Selective fetal growth restriction in monochorionic twin pregnancies

Authors:: Jena Miller, MD; Mara Rosner, MD, MPH; Ahmet Alexander Baschat, MD
Section Editor:: Lynn L Simpson, MD
Deputy Editor:: Vanessa A Barss, MD, FACOG

Literature review current through: Jan 2024.

This topic last updated: Nov 06, 2023.

INTRODUCTION — Selective fetal growth restriction (sFGR) refers to growth restriction of one fetus of a monochorionic twin pair. It is a common complication of monochorionic twins that results from discordant placental sharing and is different from the placenta-based growth restriction resulting from deficient uteroplacental perfusion that occurs in dichorionic twins and singletons [1]. sFGR is important because it is associated with significant risks for perinatal morbidity and mortality [2-4].

This topic will discuss the pathophysiology, diagnosis, and management of sFGR. The diagnosis and management of growth restriction in singletons and in dichorionic twins are reviewed separately. (See "Fetal growth restriction: Screening and diagnosis" and "Fetal growth restriction: Evaluation" and "Twin pregnancy: Management of pregnancy complications", section on 'Growth restriction and discordance'.)

PATHOPHYSIOLOGY — The "vascular equator" is an imaginary line that can be drawn along the vascular anastomoses between twins sharing a monochorionic placenta. This line can be used to estimate the percentage of placental territory belonging to each fetus. In sFGR, the placental territory is distributed unequally between twins: one twin benefits from having the majority share of the placenta while the growth-restricted twin is supported by a smaller portion of the placenta (figure 1 and picture 1) [5-8].

In addition, when the placental share is significantly different, the number and size of the vascular anastomoses between the twins are also different [9-12], which affects volume exchange between twins and transfer of nutrients and oxygen. Increasing discordance in placental share increases net volume flow between the twins, leading to more interdependent circulations [10,13-16]. For example, large bidirectional anastomoses, particularly arterioarterial anastomoses, can compensate for unequal sharing [17]. This impacts the natural history of the disease: Clinical deterioration is often less predictable and slower than would be anticipated in FGR complicating singleton or dichorionic twin pregnancies [18,19]. However, other factors can also contribute to growth restriction. For example, a velamentous placental cord insertion can further impair the smaller twin's ability to access its placental territory. Velamentous placental cord insertion is found in up to approximately 30 percent of monochorionic twins and is strongly associated with both sFGR (odds ratio [OR] 9.24, 95% CI 2.05-58.84) and growth discordance >25 percent (OR 6.81, 95% CI 1.67-34.12) [13,20,21].

INCIDENCE — sFGR affects 10 to 15 percent of monochorionic twin pregnancies [22,23].

PRESENTATION — Ultrasound examinations are routinely performed in multiple gestations. Accurate determination of chorionicity and gestational age are crucial to appropriately monitor and manage these pregnancies. (See "Twin pregnancy: Overview", section on 'Assessment of chorionicity and amnionicity' and "Twin pregnancy: Overview", section on 'Determination of gestational age'.)

Crown rump length (CRL) discordancy of a monochorionic pregnancy on a first-trimester ultrasound can be the first sign of developing sFGR [24]. If CRLs are discordant, it is important to use the CRL of the larger twin for assignment of gestational age in naturally conceived pregnancies. (See "Diagnosis and outcome of first-trimester growth delay", section on 'Twin pregnancies'.)

Most sFGR is detected during routine sonographic monitoring of monochorionic pregnancies, which is initiated in the early second trimester. Our protocol is depicted in the table (table 1) and identifies sFGR, twin-twin transfusion syndrome, and twin anemia polycythemia sequence.

DIAGNOSIS — Diagnosis of sFGR is typically made in the second trimester based on fetal biometric measurements, growth discordance, and umbilical artery (UA) Doppler parameters. Third-trimester diagnosis is less common and associated with more favorable outcomes [25,26].

sFGR is defined by Delphi criteria as [27,28]:

●Estimated fetal weight (EFW)<3^rd percentile of one fetus

●At least two of the following four criteria:

•EFW <10^th percentile for one twin

•Abdominal circumference <10^th percentile for one twin

•UA pulsatility index >95^th percentile for the smaller twin

•Weight discordance ≥25 percent

Percent weight discordance is calculated using the following equation:

(EFW larger twin weight – EFW smaller twin weight) / (EFW larger twin weight × 100)

Doppler technique — Importantly, interpretation of the UA Doppler is not the same as in singleton or dichorionic multiple pregnancies since it not only reflects the relative size differences in placental share but also the magnitude of hemodynamically significant vascular communications between the twins [29].

Proper acquisition of the UA waveform is required for accurate assessment and interpretation.

●Reproducibility of measurements is greater if the measurement is obtained in a free loop of the umbilical cord with an insonation angle close to 0 degrees during fetal quiescence.

●Focal zone, gain, and pulse repetition frequency should be adjusted to maximize the frame rate.

●The sweep speed should initially be set to visualize four to six waveforms and should take up approximately 75 percent of the Doppler screen [30]. To evaluate variation or oscillation of end-diastolic velocity in the UA, the sweep speed needs to be slowed to demonstrate the classic pattern in >6 waveforms (waveform 1).

●Maternal breath holding may be required to exclude interference during measurement of the waveform [29,31].

●Both UAs should be sampled as the flow pattern may differ. However, interarterial anastomoses, if present, can equalize blood flow between arteries even though the placental territories supplied by the umbilical arteries are different [32].

●UA waveforms are best identified close to the placental cord insertion where intertwin anastomoses on the placenta have the most impact on the umbilical artery Doppler flows, particularly in the setting of close placental cord insertions. Evaluation for proximate placental cord insertion (distance between cord insertions below the fifth percentile, or 3.3 to 4.0 cm across gestation) is prudent as intermittent absent or reversed end-diastolic velocity (as in type 3 sFGR, discussed below) is more common in this setting [33].

CLASSIFICATION — The pattern of the umbilical artery (UA) waveform and end-diastolic velocity of the smaller fetus are used to classify sFGR into three types (waveform 2) that are predictive of the anticipated clinical course and risk profile [34-36]. This is an important designation to make since it is used to guide counseling and management decisions.

●Type 1 sFGR is characterized by persistently forward UA end-diastolic velocity without variation in the waveform with normal or elevated resistance. It is associated with the most stable course and a typically favorable outcome; the mean gestational age at birth was 35.4 weeks in one large series [34]. In a meta-analysis of observational studies including 786 monochorionic pregnancies complicated by sFGR, when expectantly managed, type 1 sFGR was associated with the lowest risk for unanticipated fetal demise, 3.1 percent (95% CI 1.1-5.9), and a high rate of intact survival, 97.9 percent (95% CI 93.6-99.9) [37].

Late onset sFGR (ie, identified after 26 weeks) is typically type 1. Although these fetuses usually have a benign course, they are at increased risk for hemoglobin differences at birth (ie, twin anemia polycythemia sequence), which occurs in up to 38 percent of cases [6].

●Type 2 sFGR is characterized by fixed absent or fixed reversed UA end-diastolic velocity without variation of the waveform in the smaller twin. It is associated with midtrimester deterioration of the growth-restricted fetus; the mean gestational age at birth was 30.7 weeks in the same large series described above [34].

Although pregnancies with type 2 sFGR are anticipated to have a predictable pattern of deterioration and a longer latency period between diagnosis and deterioration than type 3 sFGR, they are considered to have the worst prognosis due to the significant risk of single fetal demise and preterm birth [37,38].

In the meta-analysis described above, when expectantly managed, fetal demise occurred in 16.6 percent (95% CI 6.9-29.5) of cases, with neonatal death in an additional 6.4 percent (95% CI 0.2-28.2) [37]. For survivors, 89.3 percent (95% CI 71.8-97.7 percent) were neurologically intact.

●Type 3 sFGR is characterized by a pathognomonic UA waveform that has a variable flow pattern that cycles between forward, absent, and reversed flow over a short interval (waveform 1), which is termed intermittent absent/reversed end-diastolic flow (iAREDF). This results from a large artery-to-artery anastomosis (AAA) on the placental surface and represents the bidirectional volume flow across these vessels. It is more commonly observed in the UA of the smaller fetus since the interface of the two waveforms is shifted toward the smaller twin and the AAA has a larger proportionate impact on the fetus with smaller placental share [12]. An AAA allows perfusion of oxygen and nutrients from the larger fetus to a portion of the smaller twin's placenta; consequently, type 3 sFGR is associated with the largest degree of placental territory discordance [9,16,34,39,40].

These cases have the most unpredictable clinical course, and unanticipated fetal demise can occur in a short interval, even after a reassuring ultrasound assessment. In the meta-analysis described above, when expectantly managed, fetal demise occurred in 13.2 percent (95% CI 7.2-20.5), with neonatal death in an additional 6.8 percent (95% CI 0.7-18.6) [37]. In a large multicenter study of 328 pregnancies with type 3 sFGR, single fetal demise occurred in 5.8 percent and double demise occurred in 4.9 percent of expectantly managed patients [41]. Normalization of umbilical artery Doppler flow occurred in 13.7 percent of cases and was associated with improved fetal growth of the smaller twin [19]. Deterioration of umbilical artery Doppler to persistent absent or reversed flow is a poor prognostic sign, especially in cases diagnosed at an early gestational age. In a study of 245 cases of type 3 sFGR, fetal death occurred in 7 of 12 fetuses (58 percent) diagnosed before 16+5 weeks who had Doppler deterioration and 7 of 43 fetuses (16 percent) diagnosed after 16+5 weeks who had Doppler deterioration, but only 13 of 190 fetuses (7 percent) without Doppler deterioration [42].

These pregnancies are also at the highest risk for neurologic morbidity, particularly of the larger twin. Only 61.9 percent (95% CI 38.4-81.9) have been reported to have intact survival, most likely attributable to the more unstable hemodynamic environment [31,37].

DIAGNOSTIC EVALUATION — Due to substantial overlap between sFGR, twin-twin transfusion syndrome [TTTS], and twin anemia polycythemia sequence [TAPS] (table 2), a systematic approach to evaluation is required to arrive at the correct diagnosis and initiate management planning [43]. All variables that define these conditions need to be ascertained. The final diagnosis should describe the entire spectrum of findings.

●Once sFGR or discordant fetal growth is suspected, the first step is a detailed anatomic survey to assess for structural fetal anomalies that may complicate up to 7 percent of monochorionic twin pairs and contribute to abnormal growth [44-47]. Among sFGR cases, a major fetal anomaly in at least one twin (usually the smaller twin) has been noted in 16 percent of cases [48].

Viral infection can affect one or both fetuses and lead to growth restriction, so maternal history of signs/symptoms or ultrasound markers of viral infection other than isolated FGR require additional investigation, such as maternal serology for CMV and toxoplasmosis [49].

Rarely, monochorionic twins have discordant karyotypes. This is most often observed in the context of discordant fetal anomalies [50,51]. Screening or diagnostic testing for aneuploidy is recommended in anomalous fetuses when the findings will impact clinical decision making [52,53]. (See "Prenatal genetic evaluation of the fetus with anomalies or soft markers".)

●The second step is to evaluate amniotic fluid for oligohydramnios/polyhydramnios sequence to diagnose or exclude coexistent TTTS [54]. Distinguishing TTTS complicated by growth restriction of the donor twin from sFGR can be difficult since in both situations the growth restricted fetus may have oligohydramnios (table 2). Once fluid criteria for TTTS are met (defined as maximum vertical pocket <2 cm for the donor and >8 cm for the recipient), appropriate management for stage-based disease is required, regardless of coexisting sFGR or twin weight discordance [55]. (See "Twin-twin transfusion syndrome: Screening, prevalence, pathophysiology, and diagnosis" and "Twin-twin transfusion syndrome: Management and outcome".)

●The third step is to evaluate middle cerebral artery-peak systolic velocity (MCA-PSV) in both twins to diagnose or exclude coexistent TAPS. (See "Twin anemia-polycythemia sequence (TAPS)", section on 'Diagnostic criteria'.)

Fetal anemia in monochorionic twins can also be caused by parvovirus infection, alloimmunization, hemoglobinopathy (eg, alpha-thalassemia major), or massive fetomaternal transfusion. (See "Parvovirus B19 infection during pregnancy" and "RhD alloimmunization in pregnancy: Overview" and "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis" and "Spontaneous massive fetomaternal hemorrhage".)

When TTTS and TAPS were not present at diagnosis of sFGR, TTTS subsequently developed in 10 percent of cases and TAPS subsequently developed in 3 percent of cases in a retrospective series of 177 sFGR cases [48].

PREGNANCY MANAGEMENT — The goal when managing pregnancies with sFGR is to identify those that can be safely managed conservatively versus those that might benefit from fetal intervention. The strategy for risk assessment and management that has evolved is based on gestational age, prognosis, technical considerations, and patient values and preferences [43].

Classification-based approach — The approach depicted in the algorithms and described below is based on personal experience, expert opinion, and data from observational studies. Randomized trials have not been performed.

●sFGR type 1 – Expectant management with weekly ultrasound surveillance (umbilical artery [UA], middle cerebral artery [MCA]) is the preferred approach for these mild cases identified in the second trimester, as described in the algorithm (algorithm 1). Weekly biophysical profile scoring (BPP) is added at 28 to 32 weeks. If the UA pulsatility index increases to >95^th percentile or the MCA pulsatility index falls below the 5^th percentile, we would increase surveillance to twice weekly and also monitor for abnormalities in the ductus venosus (DV) waveform. Worsening of the UA Doppler pattern in the growth-restricted fetus is observed in up to 26 percent of these cases [18]; however, this typically takes months to develop, and the likelihood for serious fetal deterioration (venous Doppler abnormalities, a low BPP score, or oligohydramnios [34,56,57]) or demise is low when the UA flow is consistently forward.

If fetal status remains reassuring, as it usually does, we suggest delivery at 34+0 to 35+6 weeks as pregnancies with sFGR are not "uncomplicated" twins and have a higher rate for unanticipated demise than uncomplicated monochorionic twins in which delivery may be delayed until 37+6 weeks [58]. Earlier delivery is indicated if standard maternal or fetal indications for delivery develop.

The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) suggests timing delivery in sFGR based on assessment of fetal well-being, interval growth, BPP, DV waveform, and/or nonstress testing and points out that the risk of fetal demise in these pregnancies is increased, so delivery might be indicated even before fetal deterioration becomes evident [27].

●sFGR types 2 and 3 – The approach to moderate and severe sFGR is more complicated (algorithm 2) due to the higher rates of adverse outcomes, particularly fetal demise [2,44] (see 'Outcome by severity of sFGR' below). Demise of one twin can result in acute fetal transfusion and volume shifts, which leads to double fetal demise or neurologic damage in the surviving co-twin in up to 30 percent of cases [14,56,59-62].

Prior to the lower limit of viability, intervention with either selective fetal reduction [63-65] or fetoscopic laser ablation of intertwin placental vascular anastomoses can be considered in cases with fetal deterioration (progression from type 2 to type 3 sFGR, venous Doppler abnormalities [34,56,57], or oligohydramnios in the growth-restricted fetus [59,66]). Coexisting oligohydramnios has been associated with impending fetal mortality. Fetoscopic laser ablation is associated with high mortality for the sFGR fetus and does not guarantee survival for the normally grown fetus, but may protect this fetus from the consequences of co-twin demise [67]. Elevated MCA Doppler peak systolic velocity (PSV) and abnormal venous Dopplers have been suggested as strong predictors of demise of the growth restricted fetus after laser [68]. The procedure may be more technically challenging compared with fetoscopic laser ablation for treatment of twin-twin transfusion syndrome and may not always be possible in cases of pure sFGR [59,69,70]. If laser ablation is performed and the procedure is considered complete, then these pregnancies are managed similarly to dichorionic twins.

In patients who decline these interventions, we perform weekly Doppler surveillance of UA, MCA, and DV beginning at diagnosis and begin BPPs with each ultrasound assessment performed at ≥28 weeks. If Doppler findings remain stable and BPPs are reassuring, weekly outpatient monitoring until delivery is reasonable. After viability, if Doppler findings worsen (eg, deterioration of the UA Doppler pattern, such as progressive reversed end-diastolic velocity or DV pulsatility index >95^th percentile) or if oligohydramnios develops, we would increase surveillance with Dopplers/BPP to two to three times weekly and consider hospital admission for daily fetal monitoring with nonstress tests if delivery for fetal indications would be considered [71].

We deliver these pregnancies by 32+0 for UA reversed end-diastolic flow and by 34+0 weeks for UA absent end-diastolic flow, with earlier delivery for standard obstetric indications [29,41,72].

Antenatal corticosteroids — Betamethasone or dexamethasone is administered if fetal status deteriorates or prior to planned preterm delivery (see "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery"). UA Doppler flow may improve transiently after administration of betamethasone [73].

OUTCOME — A core outcome set is available for studies investigating management of these pregnancies [74].

Outcome by severity of sFGR — Type I sFGR twin pregnancies are generally delivered at a more advanced gestational age than type II and type III sFGR twin pregnancies and these pregnancies have lower overall rates of fetal demise, neonatal mortality, and cerebral injury compared with type II and type III sFGR twin pregnancies [75]. Nearly all studies report that the smaller twin is at highest risk for adverse perinatal outcome.

The risks of fetal demise of one or both fetuses, progression, preterm birth, and survival are depicted in the table (table 3). In a review including 177 cases of sFGR, isolated sFGR (no subsequent twin-twin transfusion syndrome [TTTS] or twin anemia polycythemia sequence [TAPS]) had a 91 percent survival rate; survival was lower in sFGR associated with a major anomaly (70 percent survival) or subsequent development of TTTS (65 percent survival) [48]. The majority of cases were type 1 sFGR (110/177) and had a survival rate of 96 percent, as compared with a survival rate of 55 percent (12/22) in those with type 2 sFGR and 83 percent (55/66) in those with type 3 sFGR.

Neurodevelopmental outcome — A systematic review on the impact of sFGR or birth weight discordance on long-term neurodevelopment in monochorionic twins found that survivors of sFGR are at increased risk for neurodevelopmental impairment, with the smaller twin having the poorer outcomes, but highlighted the lack of available data [76]. For the sFGR twin, the analysis reported long-term rates of moderate and severe neurologic morbidity of 3 and 6 percent, respectively; for the larger co-twin, these rates were 1 and 5 percent, respectively.

Outcome of sFGR with coexistent TTTS — In a meta-analysis of retrospective studies, pregnancies with both sFGR and TTTS undergoing laser therapy were at higher overall risk of fetal loss compared with those with TTTS alone (20.9 versus 14.4 percent, OR 1.57, 95% CI 1.30-1.91; four studies, >3000 twins) [77]. The donor twin of pregnancies with both sFGR and TTTS was at the highest risk of loss (25.7 percent versus approximately 16 percent in the recipient twin of such pregnancies and in the donor twin of pregnancies with TTTS without sFGR).

Pregnancies with both sFGR and TTTS undergoing laser therapy were also at higher risk of neurological morbidity (intraventricular hemorrhage grade III and IV or periventricular leukomalacia grade II) than those with TTTS alone (12.4 versus 6.3 percent; pooled OR 1.8, 95% CI 1.1-2.9; two studies, nearly 1000 twins). The risk of neurological morbidity was significantly higher for the donor twin of pregnancies with both sFGR and TTTS than in those with TTTS alone (12.2 versus 5.6 percent; pooled OR 2.4, 95% CI, 1.1-5.2) but the difference was not statistically significant for the recipient twin (11.9 versus 6.6 percent; OR 1.56, 95% CI 0.60-4.05). In pregnancies with both sFGR and TTTS treated with laser therapy, survival without neurological impairment at two years was approximately 70 percent for both donor and recipient twins.

Outcome of sFGR without coexistent TTTS — In a meta-analysis of retrospective and prospective studies of pregnancies with sFGR without TTTS, the incidence of stable, deteriorating, or improving umbilical artery Dopplers in type I cases was 68 percent (95% CI 26-89), 23 percent (95% CI 7-40), and 9 percent (95% CI 0.0-100), respectively [78]. In type II cases, the incidence was 40 percent (95% CI 18-81), 50 percent (95% CI 23-82), and 10 percent (95% CI 4-37), respectively. In type III cases, the incidence was 55 percent (95% CI 2-99), 23 percent (95% CI 9-43), and 22 percent (95% CI 6-54), respectively.

Risk factors for smaller twin demise were earlier gestational age at diagnosis, larger intertwin weight discordance, deterioration of umbilical artery Dopplers for type II and III cases, and absent or reversed a-wave for type II and III cases. Development of TTTS was not significantly associated with smaller twin demise for type II and III cases.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fetal growth restriction" and "Society guideline links: Multiple gestation".)

SUMMARY AND RECOMMENDATIONS

●Incidence – Selective fetal growth restriction (sFGR) refers to growth restriction of one fetus of a monochorionic twin pair due to discordant placental sharing (figure 1 and picture 1). It affects 10 to 15 percent of these pregnancies. (See 'Introduction' above and 'Pathophysiology' above and 'Incidence' above.)

●Identification of sFGR – Beginning in the early second trimester, monochorionic twin pregnancies should routinely undergo serial ultrasound examinations to monitor for development of sFGR as well as twin-twin transfusion syndrome (TTTS) and twin anemia polycythemia sequence (TAPS). An example of a monitoring protocol is depicted in the table (table 1). (See 'Presentation' above.)

●Diagnosis – The diagnosis of sFGR is based on the following (see 'Diagnosis' above):

•Estimated fetal weight (EFW)<3^rd percentile of one fetus or

•At least two of the four following criteria:

-EFW <10^th percentile for one twin

-Abdominal circumference <10^th percentile for one twin

-Weight discordance ≥25 percent

-Umbilical artery (UA) pulsatility index >95^th percentile for the smaller twin

●Classification – The pattern of the UA waveform and end-diastolic velocity of the smaller fetus are used to classify affected fetuses into type 1, type 2, or type 3 sFGR (waveform 2), which predicts the anticipated clinical course (table 3) and risk profile. Type 2 sFGR has the worst prognosis due to the high risk of single fetal demise and preterm birth. Proper Doppler technique is essential to accurately assess the umbilical artery Doppler pattern. (See 'Classification' above and 'Doppler technique' above.)

●Diagnostic evaluation – In a high proportion of cases, sFGR coexists with TTTS, TAPS, or discordant fetal anomalies. Due to substantial overlap between these disorders, a systematic approach to evaluation is required to arrive at the correct diagnosis and initiate management planning. (See 'Diagnostic evaluation' above.)

●Management – Our approach to managing these pregnancies is depicted in the algorithms (algorithm 1 and algorithm 2). (See 'Pregnancy management' above.)

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Topic 120803 Version 20.0

خرید پکیج

Selective fetal growth restriction in monochorionic twin pregnancies

References