1. What every clinician should know
A. Clinical features and incidence
In the United States, as in many other developed nations, the number of multiple births has risen dramatically over the past 3 decades, with a quadrupling of triplet births. The rate of triplet and higher-order multifetal gestations has increased by over 400% since 1980 with a peak of 193.5/100,000 births in 1998, followed by a slight decrease to 153.4/100,000 births in 2009 and fewer than 20% were reported as spontaneous conceptions.(Reference 1) ,The natural incidence of spontaneous triplet pregnancy conception is estimated to be approximately 1 per 6,000-8,000 births and the remainder are attributable to childbearing at older ages and availability of fertility therapies and assisted reproductive techniques (ART). (Reference 2)
Triplet pregnancies have significantly higher risks than twins or singletons for most maternal and neonatal complications. Major morbidity in these pregnancies is attributable the high rate of preterm births and extreme low birth weight (ELBW). The management of these high risk pregnancies irrespective of the mode of conception is a common challenge in modern obstetrics.
B. Risk factors
In developed countries there has been an exponential increase in the rate of high-order multiple pregnancies since the 1980s. These epidemiological trends are the direct result of advances in modern infertility treatments. Concurrently, there has been significant increase in pregnancies in women of advanced maternal age. The reduced fecundity of older age significantly increases the need for infertility treatment. More aggressive measures are employed to achieve pregnancy, often with the transfer of multiple embryos and aggressive ovulation induction therapies. It is reported that in women older than 40 years old there has been a 12-fold increase in triplet and higher-order multiples (Reference 3).
2. Diagnosis and differential diagnosis
A. Establishing the diagnosis
Triplet pregnancies are diagnosed prenatally with ultrasound. The majority are diagnosed in the first trimester particularly due to the close surveillance of pregnancies conceived using fertility treatments. Other features that may prompt early sonographic examination include uterine fundus size-date discrepancy or hyperemesis gravidarum.
Women known to be carrying triplets should be offered first trimester ultrasound when the crown-rump length measures from 45mm to 84mm (at approximately 11 weeks 0 days to 13 weeks 6 days) to estimate gestational age, determine chorionicity and screen for aneuploidy. Screening involves nuchal translucency (NT) thickness measurement alone, as serum analyte levels are not applicable in a triplet pregnancy.
Early assignment of nomenclature to each fetus (for example, upper and lower, or left and right) should be documented clearly to ensure consistency throughout the pregnancy. As in twin pregnancies, chorionicity is assigned following visualization of the twin peak or lambda sign, the thickness of the intertwin membrane and assessment of the number of placental masses. Later in the pregnancy, fetal sex determination can aid assignment of chorionicity. Although most triplet pregnancies arise from three different oocytes, monozygotic gestations can also occur. Identification of a monochorionic triplet gestation or a monochorionic pair within a triplet gestation is essential due to the associated additional risk of this type of placentation. (See Figure 1, Figure 2, and Figure 3)
B. Diagnostic tests
There is an increased risk of aneuploidy in triplet pregnancy especially in the setting of multizygotic gestations. Multiple maternal serum analyte screening for neural tube defects or trisomy 21 is not available for triplet pregnancies. However, diagnostic testing can be performed. If there is concern for aneuploidy based on other factors such as family/genetic history or sonographic findings such as thickened nuchal translucency (NT), diagnostic testing is recommended. NT measurements are distributed in the same manner as a singleton pregnancy.
CVS is challenging; however, this technique can provide early diagnosis to high risk patients who are planning multifetal pregnancy reduction based on karyotype results. Amniocentesis is another option for diagnostic testing. Double sampling of one fetus’ amniotic sac can be avoided by injecting indigo carmine into each sac after obtaining the specimen, which in turn colors the fluid that has already been sampled.
There is a dearth of evidence regarding pregnancy loss rates following diagnostic testing in triplet pregnancies; however, logically the risk is expected to be greater than in singleton pregnancies. Nevertheless, as the risks are inversely proportional to the experience of an operator, only experienced clinicians should perform these procedures in high-order multiple gestations.
The main counseling points to be addressed include the potential adverse events associated with higher order multiples, specifically preterm birth, the option of multifetal reduction and the necessity for close clinical and sonographic surveillance if the pregnancy is continued. Prolonged hospitalization may be required and there is also a high likelihood of birth by cesarean delivery.
The nutritional requirements of women with triplet pregnancies are greater than for singleton gestations. Optimal pregnancy outcomes have been reported with maternal weight gain of at least 16kg by 24 weeks of gestation.
Generally antenatal surveillance of a triplet pregnancy involves serial sonographic growth evaluations. If the pregnancy is further complicated by a monochorionic pair, weekly surveillance for twin to twin transfusion syndrome is advised from 15-16 weeks gestation.
With the demonstration of concordant growth and normal fluid volumes, generally weekly surveillance with biophysical profiles is implemented from the third trimester onwards. A discordance of 25% between fetuses in multiple pregnancies is considered to be a clinically important indicator of intrauterine growth restriction. In the setting of discordant growth, closer surveillance from an earlier gestation is often warranted, along with consideration of inpatient care and elective preterm delivery.
Due to the increased incidence of both aneuploidy and fetal malformations in triplet pregnancy, a detailed anatomical survey should be performed by experienced sonographers. Given the increased risk of congenital heart disease among monozygotic multiples and among IVF pregnancies regardless of zygosity, fetal echocardiographic assessment is also recommended.
Indications for referral to a tertiary level fetal medicine centre include:
Monochorionic monoamniotic triplet pregnancies.
Monochorionic diamniotic triplet pregnancies.
Dichorionic diamniotic triplet pregnancies.
Complications such as discordant fetal growth, fetal anomaly, discordant fetal death, feto-fetal transfusion syndrome.
The role of cervical length assessment to aid prediction of preterm labor in asymptomatic patients continues to be evaluated; however, this modality is often practiced routinely. Increased maternal surveillance is also warranted due to the increased incidence of gestational anemia, diabetes, hypertensive disorders, intrahepatic cholestasis and acute fatty liver.
Current recommendations for timing of elective delivery of triplet pregnancy is from 35 weeks 0 days, as beyond this gestation there is an increased risk of intra-uterine demise in uncomplicated triplet pregnancies. However, 75% of triplet pregnancies will deliver before 35 weeks gestation.
Cesarean delivery is the commonest and most accepted mode for triplet pregnancies; however, there remains a need for large prospective studies to determine the optimal mode of delivery. There is an argument that vaginal delivery may be offered safely to a selected population of triplet pregnancies, but this is a controversial option.
The incidence of hemorrhage after a triplet delivery is quoted up to 35%, therefore corrective measures should be ready and in place at the time of delivery to reduce the associated morbidity. Of note, women with triplet pregnancies complicated by pre-eclampsia are particularly sensitive to volume overload and the development of pulmonary edema.
Complications arising from the condition
Preterm delivery is the most common complication, with approximately 75% of triplets born prematurely. There is a lack of prospective randomized trials to determine the benefit of bed rest, routine hospitalization, cerclage, home uterine activity monitoring (HUAM) and tocolysis. Progesterone supplementation has been shown not to reduce preterm birth in triplet gestations.
There is insufficient data to demonstrate the value of sonographic cervical assessment of triplet pregnancy, although this technique may serve as an adjunct to other forms of monitoring and to the decision about when to administer antenatal corticosteroids.
There is an over-representation of multiple births among low birthweight (VLBW) infants that is accentuated for triplets. The risk of delivering ELBW (less than 1500g) infants is 10 times higher than in the general population.
Dichorionic and monochorionic triplet pregnancies have a five-fold greater risk of adverse perinatal outcomes than trichorionic pregnancies, attributable to greater incidences of growth discordance, feto-fetal transfusion, fetal demise and preterm delivery, both spontaneous and iatrogenic.
Preeclampsia complicates 20-46% of triplet pregnancies, compared to 5% of singleton pregnancies. It is often more severe pre-eclampsia occurring earlier in the pregnancy, which in turn contributes iatrogenically to the preterm delivery rate.
Primary prevention. Prevention of excess multiple births that are associated with ART has been advocated through recommendations of reducing the number of embryos that are transferred and single embryo transfer in clinically appropriate patients. There was initially a significant fall in triplet pregnancies arising from ART in 2001 attributable to refinements in ART procedures followed by a plateau since 2002.
The effect of reducing embryos is being eroded by the more recent phenomenon of ‘fertility tourism,’ where patients travel abroad to have IVF treatment that may not have the same regulatory restrictions. Approaches such as ultrasound monitoring of ovulation induction, and super-ovulation-intrauterine insemination cycles with cancellation or transfer to IVF if excessive ovulation is predicted, are other preventative measures to reduce the high order multiple birth rate without significantly reducing the pregnancy rate.
The significant risk of adverse outcomes for both the mother and her infants in a high order multiple pregnancy is often not appreciated by women seeking fertility treatment; therefore, improved education may reduce the patient’s desire for aggressive measures.
Secondary prevention. The option of multifetal reduction is a necessary part of counseling when a triplet pregnancy occurs. The primary aim of reduction is to reduce the risk of preterm delivery and adverse outcome in the remaining pregnancy. While some argue that the morbidity gap is closing between twin and triplet pregnancies and that reduction of triplets to twins is a social rather than a medical issue, there is clear evidence of poorer outcomes in triplet pregnancies, especially when chorionicity is taken into consideration.
When comparing expectant management of trichorionic triplets to those pregnancies selectively reduced to twins, there is a significantly higher pregnancy loss before 24 weeks and preterm births before 32 weeks. The majority of higher order multiple pregnancies are reduced to twins, however reduction to a singleton pregnancy is also possible, most commonly occurring in dichorionic triplet pregnancies. More recent developments of vaso-occlusive techniques such as bipolar cord occlusion and radiofrequency ablation have allowed for the possibility of reducing dichorionic triamniotic triplet pregnancies to dichorionic diamniotic twin pregnancies with initial favorable results; however, pregnancy outcome data is limited.
Complications as a consequence of management
Pregnancy loss rates related to the procedure are highly dependent on operator experience. In the appropriate setting the procedure related pregnancy loss rate is estimated to be between 4-6%. Chorionic villus sampling before multifetal pregnancy reduction does not increase post-procedural loss rates.
5. Prognosis and outcome
Spontaneous loss of one or more triplets is common in the first trimester. Spontaneous loss of the entire pregnancy is estimated to occur in approximately 5-10% of triplet pregnancies.
A 95% rate of antenatal complications is reported that includes maternal risks such as anemia, gestational diabetes, hypertensive disorders and liver disorders. There is also a significantly increased risk of fetal growth discordance, growth restriction and intrauterine fetal demise.
The average gestational age at delivery is 32 weeks, with 7-18% of pregnancies delivering before 29 weeks of gestation.
As prematurity is the most common complication of triplet pregnancy, there are numerous sequelae, including perinatal mortality, respiratory and gastrointestinal complications.
Up to 35% of triplets have birth weights below 1500 grams. This rate of ELBW is increased in triplet pregnancies when compared to both twin and singleton pregnancies, even when corrected for gestational age.
Whereas contemporary perinatology and neonatology and its interventions can save the lives of ELBW and premature infants, prevention of neurological morbidity remains unsolved. There are high rates of major neurological abnormalities, subnormal (less than 70) Bayley Mental Developmental Index, and subnormal (less than 70) Psychomotor Developmental Index among extremely LBW infants. Cerebral palsy is more common in triplet pregnancies; with some reports indicating a 47-fold higher risk compared to singletons.
6. What is the evidence for specific management and treatment recommendations
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Bajora, R, Ward, SB, Adegbite, AL. “Comparative study of dichorionic and trichorionic iatrogenic triplets”. Am J Obstet Gynecol. vol. 194. 2006. pp. 415-24.
Wimalasundera, RC. “Selective reduction and termination of multiple pregnancies”. Seminars in Fetal & Neonatal Medicine. vol. 15. 2010. pp. 327-35.
Wadhawan, R, Oh, W, Vohr, BR. “Neurodevelopmental Outcomes of Triplets or Higher-Order Extremely Low Birth Weight Infants”. Pediatrics. vol. 127. 2011. pp. e654
Caritis, SN, Rouse, DJ, Peaceman, AM. “Prevention of preterm birth in triplets using 17 alpha-hydroxyprogesterone caproate: a randomized controlled trial”. Obstet Gynecol. vol. 113. 2009 Feb. pp. 285-92.
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- Triplet Pregnancy
- 1. What every clinician should know
- 2. Diagnosis and differential diagnosis
- 3. Management
- 4. Complications
- 5. Prognosis and outcome
- 6. What is the evidence for specific management and treatment recommendations