How is TTTS diagnosed?
Twin-twin transfusion syndrome and other complications of monochorionic (shared placenta) twin pregnancies are usually diagnosed by ultrasound. There are usually twin-to-twin blood vessel connections in the MC placenta that cause the twins to interact with each other through their circulatory systems. These problems do not occur in twins who have two placentas (dichorionic, DC), and therefore it is important to distinguish between MC and DC twins at an ultrasound examination.
Antenatal twin-twin transfusion syndrome (TTTS) This is a serious, progressive disorder that affects up to 15% of MC twins. The twins do not have malformations, but one transfuses the other through a particular vascular structure. In this structure, an artery from the donor twin enters the placental substance to exchange oxygen and nutrients. Unfortunately, the corresponding vein returns "by mistake" to the other twin (the recipient) via this arterio-venous connection. The donor twin responds by partially shutting down blood supply to many of its internal organs, especially the kidneys, has reduced urine output and therefore a small amniotic fluid volume (oligohydramnios) in its amniotic cavity. The recipient responds to the blood transfusion by producing excessive amounts of urine, and is surrounded by a large volume of amniotic fluid (polyhydramnios). It is the combination of oligohydramnios/polyhydramnios that suggests the diagnosis of TTTS. The twins are often discrepant in size, as well, with significant discordance in estimated fetal weights. The recipient's blood becomes viscous and difficult to pump around the body, and this can result in heart failure, generalized soft tissue swelling (hydrops) and fetal demise. Because of the blood vessel connections across the placenta, if one twin dies, the co-twin faces significant risk for in utero demise. If a co-twin survives, there is a high risk of brain injury. Without treatment, about 70-80% of twins with TTTS will die. Survivors may have injuries to their brains, hearts and kidneys.
Candidates for Intervention Before Birth
There are mutliple complications of monochorionic twin pregnancies for which fetal intervention may be considered. The use of detailed ultrasound can help determine which pregnancies would best benefit from fetal intervention.
How it's diagnosed
A routine prenatal ultrasound will show whether there are twins in a pregnancy, and we can see if the twins are identical and sharing a placenta. This is a critical determination because if so, your babies are at risk for developing TTTS (15-20% risk).
At the SSM Health St. Louis Fetal Care Institute, we recommend that screening ultrasounds be performed every two weeks between 16 and 24 weeks of the pregnancy. If signs of TTTS develop, such as different amniotic fluid levels or growth differences, then ultrasounds can be performed more frequently to determine if the TTTS is really progressing. We will determine what stage of TTTS is present. A fetal echocardiogram (echo) gives us much more information about the heart function and anatomy. Your treatment options depend on the stage of TTTS, and range from observation to placental laser surgery.
The following criteria will present itself in a TTTS Pregnancy during different stages of severity:
The above can be confirmed in a sonar evaluation of the babies.
It is very important in any twin pregnancy to determine as soon as possible a monochorionic-diamniotic twin pregnancy so that any signs of TTTS can be identified as soon as possible.
The first warning sign of TTTS in a monochorionic-diamniotic twin pregnancy is polyhydramnios / oligohydramnios, followed by a size discrepancy in the twins and then as the pregnancy proceeds, stuck twin, skin edema, hydrops and possibly death of the smaller donor.
When taking the ultrasound be careful in the diagnoses of polyhydramnios in both sacs due to the membrane not being visible. On closer inspection you will see the membrane is not where it is expected to be, glad-wrapped around the baby! Request the mother turn on her side during the examination and identify that the donor twin is still stuck in the same position (stuck twin) on the sonar, evidencing TTTS diagnosis. The stuck twin also seems to adopt a fetal position and the sex may be difficult to tell as the baby always seems this way presented at each sonar.
Until a few years ago, our knowledge of the pathophysiology of TTTS was limited. Recently, ultrasound and Doppler studies of the placenta have contributed new information with which to better understand the complex mechanisms involved. It now appears that vascular connections in the placenta between twins must be present before TTTS develops.6 Vascular anastomoses are rare in di-chorionic twins, but are present in nearly 100% of pregnancies with mono-chorionic twins.7,8 With rare exception,9 TTTS is present only in mono-chorionic twins and will occur in 5% to 10% of mono-chorionic pregnancies.10The progressive nature of TTTS in utero is thought to be due to one twin (the donor) slowly pumping blood to the other (the recipient) through the placental vascular anastomoses. Why TTTS occurs in only a small proportion of mono-chorionic twin pregnancies remains unknown.
Recent studies have improved our knowledge of the pathophysiology of TTTS. In a study of 10 mono-chorionic pregnancies diagnosed with TTTS and 10 mono-chorionic pregnancies without TTTS, Bajoria et al performed immediate post-delivery placental injection studies to characterize placental vascular anastomoses and reported arterioarterial, venovenous and ateriovenous (A-V) anastomoses.11 The data suggest that vascular anastomoses of the A-V type, which run from the donor to the recipient deep within the placenta and are uncompensated by A-V anastomoses running in the reverse direction, may be one etiological factor for TTTS. Although the findings are a promising new development, the sample size of this study was small. What causes the development of these uncompensated anastomoses is unknown. There is a difference of opinion as to whether TTTS can occur in mono-amniotic twins; if it does it is extremely rare. Bajoria12 compared these anastomoses between mono-amniotic and mono-chorionic pregnancies and observed a greater number of anastomoses of all types in mono-amniotic pregnancies, which suggests that the syndrome may develop when there is a relative lack, rather than an absolute presence, of these vascular connections.
Recent ultrasound studies have demonstrated that TTTS is a slowly progressive disease.13-15 It may initially present as early as 13 gestational weeks, but obstetrical ultrasound will usually detect the syndrome between 17 to 26 weeks. The rule is that progressive oligohydramnios develops in one sac and polyhydramnios develops in the other. Subsequent perinatal complications vary; pre-term delivery may occur very soon after the diagnosis or not until several months later. Death of the fetuses or neonates may be due to pre-viable delivery, severe growth restriction of the donor, hypoplastic lungs in the donor, or high output cardiac failure in the recipient. These confounding factors complicate the analysis of studies designed to evaluate the efficacy of interventions.
1) AV - Unidirectional artery-to-vein connection in an equally shared placenta
A predicted blood flow from donor to recipient of <1ml per day produces a steadily increasing difference in size between the babies. From other studies it is estimated that 39% of TTTS cases have this placental type, and that these have by far the highest mortality rate, being the most difficult to treat.
2) AV + VA, AA, VV - Unidirectional artery-to-vein connection with compensating anastomoses in an equally shared placenta
Thought to occur in around 50% of TTTS cases.The AV anastomosis sets up fetal discordance and an increasingly high blood pressure in the Recipient, with a low blood pressure in the Donor. This continues until the compensating and AV blood flows are equal to each other. Then, a steady state of discordant growth occurs with opposing blood flows striving towards minimal transfusion. Widely varying discoedances are reported, depending on the resistance ratio of the AV and compensating anastomoses. Mortality is lower than in 1).
3) Unequal Placental Sharing + Superficial compensating anastomoses (AA, VV)
Fetal growth discordance is started by the difference between the available placental cotyledonic fractions. A steady state of virtually equal growth and almost equal blood pressures establishes later on because of the compensating AA and VV anastomoses. Mortality is low.
At the SSM Health St. Louis Fetal Care Institute, we recommend that screening ultrasounds be performed every two weeks between 16 and 24 weeks of the pregnancy. If signs of TTTS develop, such as different amniotic fluid levels or growth differences, then ultrasounds can be performed more frequently to determine if the TTTS is really progressing. We will determine what stage of TTTS is present. A fetal echocardiogram (echo) gives us much more information about the heart function and anatomy. Your treatment options depend on the stage of TTTS, and range from observation to placental laser surgery.
The following criteria will present itself in a TTTS Pregnancy during different stages of severity:
- monochorionic-diamniotic twin pregnancy
- babies of same sex
- polyhydramnios larger twin (recipient)
- oligohydramnios smaller twin (donor)
- size difference in twins
- possible stuck twin
- signs of skin edema - recipient
- signs of hydrops - recipient
- swelling of the head and abdomen (ascites)
- the heart contracts poorly, and heart failure is present - recipient
- smaller umbilical cord - donor
- abnormal umbilical cord resistance to flow in the donar (poor blood flow)
- mother presents extended abdomen due to polyhydramnios and looks larger than gestational age suggests
The above can be confirmed in a sonar evaluation of the babies.
It is very important in any twin pregnancy to determine as soon as possible a monochorionic-diamniotic twin pregnancy so that any signs of TTTS can be identified as soon as possible.
The first warning sign of TTTS in a monochorionic-diamniotic twin pregnancy is polyhydramnios / oligohydramnios, followed by a size discrepancy in the twins and then as the pregnancy proceeds, stuck twin, skin edema, hydrops and possibly death of the smaller donor.
When taking the ultrasound be careful in the diagnoses of polyhydramnios in both sacs due to the membrane not being visible. On closer inspection you will see the membrane is not where it is expected to be, glad-wrapped around the baby! Request the mother turn on her side during the examination and identify that the donor twin is still stuck in the same position (stuck twin) on the sonar, evidencing TTTS diagnosis. The stuck twin also seems to adopt a fetal position and the sex may be difficult to tell as the baby always seems this way presented at each sonar.
The diagnosis of Twin to Twin Transfusion Syndrome
The diagnosis of TTTS was originally based on the identification of anemia of one twin and polycythemia of the other with a growth-restricted donor twin,24 birthweight discordance of greater than 20%, or a hemoglobin difference of >5 g/dl.25 A number of hospital-based cohort studies adopted the neonatal criteria to evaluate the incidence and outcome of pregnancies diagnosed with TTTS (Table 2.2). In a retrospective review of 49 twin pregnancies, ?28 weeks’ gestation, Shah and Chaffin26 used a hematocrit difference of 15% or a birthweight discordance of >15% in a histologically confirmed monochorial placenta. The incidence of TTTS was estimated to be 20% of all twins in this preterm population.
Tan et al25 used plethora and pallor color differences between liveborn twins in addition to a difference in hemoglobin of 5 g/dl and found an incidence of TTTS of 7% of all twin pregnancies. Rausen et al27 used the clinical appearance of pallor and plethora, hemoglobin difference of >5 g/dl, weight and size discordance, and postmortem findings, and found an incidence of 3% of twin pregnancies (15% of monochorionic twins). This study may have been limited by inadequate clinical and placental data.
Seng and Rajadurai20 used pallor, plethora, birthweight discordance, and hemoglobin difference and found an incidence of 6.2% of twin birth. However, neonatal findings may exist in the absence of TTTS, and antenatal ultrasound criteria have been adopted for the diagnosis of TTTS.28 In addition, a staging system has been developed to describe the spectrum of severity of the disease. 29 In instances where antenatal ultrasound is not readily available, the cautious use of the neonatal criteria may still offer some guide in the management of these newborns. The incidence of TTTS using obstetrical diagnostic criteria28,29 is summarized in Table 2.3. Cincotta et al21 (hospitalbased cohort) quoted an incidence of TTTS of 15% of monochorionic twins.
Dickinson and Evans19 (population-based study) found an incidence of 1.7% of all twins born in a single Western Australia tertiary center. In Qatar, an annual birth of >12 000 constituting >98% of birth of the Gulf state, are seen in one tertiary center. Over a 30-month retrospective review of delivery records, only six twins of 522 twin sets born, were diagnosed as TTTS utilizing obstetrical criteria.
This resulted in a TTTS incidence of 1.1% of all twin births (unpublished data). Lutfi et al18 (populationbased study), described an incidence of TTTS of 2.9% of all twins born >20 weeks’ gestation, using both obstetrical ultrasound and neonatal criteria. The obstetrical ultrasonographic criteria used included confirming monochorionic placental mass using absence of the twin-peak sign, oligo- or anhydramnios in the donor using amniotic fluid pocket measurements (defined as a vertical fluid pocket <2 cm or an amniotic fluid index <5 cm), and the absence of fetal bladder, polyhydramnios (defined by a vertical pocket >8 cm or an amniotic fluid index >20 cm) in the recipient and signs of significant fetal cardiac decompensation, cardiac hypertrophy, tricuspid insufficiency and hydrops. Using the above criteria, TTTS was diagnosed in 0.018% of all births >20 weeks, gestation, 1.6% of all twins, and 5.8% of monochorionic twins (Table 2.4).
When a fetus doesn't have enough blood and oxygen, it tries to use what it has most efficiently. Blood is shunted preferentially to the most important organs, the brain and the heart, and away from less vital organs like the kidneys.
This causes the kidneys to partially shut down, and the fetus makes less urine. Because amniotic fluid is mostly comprised of fetal urine, the reduced urine output causes low amniotic fluid levels, called oligohydramnios. As the kidneys make less and less urine and the oligohydramnios worsens, the fetal bladder may empty and will no longer be visible by ultrasound, since it is not being filled with urine.
Meanwhile, the recipient becomes overloaded with fluid as a result of the ongoing blood transfusion from the donor twin, and responds by producing large amounts of urine. This leads to very large amounts of amniotic fluid in the recipient's sac, called polyhydramnios.
An ultrasound showing this combination of oligohydramnios and polyhydramnios in a monochorionic twin pair indicates the diagnosis of TTTS. True TTTS is diagnosed when ultrasound examination shows that the deepest pocket of amniotic fluid in one twin's sac measures less than 2 centimeters, while the deepest pocket of amniotic fluid measures greater than 8 centimeters in the other twin's sac.
Although TTTS is diagnosed based on the amniotic fluid levels in each sac, the twins may also differ significantly in weight and size. Some of the size differences may be due to the TTTS process. However, much of it is due to the different portion of the placenta devoted to each twin, or unequal placental sharing.
Most monochorionic twins that develop TTTS also have some unequal placental sharing, with a smaller portion of the placenta assigned to the donor twin. Many twins that only have unequal placental sharing, but are not transfusing one another, may be incorrectly diagnosed as having TTTS. Differences may be subtle, but outcomes are dependent on accurate diagnosis, and the treatment and management are different for each condition.
Careful ultrasound is crucial for correctly detecting and diagnosing TTTS. At the UCSF Fetal Treatment Center, ultrasounds are performed by specialists widely renowned for their diagnostic skills and expertise in this field, who have written textbooks and many scientific articles about fetal conditions such as TTTS and unequal placental sharing.
The severity of TTTS is partially based on when the condition becomes evident. The earlier it presents, the more serious the problem. In addition, the degree of fluid imbalance between the twins is important in staging TTTS.
A bladder that remains empty in the donor twin is a concerning sign, indicating a more advanced stage of TTTS. The situation worsens further when, in addition to the abnormal discrepancy in fluid volumes, ultrasound shows abnormal blood flow patterns in the umbilical cord vessels of either one or both of the twins. Finally, evidence of heart failure and tissue swelling, called hydrops, in either twin — usually the recipient — indicates a very serious, advanced stage.
Many patients in whom TTTS is suspected may, on further investigation, be found to have twins with discrepant fluid volumes that do not meet the definition for stage I TTTS. Still, all patients carrying monochorionic twins with significantly unequal amniotic fluid volumes or fetal weights should be evaluated and followed very carefully for changes, as true TTTS can develop and worsen rapidly.
To further evaluate the severity of TTTS, UCSF often performs fetal echocardiography. Fetal echocardiograms are specialized ultrasound studies of the fetal heart, performed by pediatric cardiologists with special expertise in this area.
Early signs of heart failure are usually seen first in the recipient twin, as its heart must work hard to pump the extra blood. These exams may reveal increased size of some of the heart chambers, and changes in flow across the heart valves. If the stress and overload on the recipient continues untreated, progressive changes may include decreased function of the heart chambers and possibly narrowing of one of the heart valves, called pulmonary stenosis.
Finally, using information from both the echocardiogram and ultrasound exam, we look for blood flow patterns in the umbilical artery and vein and other major fetal blood vessels.
Blood in the umbilical artery normally flows away from the fetus and toward the placenta to obtain fresh oxygen and nutrients from the mother's circulation. If a placental condition worsens, it becomes harder for the blood to flow toward and within the placenta. With each heartbeat, the fetus pushes blood toward the placenta (the systole phase) through the umbilical artery, and normally, that beat is strong enough for blood to keep flowing forward, toward the placenta, even as the heart re-fills for its next beat (the diastole phase).
In some cases, as TTTS progresses, forward flow in the umbilical artery of the donor may diminish between heartbeats. If the condition worsens, there may be no flow or even reversal of flow direction during the re-filling (diastole phase) of the fetal heart.
All the echocardiogram and ultrasound exam findings are considered in determining the severity of TTTS for each individual pregnancy.
Reviewed by health care specialists at UCSF Benioff Children's Hospital.
Possible causes of IUGR related to the placenta and/or umbilical cord include the following:
The majority of these causes of IUGR prevent adequate gas exchange and nutrient delivery to the fetus to allow it to thrive in utero. This process can occur primarily because of maternal disease causing decreased oxygen-carrying capacity (eg, cyanotic heart disease, smoking, hemoglobinopathy), a decreased oxygen delivery system secondary to maternal vascular disease (eg, diabetes with vascular disease, hypertension, autoimmune disease affecting the vessels leading to the placenta), or placental damage resulting from maternal disease (eg, smoking, thrombophilia, some autoimmune disease). Identifying a cause may not be possible in as many as 40% of cases
An important distinction to make when reviewing the causes of IUGR is that these factors are not identical to the factors that cause a baby to be classified as small for gestational age (SGA). Not all fetuses who are SGA (<10th percentile) have IUGR, and not all fetuses who have IUGR are SGA. For example, if a couple has had 3 term 4-kg babies and then has a 2.7-kg term baby, that infant is not SGA but may have IUGR.
The clinician's job is to identify the fetus whose health is endangered in utero due to a hostile intrauterine environment and to intervene appropriately in a timely fashion. This job also includes identifying the small but healthy fetus and avoiding harm to that fetus or to the mother.
Neonates with IUGR who survive the intrauterine experience are at increased risk for neonatal morbidity and mortality. With no nutritional reserve, the fetus redistributes blood flow to sustain function and help in the development of vital organs. This is called the brain-sparing effect and results in increased relative blood flow to the brain, heart, adrenals, and placenta, with diminished relative flow to the bone marrow, muscles, lungs, GI tract, and kidneys. This physiology in utero produces detectable results that aid in the diagnosis and monitoring of the fetus with IUGR (see Diagnosis and Management) but also results in some of the neonatal morbidity that neonates with IUGR face. Morbidity for neonates with IUGR includes increased rates of necrotizing enterocolitis, thrombocytopenia, temperature instability, and renal failure.
Neonates with IUGR who survive the intrauterine experience are at increased risk for neonatal morbidity and mortality. With no nutritional reserve, the fetus redistributes blood flow to sustain function and help in the development of vital organs. This is called the brain-sparing effect and results in increased relative blood flow to the brain, heart, adrenals, and placenta, with diminished relative flow to the bone marrow, muscles, lungs, GI tract, and kidneys. This physiology in utero produces detectable results that aid in the diagnosis and monitoring of the fetus with IUGR (see Diagnosis and Management) but also results in some of the neonatal morbidity that neonates with IUGR face. Morbidity for neonates with IUGR includes increased rates of necrotizing enterocolitis, thrombocytopenia, temperature instability, and renal failure.
The brain-sparing effect may result in different fetal growth patterns. In 1977, Campbell and Thomas introduced the idea of symmetric versus asymmetric growth. Symmetrically small fetuses were thought to have some sort of early global insult (eg, aneuploidy, viral infection, fetal alcohol syndrome). The asymmetrically small fetus was thought to be more likely small secondary to an imposed restriction in nutrient and gas exchange.
Investigators since then have differed on the importance of this differentiation in the diagnosis and management of pregnancies in which fetal growth restriction is present.
Women with conditions that are associated with IUGR should undergo serial sonography during their pregnancies. If sonography is a limited resource, obtaining a scan in the middle of the second trimester (at 18-20 wk) is reasonable in order to confirm dates, evaluate for anomalies, and confirm the number of fetuses). A repeat scan scheduled at 28-32 weeks’ gestation based on the earlier scan would allow for detection of abnormal growth, evidence of asymmetry, and supporting evidence of the brain-sparing physiology (eg, oligohydramnios, abnormalities based on Doppler findings).
Most ultrasound machines report aggregate gestational age measurements and individual parameters. Importantly, also assess individual values in order to identify a fetus who is growing asymmetrically. Making this a habit is critical. Abdominal circumference (AC) measurement of less than 2 standard deviations below the mean appears to be a reasonable cutoff point. Baschat and Weiner showed that a low AC percentile had the highest sensitivity (98.1%) for diagnosing IUGR (birth weight below the 10th percentile). The sensitivity of EFW (birth weight below the 10th percentile) is 85.7%; however, AC below the 2.5 percentile had the lowest positive predictive value (36.3%) while a low EFW had a 50% positive predictive value.
Other data to examine include amniotic fluid volume. Chauhan et al found that the frequency of IUGR was significantly higher among those pregnancies at or beyond 24 weeks’ gestation. Frequency was 19% with an amniotic fluid index (AFI) of less than 5 and 9% in those with an AFI higher than 5 (odds ratio 2.13 with 95% CI = 1.10-4.16).
Banks and Miller noted a significantly increased risk of IUGR in the borderline group relative to the normal group (13% vs 3.6%; rate ratio 3.9, 95% CI = 1.2-16.2) with an AFI below 10. These results reiterate much earlier work by Chamberlain et al. Using maximum vertical pocket (MVP) measurements, these authors showed an increased rate of IUGR among fetuses with decreasing MVP values. An MVP measurement of larger than 2 cm was associated with an IUGR rate of 5%, an MVP smaller than 2 cm was associated with an IUGR rate of 20%, and an MVP of smaller than 1 cm was associated with an IUGR rate of 39%. Chamberlain et al concluded that decreased AFI may be an early marker of declining placental function. This conclusion is valid today.
Doppler velocimetry contributes to the identification of fetuses at risk of IUGR. IUGR can result from abnormal invasion of the trophoblast and inadequate changes in intrafetal blood flow. Use of uterine artery blood flow characteristics has been studied most widely in Europe.
Albaiges et al suggest that a one-stage uterine artery screening at 23 weeks’ gestation is effective in identifying pregnancies that have the most adverse perinatal outcomes prior to 34 weeks’ gestation related to uteroplacental insufficiency. In their study of 1751 women who were seen at 23 weeks’ gestation for any reason, an abnormal uterine artery study result included bilateral uterine artery notches or a mean pulsatility index (PI) of greater than 1.45 for the 2 arteries. These criteria were seen in approximately 7% of the population. Within this 7% were 90% of the women who later developed preeclampsia and required delivery before 34 weeks’ gestation, 70% of women with a fetus below the 10th percentile who required delivery before 34 weeks’ gestation, 50% of placental abruptions, and 80% of fetal deaths. Importantly, the negative predictive value for these adverse events prior to 34 weeks’ gestation was higher than 99%.
Chien and colleagues conducted an overview of published studies on the efficacy of uterine artery Doppler findings as a predictor of preeclampsia, IUGR, and perinatal death. In reports of studies performed on low-risk women, an abnormal uterine artery Doppler result gave a likelihood ratio (LR) of developing IUGR of 3.6 (95% CI = 3.2-4), while a normal test result reduced the risk to below background, with an LR of 0.8 (95% CI = 0.08-0.09). For women who a priori were at high risk, an abnormal test result indicated an LR of 2.7 (95% CI = 2.1-3.4) while a normal result reduced the risks by 30% (LR of 0.7, 95% CI = 0.6-0.9).
Umbilical artery Doppler measurement also plays a role in helping the clinician decide whether the small fetus is at risk. Baschat and Weiner asked if abnormal uterine artery resistance can help improve the accuracy of diagnosing IUGR and if it can help identify a small fetus who is at risk of chronic hypoxemia who might benefit from close surveillance. These investigators studied 308 babies with biometry (either AC <2.5 percentile or EFW <10th percentile) who were delivered after 23 weeks’ gestation. The positive predictive value for IUGR was least for AC below or at the 2.5 percentile (36.6%). For EFW below the 10th percentile, the positive predictive value was 50.9%, and an elevated uterine artery systolic-to-diastolic (S-to-D) ratio gave a positive predictive value of 53.3%.
The highest sensitivity (100%) for prediction of IUGR occurred with those fetuses who had a small AC and elevated S-to-D ratio; this combination gave a 57% positive predictive value. The combination of EFW below the 10th percentile and an elevated S-to-D ratio had a sensitivity of only 86.3% but a positive predictive value of 63%. Among all presumably small fetuses with an elevated umbilical artery S-to-D ratio, a 10-fold increase occurred in the rate of admissions to and duration of stays in neonatal intensive care units and frequency and severity of RDS.
Baschat and others observed small fetuses (AC <5th percentile) with severely abnormal umbilical artery S-to-D ratio (absent or reversed end-diastolic flow). Their theory was that IUGR may be related to obliteration of small muscular arteries in tertiary stem villi or developmental abnormalities in the terminal villous vascular tree. Vascular endothelial damage could result in platelet consumption with resultant thrombocytopenia. Table 3 shows their data on 115 small fetuses with umbilical artery Doppler measurements performed less than 24 hours prior to delivery.
The protocol for antenatal testing suggested by Kramer and Weiner is but one example. It relies heavily on the use of umbilical artery Doppler testing. Because severely abnormal Doppler findings (absent or reversed end-diastolic flow) can precede abnormal fetal heart rate abnormality by several weeks.
At this point, the only reasonable goals in the treatment of IUGR are to deliver the most mature fetus in the best condition possible with minimal risk to the mother. Such a goal requires the use of antenatal testing in hope of identifying the fetus with IUGR before it becomes acidotic. Developing a testing scheme, following it, and having a high index of suspicion in this population when results of testing are abnormal is important. The positive predictive value of an abnormal antenatal test in those with IUGR is relatively high because the prevalence of acidemia and chronic hypoxemia is relatively high.
Tan et al25 used plethora and pallor color differences between liveborn twins in addition to a difference in hemoglobin of 5 g/dl and found an incidence of TTTS of 7% of all twin pregnancies. Rausen et al27 used the clinical appearance of pallor and plethora, hemoglobin difference of >5 g/dl, weight and size discordance, and postmortem findings, and found an incidence of 3% of twin pregnancies (15% of monochorionic twins). This study may have been limited by inadequate clinical and placental data.
Seng and Rajadurai20 used pallor, plethora, birthweight discordance, and hemoglobin difference and found an incidence of 6.2% of twin birth. However, neonatal findings may exist in the absence of TTTS, and antenatal ultrasound criteria have been adopted for the diagnosis of TTTS.28 In addition, a staging system has been developed to describe the spectrum of severity of the disease. 29 In instances where antenatal ultrasound is not readily available, the cautious use of the neonatal criteria may still offer some guide in the management of these newborns. The incidence of TTTS using obstetrical diagnostic criteria28,29 is summarized in Table 2.3. Cincotta et al21 (hospitalbased cohort) quoted an incidence of TTTS of 15% of monochorionic twins.
Dickinson and Evans19 (population-based study) found an incidence of 1.7% of all twins born in a single Western Australia tertiary center. In Qatar, an annual birth of >12 000 constituting >98% of birth of the Gulf state, are seen in one tertiary center. Over a 30-month retrospective review of delivery records, only six twins of 522 twin sets born, were diagnosed as TTTS utilizing obstetrical criteria.
This resulted in a TTTS incidence of 1.1% of all twin births (unpublished data). Lutfi et al18 (populationbased study), described an incidence of TTTS of 2.9% of all twins born >20 weeks’ gestation, using both obstetrical ultrasound and neonatal criteria. The obstetrical ultrasonographic criteria used included confirming monochorionic placental mass using absence of the twin-peak sign, oligo- or anhydramnios in the donor using amniotic fluid pocket measurements (defined as a vertical fluid pocket <2 cm or an amniotic fluid index <5 cm), and the absence of fetal bladder, polyhydramnios (defined by a vertical pocket >8 cm or an amniotic fluid index >20 cm) in the recipient and signs of significant fetal cardiac decompensation, cardiac hypertrophy, tricuspid insufficiency and hydrops. Using the above criteria, TTTS was diagnosed in 0.018% of all births >20 weeks, gestation, 1.6% of all twins, and 5.8% of monochorionic twins (Table 2.4).
TTTS Diagnosis
When a fetus doesn't have enough blood and oxygen, it tries to use what it has most efficiently. Blood is shunted preferentially to the most important organs, the brain and the heart, and away from less vital organs like the kidneys.
This causes the kidneys to partially shut down, and the fetus makes less urine. Because amniotic fluid is mostly comprised of fetal urine, the reduced urine output causes low amniotic fluid levels, called oligohydramnios. As the kidneys make less and less urine and the oligohydramnios worsens, the fetal bladder may empty and will no longer be visible by ultrasound, since it is not being filled with urine.
Meanwhile, the recipient becomes overloaded with fluid as a result of the ongoing blood transfusion from the donor twin, and responds by producing large amounts of urine. This leads to very large amounts of amniotic fluid in the recipient's sac, called polyhydramnios.
An ultrasound showing this combination of oligohydramnios and polyhydramnios in a monochorionic twin pair indicates the diagnosis of TTTS. True TTTS is diagnosed when ultrasound examination shows that the deepest pocket of amniotic fluid in one twin's sac measures less than 2 centimeters, while the deepest pocket of amniotic fluid measures greater than 8 centimeters in the other twin's sac.
Although TTTS is diagnosed based on the amniotic fluid levels in each sac, the twins may also differ significantly in weight and size. Some of the size differences may be due to the TTTS process. However, much of it is due to the different portion of the placenta devoted to each twin, or unequal placental sharing.
Most monochorionic twins that develop TTTS also have some unequal placental sharing, with a smaller portion of the placenta assigned to the donor twin. Many twins that only have unequal placental sharing, but are not transfusing one another, may be incorrectly diagnosed as having TTTS. Differences may be subtle, but outcomes are dependent on accurate diagnosis, and the treatment and management are different for each condition.
Careful ultrasound is crucial for correctly detecting and diagnosing TTTS. At the UCSF Fetal Treatment Center, ultrasounds are performed by specialists widely renowned for their diagnostic skills and expertise in this field, who have written textbooks and many scientific articles about fetal conditions such as TTTS and unequal placental sharing.
Evaluating the Severity of TTTS
The severity of TTTS is partially based on when the condition becomes evident. The earlier it presents, the more serious the problem. In addition, the degree of fluid imbalance between the twins is important in staging TTTS.
A bladder that remains empty in the donor twin is a concerning sign, indicating a more advanced stage of TTTS. The situation worsens further when, in addition to the abnormal discrepancy in fluid volumes, ultrasound shows abnormal blood flow patterns in the umbilical cord vessels of either one or both of the twins. Finally, evidence of heart failure and tissue swelling, called hydrops, in either twin — usually the recipient — indicates a very serious, advanced stage.
Many patients in whom TTTS is suspected may, on further investigation, be found to have twins with discrepant fluid volumes that do not meet the definition for stage I TTTS. Still, all patients carrying monochorionic twins with significantly unequal amniotic fluid volumes or fetal weights should be evaluated and followed very carefully for changes, as true TTTS can develop and worsen rapidly.
Fetal Echocardiography
To further evaluate the severity of TTTS, UCSF often performs fetal echocardiography. Fetal echocardiograms are specialized ultrasound studies of the fetal heart, performed by pediatric cardiologists with special expertise in this area.
Early signs of heart failure are usually seen first in the recipient twin, as its heart must work hard to pump the extra blood. These exams may reveal increased size of some of the heart chambers, and changes in flow across the heart valves. If the stress and overload on the recipient continues untreated, progressive changes may include decreased function of the heart chambers and possibly narrowing of one of the heart valves, called pulmonary stenosis.
Umbilical Artery Blood Flow
Blood in the umbilical artery normally flows away from the fetus and toward the placenta to obtain fresh oxygen and nutrients from the mother's circulation. If a placental condition worsens, it becomes harder for the blood to flow toward and within the placenta. With each heartbeat, the fetus pushes blood toward the placenta (the systole phase) through the umbilical artery, and normally, that beat is strong enough for blood to keep flowing forward, toward the placenta, even as the heart re-fills for its next beat (the diastole phase).
In some cases, as TTTS progresses, forward flow in the umbilical artery of the donor may diminish between heartbeats. If the condition worsens, there may be no flow or even reversal of flow direction during the re-filling (diastole phase) of the fetal heart.
All the echocardiogram and ultrasound exam findings are considered in determining the severity of TTTS for each individual pregnancy.
Reviewed by health care specialists at UCSF Benioff Children's Hospital.
Possible causes of IUGR related to the placenta and/or umbilical cord include the following:
- Multiple gestation
- Twin-to-twin transfusion
- Abnormal cord insertion
- Placental abnormality
- Chronic abruption
- Placenta previa
- Cord anomalies
The majority of these causes of IUGR prevent adequate gas exchange and nutrient delivery to the fetus to allow it to thrive in utero. This process can occur primarily because of maternal disease causing decreased oxygen-carrying capacity (eg, cyanotic heart disease, smoking, hemoglobinopathy), a decreased oxygen delivery system secondary to maternal vascular disease (eg, diabetes with vascular disease, hypertension, autoimmune disease affecting the vessels leading to the placenta), or placental damage resulting from maternal disease (eg, smoking, thrombophilia, some autoimmune disease). Identifying a cause may not be possible in as many as 40% of cases
An important distinction to make when reviewing the causes of IUGR is that these factors are not identical to the factors that cause a baby to be classified as small for gestational age (SGA). Not all fetuses who are SGA (<10th percentile) have IUGR, and not all fetuses who have IUGR are SGA. For example, if a couple has had 3 term 4-kg babies and then has a 2.7-kg term baby, that infant is not SGA but may have IUGR.
The clinician's job is to identify the fetus whose health is endangered in utero due to a hostile intrauterine environment and to intervene appropriately in a timely fashion. This job also includes identifying the small but healthy fetus and avoiding harm to that fetus or to the mother.
Neonates with IUGR who survive the intrauterine experience are at increased risk for neonatal morbidity and mortality. With no nutritional reserve, the fetus redistributes blood flow to sustain function and help in the development of vital organs. This is called the brain-sparing effect and results in increased relative blood flow to the brain, heart, adrenals, and placenta, with diminished relative flow to the bone marrow, muscles, lungs, GI tract, and kidneys. This physiology in utero produces detectable results that aid in the diagnosis and monitoring of the fetus with IUGR (see Diagnosis and Management) but also results in some of the neonatal morbidity that neonates with IUGR face. Morbidity for neonates with IUGR includes increased rates of necrotizing enterocolitis, thrombocytopenia, temperature instability, and renal failure.
Neonates with IUGR who survive the intrauterine experience are at increased risk for neonatal morbidity and mortality. With no nutritional reserve, the fetus redistributes blood flow to sustain function and help in the development of vital organs. This is called the brain-sparing effect and results in increased relative blood flow to the brain, heart, adrenals, and placenta, with diminished relative flow to the bone marrow, muscles, lungs, GI tract, and kidneys. This physiology in utero produces detectable results that aid in the diagnosis and monitoring of the fetus with IUGR (see Diagnosis and Management) but also results in some of the neonatal morbidity that neonates with IUGR face. Morbidity for neonates with IUGR includes increased rates of necrotizing enterocolitis, thrombocytopenia, temperature instability, and renal failure.
The brain-sparing effect may result in different fetal growth patterns. In 1977, Campbell and Thomas introduced the idea of symmetric versus asymmetric growth. Symmetrically small fetuses were thought to have some sort of early global insult (eg, aneuploidy, viral infection, fetal alcohol syndrome). The asymmetrically small fetus was thought to be more likely small secondary to an imposed restriction in nutrient and gas exchange.
Investigators since then have differed on the importance of this differentiation in the diagnosis and management of pregnancies in which fetal growth restriction is present.
Women with conditions that are associated with IUGR should undergo serial sonography during their pregnancies. If sonography is a limited resource, obtaining a scan in the middle of the second trimester (at 18-20 wk) is reasonable in order to confirm dates, evaluate for anomalies, and confirm the number of fetuses). A repeat scan scheduled at 28-32 weeks’ gestation based on the earlier scan would allow for detection of abnormal growth, evidence of asymmetry, and supporting evidence of the brain-sparing physiology (eg, oligohydramnios, abnormalities based on Doppler findings).
Ultrasound
Most ultrasound machines report aggregate gestational age measurements and individual parameters. Importantly, also assess individual values in order to identify a fetus who is growing asymmetrically. Making this a habit is critical. Abdominal circumference (AC) measurement of less than 2 standard deviations below the mean appears to be a reasonable cutoff point. Baschat and Weiner showed that a low AC percentile had the highest sensitivity (98.1%) for diagnosing IUGR (birth weight below the 10th percentile). The sensitivity of EFW (birth weight below the 10th percentile) is 85.7%; however, AC below the 2.5 percentile had the lowest positive predictive value (36.3%) while a low EFW had a 50% positive predictive value.
Other data to examine include amniotic fluid volume. Chauhan et al found that the frequency of IUGR was significantly higher among those pregnancies at or beyond 24 weeks’ gestation. Frequency was 19% with an amniotic fluid index (AFI) of less than 5 and 9% in those with an AFI higher than 5 (odds ratio 2.13 with 95% CI = 1.10-4.16).
Banks and Miller noted a significantly increased risk of IUGR in the borderline group relative to the normal group (13% vs 3.6%; rate ratio 3.9, 95% CI = 1.2-16.2) with an AFI below 10. These results reiterate much earlier work by Chamberlain et al. Using maximum vertical pocket (MVP) measurements, these authors showed an increased rate of IUGR among fetuses with decreasing MVP values. An MVP measurement of larger than 2 cm was associated with an IUGR rate of 5%, an MVP smaller than 2 cm was associated with an IUGR rate of 20%, and an MVP of smaller than 1 cm was associated with an IUGR rate of 39%. Chamberlain et al concluded that decreased AFI may be an early marker of declining placental function. This conclusion is valid today.
Doppler velocimetry
Doppler velocimetry contributes to the identification of fetuses at risk of IUGR. IUGR can result from abnormal invasion of the trophoblast and inadequate changes in intrafetal blood flow. Use of uterine artery blood flow characteristics has been studied most widely in Europe.
Albaiges et al suggest that a one-stage uterine artery screening at 23 weeks’ gestation is effective in identifying pregnancies that have the most adverse perinatal outcomes prior to 34 weeks’ gestation related to uteroplacental insufficiency. In their study of 1751 women who were seen at 23 weeks’ gestation for any reason, an abnormal uterine artery study result included bilateral uterine artery notches or a mean pulsatility index (PI) of greater than 1.45 for the 2 arteries. These criteria were seen in approximately 7% of the population. Within this 7% were 90% of the women who later developed preeclampsia and required delivery before 34 weeks’ gestation, 70% of women with a fetus below the 10th percentile who required delivery before 34 weeks’ gestation, 50% of placental abruptions, and 80% of fetal deaths. Importantly, the negative predictive value for these adverse events prior to 34 weeks’ gestation was higher than 99%.
Chien and colleagues conducted an overview of published studies on the efficacy of uterine artery Doppler findings as a predictor of preeclampsia, IUGR, and perinatal death. In reports of studies performed on low-risk women, an abnormal uterine artery Doppler result gave a likelihood ratio (LR) of developing IUGR of 3.6 (95% CI = 3.2-4), while a normal test result reduced the risk to below background, with an LR of 0.8 (95% CI = 0.08-0.09). For women who a priori were at high risk, an abnormal test result indicated an LR of 2.7 (95% CI = 2.1-3.4) while a normal result reduced the risks by 30% (LR of 0.7, 95% CI = 0.6-0.9).
Umbilical artery Doppler measurement
Umbilical artery Doppler measurement also plays a role in helping the clinician decide whether the small fetus is at risk. Baschat and Weiner asked if abnormal uterine artery resistance can help improve the accuracy of diagnosing IUGR and if it can help identify a small fetus who is at risk of chronic hypoxemia who might benefit from close surveillance. These investigators studied 308 babies with biometry (either AC <2.5 percentile or EFW <10th percentile) who were delivered after 23 weeks’ gestation. The positive predictive value for IUGR was least for AC below or at the 2.5 percentile (36.6%). For EFW below the 10th percentile, the positive predictive value was 50.9%, and an elevated uterine artery systolic-to-diastolic (S-to-D) ratio gave a positive predictive value of 53.3%.
The highest sensitivity (100%) for prediction of IUGR occurred with those fetuses who had a small AC and elevated S-to-D ratio; this combination gave a 57% positive predictive value. The combination of EFW below the 10th percentile and an elevated S-to-D ratio had a sensitivity of only 86.3% but a positive predictive value of 63%. Among all presumably small fetuses with an elevated umbilical artery S-to-D ratio, a 10-fold increase occurred in the rate of admissions to and duration of stays in neonatal intensive care units and frequency and severity of RDS.
Baschat and others observed small fetuses (AC <5th percentile) with severely abnormal umbilical artery S-to-D ratio (absent or reversed end-diastolic flow). Their theory was that IUGR may be related to obliteration of small muscular arteries in tertiary stem villi or developmental abnormalities in the terminal villous vascular tree. Vascular endothelial damage could result in platelet consumption with resultant thrombocytopenia. Table 3 shows their data on 115 small fetuses with umbilical artery Doppler measurements performed less than 24 hours prior to delivery.
The protocol for antenatal testing suggested by Kramer and Weiner is but one example. It relies heavily on the use of umbilical artery Doppler testing. Because severely abnormal Doppler findings (absent or reversed end-diastolic flow) can precede abnormal fetal heart rate abnormality by several weeks.
At this point, the only reasonable goals in the treatment of IUGR are to deliver the most mature fetus in the best condition possible with minimal risk to the mother. Such a goal requires the use of antenatal testing in hope of identifying the fetus with IUGR before it becomes acidotic. Developing a testing scheme, following it, and having a high index of suspicion in this population when results of testing are abnormal is important. The positive predictive value of an abnormal antenatal test in those with IUGR is relatively high because the prevalence of acidemia and chronic hypoxemia is relatively high.
PATHOPHYSIOLOGY
Until a few years ago, our knowledge of the pathophysiology of TTTS was limited. Recently, ultrasound and Doppler studies of the placenta have contributed new information with which to better understand the complex mechanisms involved. It now appears that vascular connections in the placenta between twins must be present before TTTS develops.6 Vascular anastomoses are rare in di-chorionic twins, but are present in nearly 100% of pregnancies with mono-chorionic twins.7,8 With rare exception,9 TTTS is present only in mono-chorionic twins and will occur in 5% to 10% of mono-chorionic pregnancies.10The progressive nature of TTTS in utero is thought to be due to one twin (the donor) slowly pumping blood to the other (the recipient) through the placental vascular anastomoses. Why TTTS occurs in only a small proportion of mono-chorionic twin pregnancies remains unknown.
Recent studies have improved our knowledge of the pathophysiology of TTTS. In a study of 10 mono-chorionic pregnancies diagnosed with TTTS and 10 mono-chorionic pregnancies without TTTS, Bajoria et al performed immediate post-delivery placental injection studies to characterize placental vascular anastomoses and reported arterioarterial, venovenous and ateriovenous (A-V) anastomoses.11 The data suggest that vascular anastomoses of the A-V type, which run from the donor to the recipient deep within the placenta and are uncompensated by A-V anastomoses running in the reverse direction, may be one etiological factor for TTTS. Although the findings are a promising new development, the sample size of this study was small. What causes the development of these uncompensated anastomoses is unknown. There is a difference of opinion as to whether TTTS can occur in mono-amniotic twins; if it does it is extremely rare. Bajoria12 compared these anastomoses between mono-amniotic and mono-chorionic pregnancies and observed a greater number of anastomoses of all types in mono-amniotic pregnancies, which suggests that the syndrome may develop when there is a relative lack, rather than an absolute presence, of these vascular connections.
Recent ultrasound studies have demonstrated that TTTS is a slowly progressive disease.13-15 It may initially present as early as 13 gestational weeks, but obstetrical ultrasound will usually detect the syndrome between 17 to 26 weeks. The rule is that progressive oligohydramnios develops in one sac and polyhydramnios develops in the other. Subsequent perinatal complications vary; pre-term delivery may occur very soon after the diagnosis or not until several months later. Death of the fetuses or neonates may be due to pre-viable delivery, severe growth restriction of the donor, hypoplastic lungs in the donor, or high output cardiac failure in the recipient. These confounding factors complicate the analysis of studies designed to evaluate the efficacy of interventions.
Distinct placental types
1) AV - Unidirectional artery-to-vein connection in an equally shared placenta
A predicted blood flow from donor to recipient of <1ml per day produces a steadily increasing difference in size between the babies. From other studies it is estimated that 39% of TTTS cases have this placental type, and that these have by far the highest mortality rate, being the most difficult to treat.
2) AV + VA, AA, VV - Unidirectional artery-to-vein connection with compensating anastomoses in an equally shared placenta
Thought to occur in around 50% of TTTS cases.The AV anastomosis sets up fetal discordance and an increasingly high blood pressure in the Recipient, with a low blood pressure in the Donor. This continues until the compensating and AV blood flows are equal to each other. Then, a steady state of discordant growth occurs with opposing blood flows striving towards minimal transfusion. Widely varying discoedances are reported, depending on the resistance ratio of the AV and compensating anastomoses. Mortality is lower than in 1).
3) Unequal Placental Sharing + Superficial compensating anastomoses (AA, VV)
Fetal growth discordance is started by the difference between the available placental cotyledonic fractions. A steady state of virtually equal growth and almost equal blood pressures establishes later on because of the compensating AA and VV anastomoses. Mortality is low.
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