% among the MD twin pregnancies uniformly managed at a single perinatal center from the first trimester onward. This prevalence is less than half that of previous reports including the typical onset of TTTS during the second trimester [1, 9, 15]. Thorson et al. reported five cases that were diagnosed after 28 weeks among 42 TTTS pregnancies (12%) ; however, that series consisted of patients referred from a number of hospitals at an unspecified stage of gestation.
It is well-known that placental angioarchitecture [4, 6, 8] and endocrinologic mechanisms [2, 7, 12] are involved in the pathogenesis of TTTS. It has been suggested that thrombosis could cause hemodynamic changes between the twins leading to late onset TTTS [16, 24]. However, it remains to be fully clarified why TTTS develops during the third trimester after a previously uncomplicated prenatal course.
As twin pregnancies tend to be accompanied with threatened preterm labor, especially after the mid-trimester, uterine contractions might play some role in the development of TTTS. In animal studies, it has been demonstrated that non-labor uterine contractions cause significantly increased arterial and venous pressure in fetuses with oligohydramnios . This could amplify blood transfusion from twins with relatively less amniotic fluid volume to co-twins. Moreover, it has been reported that uterine contractions could also affect fetal hemodynamic status in both normal and TTTS conditions [22, 23]. It appears to be imperative to explore the development of TTTS closely in MD twin pregnancies with clinical manifestations of TPL. However, the use of prophylactic tocolysis cannot be endorsed, considering that our five TTTS cases included two patients under medical treatment with intravenous tocolytic for TPL.
Several studies have shown that the presence of placental AAA plays a protective role against TTTS [5, 6]. In our series, AAA was detected in three out of five cases. Although our series is too small to verify the pathological significance of the presence of AAA, it is presumed that AAA may play a protective role against development of TTTS before the third trimester unless additional events, such as thrombosis and uterine contractions occur.
Recently, several studies have been published concerning cases treated with FLP outside the customary period [3, 14, 26]. Middeldrop et al. demonstrated that FLP performed after 26 weeks of gestation prolonged gestational age and reduced neonatal morbidity compared to serial amnioreduction (AR) . Baud et al. reported FLP performed between 26+1 and 30+3 weeks of gestation resulted in an improved survival rate with similar surgical feasibility compared to the customary period . Conversely, the neonatal care of TTTS survivors is challenging because of hemodynamic aberrations in addition to prematurity . In our series, recipient fetuses tended to require more intensive cardiopulmonary treatment than donor fetuses; however, neither neonatal death nor neurological impairment were seen in our series. Although serial amnioreduction is related to a low survival rate and high neuromorbidity rate [10, 13], the expectant management including strict monitoring, antenatal corticosteroid administration and amnioreduction would be a option, especially stage I TTTS in early third trimester. In contrast, for the TTTS cases with advanced staging or in late third trimester, the most reasonable option appears to be intensive fetal surveillance, to deliver promptly the patient when fetal status deteriorates, and to initiate intense neonatal treatment. In order to determine the optimal management of TTTS during the third trimester, a larger series of cases and long-term outcome must be evaluated.
In conclusion, TTTS occurs during the third trimester in 4% of MD twin gestations. Although the current study includes a case number too small to derive enough clinical considerations, it appears to be important to closely monitor women with MD twin pregnancies for the development of TTTS when they develop symptoms of threatened preterm labor even if their pregnancy has been uneventful until that point. Currently, therapeutic preterm delivery might be a primary option for third trimester TTTS.
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The authors stated that there are no conflicts of interest regarding the publication of this article.