Multifetal Pregnancy

Twins can be classified as monozygotic, originating from the fertilization and subsequent division of one egg, or dizygotic, originating from the fertilization and development of two eggs. Approximately one third of twins are thought to be monozygotic in the United States.[1]

Twins can be further classified by their chorionicity. Dizygotic twins are almost always dichorionic, diamniotic. The chronicity of monozygotic twins depends on the timing of division of the fertilized egg. Dichorionic, diamniotic twins result if the fertilized egg splits 0-3 days after fertilization. This is thought to occur in approximately 20-30% of monozygotic twins. Monochorionic, diamniotic twins occur at days 4-8 after fertilization and account for approximately 70% of monozygotic twins. Monochorionic, monoamniotic twins are rare (1-5% of monozygotic twins) and result secondary to division 8-12 days postfertilization. Conjoined twins occur with division 13 days or later; this is extremely rare.

The etiology of monozygotic twinning is unknown. Dizygotic twins are thought to result from the ovulation of multiple follicles caused by elevations in serum gonadotropin levels. Hence, advanced maternal age is associated with an increased prevalence of twin birth.

The availability of assisted reproductive technology has contributed to the increase in multiple gestations seen over the past 20 years. During ovulation induction treatment, the ovaries are stimulated to produce several follicles, thus increasing the risk of multiple eggs being released and subsequently fertilized. The risk of multiple gestations during in-vitro fertilization is directly related to maternal age and number of embryos transferred. With two embryos transferred, the risk of a multiple gestation was found to be 22.7% and 19.7% for women aged 20-29 years and 30-34 years, respectively. This risk increased to 45.7% in women aged 20-29 years and 39.8% for women aged 30-34 years if 3 embryos were transferred.[2]

Dizygotic twinning can occur more frequently in some families. This is thought to be secondary to genetic factors leading to ovulation of several eggs during the menstrual cycle. In contrast, monozygotic twinning has not been shown to have a familial inheritance.

The incidence of multiple gestations varies by country due to regional variations in dizygotic twin rates; monozygotic twinning rates are fairly constant across nations. In Nigeria, the rate of twinning has been reported as high as 49 per 1000 births.[3] In contrast, in Japan, the rate of twinning is 1.3 per 1000 births.[4] The incidence of spontaneous twins is thought to be approximately 1 in 80 pregnancies.[5] For spontaneous triplets, the incidence is estimated at 1 in 8,000.[5] In the United States, the twin birth rate was 33.3 per 1,000 births in 2009.[6] This rate had risen 70% from 1980-2004 and is thought to be secondary to older maternal age at childbirth and the use of fertility treatment. The rate of triplet and higher order multiple births was 1.5 per 1,000 total births in 2009. This number had initially increased during the 1980s and 1990s but has since declined.

Twin birth rates in 2005-2006 for non-Hispanic whites were 36 per 1,000, for non-Hispanic blacks, 36.8 per 1,000, and for Hispanics, 21.8 per 1,000. Since 1990, rates have risen 57% for non-Hispanic whites, 38% for non-Hispanic blacks, and 21% for Hispanic women.[6]

As maternal age increases, the risk of dizygotic twinning also increases. This is thought to be due to increased levels of follicle-stimulating hormone with advancing maternal age.[7] From 1980-2006, twin birth rates rose 27% for mothers younger than 20 years compared with 80% for women in their thirties. In 2006, 20% of births to women aged 45-54 were twins, compared with approximately 2% of births to women aged 20-24 years.[6] This increase can also be attributed in part to the use of assisted reproductive technology.

Although the frequency of multiple gestations is lower than singleton gestations, multiple gestations account for a disproportionate share of neonatal morbidity and mortality. Much of this can be attributed to a higher rate of preterm delivery for multiple gestations. The mean gestational age at delivery is 35 weeks for twins, 32 weeks for triplets and 29 weeks for quadruplets. [1]  As a result, 25% of twins and 75% of triplets require admission to the neonatal intensive care unit (NICU).[8] Neurologic outcomes also appear to be worse in multiple births. When matched for gestational age at delivery, infants born from multifetal pregnancies have an approximately 3-fold increase in cerebral palsy[9] (see the Gestational Age from Estimated Date of Delivery calculator).  There is an approximate fivefold increased risk of stillbirth and sevenfold increased risk of neonatal death. [10]

Monochorionic gestations are at risk for twin-to-twin transfusion syndrome (TTTS), which occurs in about 15% of monochorionic pregnancies.[1]  TTTS is thought to be caused by vascular anastomoses within the placenta, causing one twin to become underperfused (the "donor" twin) and the other twin to show signs of overperfusion (the "recipient" twin).  Pregnancies complicated by TTTS are at significantly increased risk of neonatal morbidity and mortality.

Maternal morbidity is also increased in a multifetal gestation. Women with multiples are more likely to be hospitalized with complications including preterm labor, preterm premature rupture of membranes, preeclampsia, placental abruption, pulmonary embolism, and postpartum hemorrhage. As a result, hospital costs are higher in these pregnancies.[10]

Women carrying multiple gestations may be initially asymptomatic or may have normal signs and symptoms of pregnancy (eg, breast tenderness, fatigue, nausea, vomiting). Multiple gestations may be suspected in the setting of hyperemesis gravidarum or in a patient who has undergone assisted reproductive technology. A complete history, including a family history, should be taken in every woman suspected to have multiples.

A complete physical examination should be performed in every woman presenting for prenatal care. A twin gestation may be suspected if the uterine size is greater than expected compared to menstrual dates.

Ultrasound examination remains the most reliable method for diagnosis of multiple gestations. Chorionicity should be established as soon as possible during pregnancy because it can affect future management decisions. The optimal time for diagnosis is in the first trimester or early second trimester.[11]

The most reliable predictor of a dichorionic gestation is the presence of two separate placentas. However, if the placentas have fused by the time an ultrasound examination is performed, a dichorionic, diamniotic gestation can show evidence of a “twin peak” or “lambda” sign on ultrasound. This refers to a triangular portion of the chorion fused between two layers of amnion. See the images below.

A monochorionic, diamniotic gestation can have the presence of a “T” sign, which is the appearance of the amnion as it comes off the placenta at a 90° angle. See the image below.

These signs can be more difficult to appreciate as the pregnancy progresses.

Routine prenatal care should be performed in pregnancies with multiple gestations. More frequent visits and modification of activity may be advised, depending on the clinical course of the pregnancy.

Given the risks that multiple gestations confer, some women elect for fetal reduction, especially in the setting of higher order multiples. This is typically performed by potassium chloride injection into the selected fetus. Multifetal reduction in a monochorionic twin setting is typically not recommended due to unknown effects on the remaining twin.[10]  The overall post procedure pregnancy loss rate is estimated at approximately 6-12%, depending on gestational age. The ongoing early preterm delivery (between 24-28 weeks’ gestation) risk is approximately 4.5%.[12]

Improved pregnancy outcomes have been reported from multifetal pregnancy reduction of triplets to twins and particularly in those with reduction from triplets to singleton gestations (higher mean birth weights and later deliveries).[13] However, the rates of pregnancy loss before 24 weeks and preterm delivery before 32-34 weeks' gestation were similar in the twin and singleton pregnancies, and the prevalence of gestational diabetes and gestational hypertension was not significantly different between the groups with triplet reduction to twin and triplet reduction to singleton gestations.[13]

Women carrying multiples are subject to significant changes in maternal physiology beyond normal pregnancy adaptations. Maternal resting energy expenditure in twin pregnancies increased by 10% compared with singleton pregnancies.[14] The 2009 Institute of Medicine guidelines recommend body mass index (BMI)-specific weight gains in twin pregnancies for normal weight women of 37-54 pounds, overweight women of 31-50 pounds, and obese women of 25-42 pounds.[15] In addition to a prenatal vitamin, nutritional supplementation with iron, calcium, and folate is also recommended in women with multiple gestations.[16]

Given the increased risk of fetal growth restriction and growth discordance in multiple gestations, serial growth ultrasounds are recommended beginning in the second trimester. In monochorionic twins, ultrasounds should be performed every 2 weeks to look for evidence of twin-twin transfusion syndrome. In dichorionic twins with concordant growth, growth scans can be performed approximately every 4-6 weeks in the absence of any other pregnancy complications.[10]

Multiple gestations are at increased risk for stillbirth. A few retrospective studies of nonstress testing and fetal biophysical profiles have been shown to detect compromised twin and triplet pregnancies.[17, 18]  However, the American College of Obstetricians and Gynecologists does not advocate for routine antenatal testing in multiple gestations.[10]

There are no known interventions that have been shown to prolong a pregnancy in women with multifetal gestations (ie, prophlyactic cerclage, bed rest, tocolytics, etc). Treatment with progesterone does not reduce the risk of preterm birth in twin and triplet gestations.[19, 20]

 

 

Multifetal pregnancies reach a nadir of perinatal mortality earlier than singleton pregnancies.[21] For twin pregnancies, this occurs at approximately 38 weeks’ gestation and for triplets it occurs at 35 weeks’ gestation. Timing of delivery has not been well established in higher order multiples and therefore should be individualized. Prospective evidence regarding optimal timing of delivery for twins is also lacking. 

Monochorionic, diamniotic twins have been shown to have increased perinatal mortality throughout pregnancy, even at term, compared with dichorionic, diamniotic twins.[22, 23] The rate of stillbirth has been estimated at 44.4 per 1000 births for monochorionic twin pregnancies versus 12.2 per 1000 births in dichorionic twin pregnancies.[24] The increased risk of stillbirth in monochorionic twins may be partly attributed to complications from twin-to-twin transfusion syndrome, although stillbirth rates due to congenital anomalies and antepartum hypoxia were also significantly higher in monochorionic twins. This is thought to be due to hemodynamic changes within the vascular anastomoses within the placenta. 

Monochorionic, monoamniotic twins are at increased risk for perinatal mortality primarily due to cord entanglement and subsequently may be offered intensive fetal monitoring during the antepartum period. 

ACOG recommends the following in terms of timing of delivery[10] :

• Uncomplicated dichorionic, diamniotic twin gestation - 38 weeks
• Uncomplicated monochorionic, diamniotic twin gestation - Between 34-37 6/7 weeks
• Uncomplicated monochorionic, monoamniotic twin gestations - 32-34 weeks

Mode of delivery should be determined by position of the fetuses.

Routine planned cesarean delivery has not been shown to have a significant difference in perinatal or neonatal mortality, neonatal morbidity, or maternal morbidity.[25] Vertex-to-vertex twin presentation occurs in approximately 42% of twins.[26] A trial of labor is generally accepted in this situation with delivery occurring in a setting that allows efficient conversion to cesarean section for the second twin if indicated. Cesarean delivery is usually indicated in the presence of nonvertex twin presentation, monoamniotic twins, and higher-order multiple gestations due to lack of evidence regarding the safety of a vaginal delivery. For the vertex-nonvertex twin presentation, several options are available, including cesarean delivery of both twins, attempted cephalic version of the second twin, or a breech extraction of the second twin.

Breech extraction of the second twin has been shown to be associated with a lower incidence of fetal distress and cesarean delivery with comparable neonatal outcome compared to cephalic version.[27] Physician experience and estimated birth weights should be considered when discussing breech extraction of the second twin. Some experts recommend attempted breech extraction for the second twin in the setting of an estimated fetal weight greater than 1500 grams and less than 500 gram discordance between the twins.

Congenital anomalies and prenatal diagnosis

Congenital malformations are twice as common in twin pregnancies compared with singletons and 4 times more common in triplets. The rate of congenital anomalies in twins is estimated at approximately 4% compared with 2% in singletons.[28] Monozygotic twins have twice the incidence of congenital abnormalities compared with dizygotic twins.[29] In a cohort of twins with known chronicity, the prevalence of congenital anomalies in monochorionic twins was estimated at approximately 6% compared with 3% for dichorionic twins.[28]

The presence of multiple fetuses increases the mathematical probability of the pregnancy being affected by a chromosomal abnormality. Therefore, the risk of Down syndrome in either fetus of a 33-year-old woman with a twin gestation is equivalent to the risk of a 35-year-old woman with a singleton pregnancy.[30] Invasive diagnostic testing in multiple gestations can be technically challenging due to positioning of the fetuses, possibility of cross-contamination of the sample obtained, and difficulty in mapping the fetuses.  

Serum screening for aneuploidy is not as sensitive in a twin gestation, with an increased false-positive rate.[31]  Single-nucleotide polymorphism-based noninvasive prenatal testing (NIPT) appears to be able to identify triploid, unrecognized twin, and vanishing twin pregnancies.[32]   However, the accuracy of screening for aneuploidy with NIPT in multiple gestations is limited and is not recommended by ACOG.[33]

Pregnancy-induced hypertension

Multiple gestations are at increased risk for developing gestational hypertension and preeclampsia compared with singleton pregnancies. In multifetal pregnancies, hypertensive disorders of pregnancy occur more often, at an earlier gestational age, and can have a more severe and/or atypical presentation than in singleton pregnancies.[34]

The incidence of preeclampsia is 2.6 times higher in twin gestations than in singleton gestations.[35] Multiple gestations are also at increased risk for complications associated with preeclampsia including preterm delivery, placental abruption, and HELLP syndrome. Current recommendations for management of preeclampsia in multiple gestations do not differ from management in singleton pregnancies.

Gestational diabetes

The incidence of gestational diabetes increases with each additional fetus in multiple gestations. Between 22-39% of triplet pregnancies and 3-6% of twin pregnancies are complicated by gestational diabetes. Each additional fetus increases the risk of gestational diabetes by an estimated factor of 1.8.[36]

Preterm delivery

As mentioned above, most multiple gestations are born prior to 37 weeks’ gestation. Preterm infants are at increased risk for developing complications related to immature organ systems such as respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage, poor feeding capacity, retinopathy of prematurity, and hypothermia. These risks decrease as the gestational age at delivery increases. Corticosteroids for fetal lung maturity have not been well studied in multiple gestations; however, it is still recommended by the National Institutes of Health for all women with threatened preterm delivery prior to 34 weeks, regardless of the number of fetuses.[37]

Intrauterine growth restriction

Intrauterine growth restriction (IUGR) and discordant growth contribute to adverse outcomes in multiple gestations. IUGR is defined as an estimated fetal weight below the tenth percentile for a singleton gestation. Discordant growth is identified when the smaller fetus weighs less than 80% of the larger fetus. Growth restriction in multiple gestations is likely secondary to uteroplacental insufficiency but can also be secondary to structural anomalies, umbilical cord abnormalities, ultrasound error, infections, or genetic abnormalities. Approximately 14-25% of twin gestations and 50-60% of triplet or higher order gestations are affected by growth restriction.[38] Due to the increase in preterm birth rates with the increased incidence of IUGR, low birth weight (< 2,500 g) is commonly seen in multiple gestations. Approximately 58% of twins and 95% of triplets had low birth weights in 2006.[6]

Other pregnancy complications

Multiple gestations are at increased risk for other pregnancy complications such as acute fatty liver of pregnancy, venous thromboembolism, anemia, polyhydramnios, malpresentation, postpartum hemorrhage, hyperemesis gravidarum, and abnormal placentation.

Twin-to-twin transfusion syndrome

Twin-to-twin transfusion syndrome (TTTS) complicates approximately 15% of monochorionic pregnancies, specifically, monochorionic, diamniotic placentations. It is thought to occur secondary to placental vascular anastomoses. This leads to increased blood flow to one fetus (recipient fetus) and reduced blood flow to the other fetus (donor fetus). It is usually diagnosed by ultrasound in the second trimester with the appearance of oligohydramnios and polyhydramnios in the recipient fetus. Development of TTTS is associated with a high rate of morbidity and mortality for both fetuses. Several therapies have been used including serial amnioreduction and laser coagulation of the communicating vessels. Serial amniocentesis though, appears less effective than laser treatment.[39]