Introduction: monochorionic (MC) diamniotic twin pregnancy
MC twins occur in one in 250 pregnancies, about 20% of twin pregnancies and 70% of monozygotic twins.1,2 Monochorionicity accounts for a significant proportion of perinatal morbidity and mortality in twins.3–5 Perinatal mortality rate is around two to four times as compared with dichorionic (DC) twins and single pregnancies respectively.6 Neurological morbidity is four to five times higher than in DC pregnancies and consequently 25–30 times higher than in singletons. Overall one in three MC twins will have a complication during pregnancy.7,8
The main feature of MC, especially monochorionic diamniotic (MCDA) twins, is a shared placenta with interfetal anastomoses, leading to a situation of bidirectional blood exchange between the fetuses. Anastomoses can be arterio-arterial (AA), veno-venous, or arterio-venous (AV)9 and they are present in variable combinations in each case. Vascular connections are the basis for several complications that are unique to MC twins.10 Most of these complications are associated with high mortality and fetal therapy can improve the prognosis substantially.
Early diagnosis and management of MCDA twin complications is critical to improve the outcomes of these pregnancies. However, recognition of these complications can be challenging. MCDA pregnancies may often show clinical signs that are difficult to understand, and the overlapping of more than one complication in the same patient is not uncommon. In this paper we provide a general description of the main MCDA twin complications and describe a systematic approach for follow-up and evaluation of MCDA twins allowing timely recognition, adequate differential diagnosis, and targeted management.
Follow-up of uncomplicated MCDA twins
The main goal in the management of MCDA twins is detecting complications as soon as possible to offer fetal therapy or elective delivery. To this end, we can distinguish three main periods in pregnancy.
11–14 weeks: early diagnosis of chorionicity and major fetal anomalies
The first critical step in the management of MCDA twins is correct identification. Even if there are earlier signs for determination of chorionicity, the diagnosis is usually established at the 11–14 weeks scan. All twins must be classified as DC or MC, according to whether a “lambda” (DC) or a “T”(MCDA) sign is observed in the first trimester placental ultrasound (Fig. 1).11,12 Correct classification is critical because the protocol for follow-up is different in MCDA and DC twins. At the moment of diagnosis it is important to remember that the prevalence of major malformation is three to four times more frequent in MC twins (see below, MCDA twins discordant for malformation). Once the diagnosis of MCDA twins is established, a 2-week interval follow-up must be conducted for the remaining of gestation. Follow-up of MCDA pregnancies should ideally be performed at specialized units. Some authors have proposed the use of first trimester markers such as increased nuchal translucency, nuchal translucency or crown-rump length discrepancy, and abnormal ductus venosus to identify those cases at higher risk of suffering complication.13 However, when evaluated prospectively, none of these characteristics have sufficient efficacy to be used in clinical management.14
15–29 weeks: detection of complications amenable by fetal therapy
The majority of the severe problems of MCDA twins appear within this gestational age timeframe. Among the various possible complications, the most feared due to its rapid evolution and high mortality is twin-to-twin transfusion syndrome (TTTS). Early detection of TTTS is the main reason for the need to follow-up MCDA twins at 2-week intervals. A 4-week interval may result in many cases detected too late to avoid fetal death of severe sequelae in the newborn. TTTS may appear a few days after a normal exam, but a 2-week interval will allow timely detection of most cases. The recommended protocol for follow-up of uncomplicated cases is described in Figure 2. Those cases presenting suspicion signs can be evaluated at closer intervals (see Diagnostic Algorithm below, Fig. 3) or referred to a fetal therapy center for consideration.
30–36 weeks: detection of late complications and elective delivery at term
The risk of serious complications decreases with gestational age, but they may still occur and progress rapidly. Therefore, a 2-week follow-up scheme must continue until the end of gestation. The third trimester risk of intrauterine fetal death (IUFD) in uncomplicated MCDA twins seems to be very low15,16 but the consequences can be devastating. Consequently, there is consensus that elective delivery around 36–37 weeks is a reasonable approach.17–19
Main complications of MCDA twins
TTTS occurs in 10%–15% of all MCDA twins.20,21 TTTS mainly occurs because at some point in pregnancy the bidirectional inter-twin flow becomes unbalanced.22 In most cases, TTTS is associated with the number and/or diameter of AV anastomoses from the donor to the recipient fetus.23 While the presence of AV anastomoses is the prerequisite for TTTS, other factors, including fetal weight discordance, relative placental growth, cord insertions or fetal cardiac defects may help triggering the disease in individual cases. TTTS is a severe hemodynamic disorder characterized by hypovolemia, oliguria and oligohydramnios in the donor, and hypervolemia, polyuria, and polyhydramnios in the recipient.24,25 Additionally, vasoactive molecules and sustained oliguria lead to hypertension and renal tubular damage in the donor, while transfer of these vasoactive molecules to the recipient is thought to produce hypertension and contribute further to hypertrophic cardiomyopathy.26–28 Irrespective of its complex pathophysiology, TTTS is invariably associated with remarkable changes in fetal diuresis that lead to very obvious differences in the amniotic fluid (AF) deepest pocket and the bladder size of each fetus.
There is a general consensus on the diagnostic criteria (Table 1), which are based on the differences in AF and bladder sizes as the key signs.29 Importantly, the diagnosis of TTTS does not include fetal weight or Doppler criteria. Once the diagnosis is established, TTTS can be staged in degrees of severity. The most widely used is the Quintero staging system (Table 1).30 It must be stressed that in a substantial number of cases, TTTS appears in combination with selective fetal growth restriction (sFGR). This does not change the management (see below Algorithm for diagnosis and management – Fig. 3) but association with sFGR may reduce survival in the small twin.
Table 1 -
Diagnostic criteria and staging of severity in TTTS.29,30
|(1) Confirmed monochorionic pregnancy(2) Polyhydramnios in the recipient with a deepest vertical pocket of 8 cm or more∗(3) Oligohydramnios in the donor with a deepest vertical pocket <2 cm(4) Discordant fetal bladders with markedly enlarged bladder in the recipient and very small or non-visible bladder in the donor during most of the examination
I The bladder is still visible in the donor twinII The bladder is no longer visible in the donorIII Critically abnormal Doppler in either twin: absent-reverse diastolic flow in the umbilical artery of the donor or recipient and/or absent/reverse flow in the DV or pulsatile flow in the UV of the recipientIV Hydrops in either fetusV Demise of one or both twins
DV: Ductus venosus; TTTS: Twin-to-twin transfusion syndrome; UV: Umbilical vein.
∗The cut-off above 20 weeks is still subject of debate. A cut-off of ≥10 cm beyond 20 weeks has been used in randomized trials and is commonly used by European groups, while a unique cut-off of 8 cm is more commonly used in the United States. Both cut-offs are considered to be acceptable for the diagnosis.
TTTS is always a severe condition. If left untreated, pregnancy loss rate is 100% when diagnosed before 20 weeks, and more than 80% between 21 and 26 weeks. The rate of severe sequelae in survivors may be as high as 80%. TTTS may progress abruptly and even lead to fetal death in very early stages.31 Consequently, fetal therapy must be offered as soon as possible. The treatment of choice between 15 and 28 weeks is fetoscopic laser coagulation of placental anastomosis. Some centers treat until 30 weeks. Laser therapy reverts the manifestations of the syndrome and results in overall survival rates of 80%–90% for at least one fetus.32–35 In cases where laser is not possible, amniodrainage is a second line palliative therapy to prolong pregnancy and improve survival (at least one fetus in 50%–60% of cases),32,36 at the cost of a much higher rate of neurological handicap (29%–35% vs. 11%–16% with laser).37,38
Laser in TTTS stage I has been questioned by some groups.39 However, the criteria for the definition of TTTS stage I may change in different countries (see Table 1 with diagnostic criteria), and consequently some classifications include as TTTS I cases that for others are just discordant AF.32,40 This may explain that in some series up to10% of TTTS stage I may complicate with fetal demise before therapy.31,41 Therefore, it is highly advisable that in the presence of a suspicion TTTS, even if it looks as stage I, the case be always referred as soon as possible to a fetal therapy center for detailed evaluation. A randomized trial comparing conservative management and laser surgery for TTTS stage I is underway (https://clinicaltrials.gov/ct2/show/NCT01220011).
Twin anemia polycythemia sequence (TAPS)
TAPS presents in two clinical forms, spontaneously or after laser therapy for TTTS. Spontaneous TAPS occurs in 3%–5% of MCDA twins, normally during the third trimester.42 TAPS is a form of inter-twin unbalanced transfusion, however, occurring in a placenta where interfetal anastomoses are very small. Thus, there is discordant AV interfetal flow, but the difference with TTTS is that in TAPS the magnitude is much smaller.43 Chronic subtle transfusion in TAPS leads to a hematological disorder, that is, anemia-polycythemia, but the severe hemodynamic fetal imbalance of TTTS does not occur. When occurring after laser, TAPS is the result of an incomplete coagulation leaving one or two very small placental vessels. This may occur in 0.5%–6% of cases, depending on definitions, laser technique, and center experience.44,45
TAPS can be diagnosed with fetal or with neonatal criteria. Fetal criteria rely in the evaluation of middle cerebral artery Doppler, since normally there are no other manifestations.44,46,47 This complication must be actively searched either in non-complicated MCDA twins from 15 weeks onwards, especially during the third trimester and in TTTS cases after laser therapy. Neonatal diagnostic criteria are based on the presence of severe hemoglobin and reticulocyte discordance.43,48 The use of reticulocyte count is important to distinguish TAPS from acute feto-fetal transfusion during delivery, which may occur in 1.8%–5.5%49 and present low level of reticulocyte. Spontaneous TAPS is diagnosed neonatally in a remarkable proportion of cases TAPS. Controversies exist,50–52 but there is expert consensus in the prenatal and postnatal diagnostic criteria,52 summarized in Table 2.
Table 2 -
Diagnostic criteria for TAPS.52
||MCA-PSV ≥1.50 MoM in the anemic
MCA-PSV ≤0.8 MoM in the fetus with polycythemia
Delta MCA-PSV ≥1.0 MoM
||Inter-twin hemoglobin difference ≥8.0 g/dL
Inter-twin reticulocyte count ratio (anemic/fetus with polycythemia) ≥1.7
MCA-PSV: Middle cerebral artery peak systolic velocity as measured with spectral Doppler; MoM: Multiple of the Median; TAPS: Twin anemia polycythemia sequence.
The prognosis in spontaneous cases of TAPS is normally good and most cases can be managed expectantly.53 However, anecdotal cases of death of the co-twin have been reported.54,55 TAPS after laser for TTTS is usually more aggressive and requires therapy. Therapy for TAPS is indicated if middle cerebral artery Doppler discordance progresses rapidly or pre-hydropic signs are observed in the donor. The only causative treatment is laser therapy. However, in post-laser cases, this option can be difficult sometimes,56 and repeat transfusions to the donor often achieve good outcomes.57
Acute feto-fetal transfusion by single intrauterine fetal death (sIUFD) and other causes
Acute feto-fetal transfusion in MC twins can occur during pregnancy or during delivery. Regarding delivery, this has been long described in MC twins. It may occur between delivery of one fetus and the other, and it normally carries a good prognosis.58
However, when acute feto-fetal transfusion occurs during pregnancy the consequences can be devastating. The characteristic clinical scenario facilitating this complication is sIUFD.59 The surviving twin may suffer a massive exsanguination into the circulation of the dying fetus, which is associated with a reported 18%–34%59–61 of brain injury, especially if the death occurs beyond 28 weeks,59 and about 15% of spontaneous co-twin death,60 with greater risk before 28 weeks.62 In addition, there is an increased risk of preterm birth with higher incidence in pregnancies complicated by TTTS.62 The risk of these complications after sIUFD depends on the size of vascular anastomoses and feto-placental mass of the demised twin,10 and, therefore, it is largely unpredictable.
Single fetal death may occur unexpectedly in approximately 1%–1.5% of uncomplicated MCDA twins, and this is the main reason to recommend elective delivery between 36 and 37 weeks.17,63–64 However, the majority of cases of sIUFD occur in pregnancies complicated with TTTS and sFGR. The risk of brain injury is lower if sIUFD occurs in the first half of gestation or before 28 weeks.59 Irrespective of the gestational age, the management is based on evaluating the presence of neurological damage in the survivor, preferably by dedicated neurosonography combined with fetal brain MRI around 30 weeks and ideally not before 3 weeks post-sIUFD.59,65–67
Acute feto-fetal transfusion may also occur when both fetuses are alive. A well-characterized situation for this is sFGR, as discussed in the next section. Aside from sFGR, a proportion of apparently uncomplicated MCDA twins present neurological handicap during childhood,8,68,69 and this is thought to be explained to acute feto-fetal transfusion accidents during pregnancy.
sFGR in MCDA twins
Early sFGR affects 10% of MCDA twins, with a similar frequency as observed in DC twins.70,71 An expert consensus study proposed for the diagnosis an estimated fetal weight (EFW) in one twin <3rd centile as a single criterion, or the presence of at least three of the following: EFW of one twin <10th centile,71 abdominal circumference of one twin <10th centile, EFW discordance of ≥25%, umbilical artery pulsatility index of the smaller twin >95th centile.72 Selective FGR in MCDA twins is mainly caused by a discordance in placental territories.73 However, the existence of interfetal anastomoses74 strongly interferes with the natural history of fetal growth restriction as compared with singletons or DC twins. Vascular connections and interfetal blood flow benefit the FGR fetus but may create hemodynamic imbalances that pose risks to both twins. The magnitude of blood flow interchange depends on the number and type of anastomoses. From a clinical point of view, sFGR behave according to one of three major patterns, that can be distinguished by Doppler umbilical flow in the FGR fetus (Table 3).75
Table 3 -
Type of sFGR in MCDA twins according to the characteristics of umbilical artery Doppler in the small twin and main clinical features of each type.75
|Type INormal Doppler (positive diastolic flow)
||(1) Low risk of poor outcome(2) Smaller degree of weight discordance(3) Very low risk of IUFD and co-twin brain damage(4) GA at delivery normally >34 weeks (good evolution of FGR)
|Type IIPersistent AREDF
||(1) High risk of poor outcome(2) Doppler evolution predictable in most cases: hypoxic deterioration and IUFD of FGR(3) Very low risk of brain injury of normal co-twin(4) Mean GA at delivery 29 weeks (deterioration of FGR)
|Type IIIIntermittent AREDF
||(1) High risk of poor outcome(2) Doppler evolution usually non-predictable: low risk of hypoxic deterioration but 10%–15% risk of unexpected IUFD of FGR(3) 10%-15% risk of brain injury in normal co-twin(4) FGR commonly survives until 32 weeks and beyond
AREDF: Absent/reverse end-diastolic flow; FGR: Fetal growth restriction; GA: Gestational age; IUFD: Intrauterine fetal death; MCDA: Monochorionic diamniotic; sFGR: Selective fetal growth restriction.
As a whole, both sFGR type II and III are at high risk of very-preterm delivery, IUFD, and neurological sequelae.76,77 Type II follows a more “predictable” course, where the small twin progressively deteriorates as shown by Doppler, while type III shows an apparently benign evolution and the smaller twin rarely deteriorates.78,79 However, an intermittent absent/reverse end diastolic flow is associated with a risk of unpredictable fetal demise of the FGR in around 15% of cases. There is also risk of brain damage of the normally grown fetus, even when both fetuses are born alive, affecting as many as 15%–30% of cases.76,79 This thought to be explained by the existence of large AA placental anastomoses, which cause also the intermittent diastolic flow in these pregnancies. AA vessels allow a large amount of blood flow interchange, helping the FGR twin to survive but increasing the risk of acute interfetal transfusion an exsanguination if the FGR twin suffers hypotension or bradycardia.
The main two differences of sFGR with respect to TTTS is that (1) it is not an emergency situation and (2) there is more than one management option. In general, sFGR type I has a good prognosis and expectant management until 34 to 35 weeks seems reasonable.80,81 Type II and III are associated with a poor prognosis, and the clinical decisions are more difficult. The main options are expectant management, cord occlusion or laser therapy. In general, they can be offered as options to protect intact survival of the larger twin and prolong the duration of pregnancy.
In sFGR type II managed expectantly, cases with normal venous Doppler can be monitored weekly, while closer follow-up every 1–2 days is recommended when ductus venosus pulsatility index becomes >95th centile. Fetal therapy can be offered in severe cases with early diagnosis (<24 weeks’ gestation) with signs of imminent fetal demise.82 Cord occlusion has elevated survival rates of the normal fetus >90%, with delivery around 36 weeks,83 while laser has been associated with approximately 40% survival of FGR and 70% survival of the normal fetus, with delivery in average gestation at 32 weeks.84 In sFGR type III, weekly follow-up seems reasonable. If fetal therapy is considered, cord occlusion is a straightforward treatment for very early or extreme cases. Laser coagulation is also feasible, but it can be technically challenging due to close cord insertions and the large size of the AA vessel.80 Fetal demise after laser can occur in 60%–80% in the FGR, and in up to 15%–30% in the normal twin.74
Late sFGR may be detected in the third trimester in about 5% of cases of MCDA twins. Late sFGR in MCDA twins is normally a much more benign condition with generally a good prognosis (Fig. 4).85
Stepwise algorithm for the differential diagnosis between MCDA twin complications
The differential diagnosis between the complications of MCDA twins has been a historic source of confusion, especially because a substantial number of the early series, particularly those dealing with TTTS, were likely to merge cases of TTTS and sFGR according to current criteria. This may justify remarkable differences in clinical behavior and outcomes that can be found in the literature.
From a clinical point of view, difficulties in the differentiation between TTTS and sFGR may remain in specific cases. In addition, situations of “high-risk-but-nothing-for-the-moment” can also be challenge. Indeed, on the follow-up of MCDA twins it is relatively common to find cases with subjective differences in AF or fetal size, but with intermediate or overlapping features. A systematic approach is key to correct classification and the adequate decision in this case. Briefly, once structurally normal fetuses are confirmed, four complication scenarios remain: TTTS, sFGR, TAPS, and non-specific AF or EFW discordance. A structured algorithm will lead to accurate classification and adequate management in virtually all cases. We use a sequence of questions, the order of which is determined by the importance and urgency of treatment86 (Fig. 3). The first entity to rule out is always TTTS, since the prognosis is invariably poor and urgent treatment is mandatory. If TTTS is diagnosed, co-existence or not with sFGR is irrelevant; it does not change the need of urgent laser therapy. The second and third questions determine whether there is sFGR and TAPS. The order of questions 2 and 3 is not so relevant, although in real practice TAPS is extremely rare during the second trimester.
Finally, if all these conditions are excluded, we are left with discordances that do not meet any diagnostic criteria. These cases are normally referred in the literature as “discordant for amniotic fluid”, although it is common that some degree of fetal weight discordance also coexists. We recommend describing exactly the observations in the report, with a clear remark that “currently diagnostic criteria for TTTS (or sFGR) are not met”. Discordant AFs represent a specific situation by itself and requires a stricter follow-up, because the risk of developing any complication over time, either TTTS or sFGR, has been reported to be nearly 50%.87 A weekly follow-up, or closer if the suspicion is high, should allow timely treatment if required in most cases. Obviously, there will remain a higher risk of unexpected rapid evolution and/or fetal demise, and this should be made clear during counseling. However, parents must be reassured that this risk is in principle much lower than that of invasive therapy and that in 50% of cases there will be a normal evolution and outcome. Therefore according to current evidence discordant AF should never be treated.
MCDA twins discordant for fetal defects
Discordant fetal anomaly is another characteristic and relatively common complication of MCDA twins. Fetal structural abnormalities affect up to 3% of cases, three times higher as compared with DC or singletons,88 and occur in only one twin in more than 80% of the instances.89,90 Most commonly, discordant malformations involve nervous and circulatory systems.91 Much more rarely MC twins can be discordant for fetal karyotypes.92,93
One particularly common discordant anomaly (up to 1% of MC twins) is the presence of an acardiac fetus, which survives thanks to twin reverse arterial perfusion sequence (TRAP).94,95 While many cases may progress well until the third trimester, pregnancy loss may be as high as 50% due cardiac failure of the normal twin, also called “pump twin”, and complications related with polyhydramnios.96 The survival rates with cord occlusion range 80%–90%.97 Similar survival rate (92%) has recently been reported after early interstitial laser coagulation of TRAP fetuses,98 but the results from the TRAP Intervention STudy, a multicenter, open-label, randomized controlled trial, are expected to provide evidence for or against the benefit of early (12–14 weeks’ gestation) vs. late (16–19 weeks) intervention in such pregnancies (https://clinicaltrials.gov/ct2/show/NCT02621645).
The number of cases in which the discordant malformation is associated with a high risk of intrauterine death of the affected twin is small. However, there is also the problem of parents’ anxiety of carrying a fetus with a serious malformation. Obviously, selective feticide by any technique will threaten the whole pregnancy and consequently survival of the structurally normal fetus. In spite of these risks, a proportion of parents will request selective interruption of pregnancy where legally available. Cord occlusion by means of laser or bipolar coagulation is the option of choice for most of these cases. Radiofrequency is also an option,99,100 especially in TRAP pregnancies, but success rate may be compromised in advanced gestations.101 Regardless of the technique used, survival rates in experienced hands for selective feticide in MCDA twins range 80%–90%.82 While these figures may suggest a high rate of pregnancy loss, the cumulative rate of fetal loss or pre-viable preterm birth has been reported to be in the range of 10%–15% in DC twins undergoing selective reduction.102
Adequate management of MCDA twins can be accomplished by means of an integrated view of the main groups of complications, and should be guided by very basic principles. The complexity and the uncountable number of combined complications that MCDA twin pregnancies can present may often blur clinical decisions in a way that such basic principles are forgotten. Even though exceptional highly difficult cases may need individualization, our simplified (but clinically useful) approach for MCDA pregnancies (Fig. 5) based in the obvious principles of early diagnosis, proper follow-up, and timely intervention covers the great majority of cases. Moreover, while it may seem too simplistic considering the vast knowledge behind MC twin pregnancy, our clinical experience of more than 20 years demonstrates that, still today, the cases of poor or suboptimal management derive from failure to comply with one or more of this basic set of principles.
Conflicts of Interest
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