Course BASIC_Graduate level learning material about the challenges of human reproductive medicine in a changing Europe

SYLLABUS

Special Challenges of Twin Pregnancies

 (Basic level)

Due to the rising number of infertilities fueled by Assisted Reproductive Techniques (ART) the rate and number of multifetal gestations have been increasing dramatically nowadays and in the last decades, creating an issue which needs to be discussed in detail. Multifetal pregnancies are out of question belong to high-risk pregnancies, with special challenges. Twin pregnancy is associated with higher rates of almost every potential complication of singleton pregnancy, with the exceptions of postterm pregnancy and macrosomia.

What is the mechanism of the twin genesis?

As presented in the lecture, there are two types of twins. The first is called dizygotic twins, when two spermatocytes fertilize two separate oocytes at the same time. Dizygotic twins are considered to be in a strict sense true twins, because they result from the ovulation and fertilization of two separate oocytes during the same ovulatory cycle, therefore their DNA completely differ, and their gender can be the same or different as well. Monozygotic (identical twins) arise from the fertilization of a single oocyte by a single spermatocyte. The created embryo will start to multiply and at some point, divides into two. Their gender is the same, with the same phenotypical features. As presented in the lecture the division of the embryo can happen in 0-4 days, 4-8 days, and 8-12 days after fertilization resulting different chorion and amnion settings. The division of the fertilized zygote into two does not necessarily result equal sharing of cellular materials, resulting discordant for genetic mutations, or they can have the same genetic disease but with marked variability in expression.

Superfetation, superfecundation and the ‘’vanishing twin’’

Superfetation is the type of fertilization in mammals where two different fertilizations happen in an interval as long as, or longer than a menstrual cycle. This type of fertilization is not proven in humans. Superfecundation means fertilization of two ova within the same cycle, but not at the same coitus, nor necessarily by sperm from the same male. 

Early spontaneous reduction from twin to singleton pregnancy (vanishing twin) is common, occurring in 7 to 36 percent of in vitro fertilization (IVF) twin pregnancies [1]. It is unclear if the rate is similar in naturally conceived pregnancies, which are not routinely imaged from the earliest stages of pregnancy. The demised twin can affect results of cell-free DNA testing when used to screen for the common fetal aneuploidies (Down syndrome, neural-tube defects).

What risks are involved in the development of twin pregnancies?

• The use of fertility enhancing treatment: Over one-third of all twins born in the USA can be related to iatrogenic interventions (IVF, ovulation induction, superovulation plus intrauterine insemination).
• Maternal age: natural twinning peaks at the age of 37. This may be related to the increasing follicle-stimulating hormone (FSH) concentration with age. Older women are also more likely to utilize fertility treatments.
• Race: Spontaneous twinning is more common in the Black population than in the White population. 
• Hereditary: dizygotic pregnancies appear to have a genetic component (maternal history of twin pregnancies). 
• Nutritional factors: folic acid supplementation increase the rate of twinning. Increased BMI (body mass index) and tall individuals has a greater risk to develop twin pregnancies. 

How can you tell if the twins are mono-, or dizygotic?

Determining amnionicity and chorionicity is critical because monochorionic twins have a shared fetoplacental circulation, which puts them at risk for specific serious pregnancy complications, such as twin-twin transfusion syndrome (TTTS), twin anemia polycythemia sequence (TAPS), selective fetal growth restriction (sFGR), and twin reversed arterial perfusion (TRAP) sequence. 

To determine the chorionicity is only possible during the first trimester, and can be achieved by sonographic evaluation, during which a thick (≥ 2mm) dividing membrane supports the diagnosis of dichorionicity. Although it is hard to distinguish one large placenta from two placentas laying side-by-side, triangular projection of placental tissue extend beyond the chorionic surface between the layers of the dividing membrane, called lambda-sign, or twin-peak sign, is a proof of dichorionicity. In contrast, in monochorionic pregnancy there is a single layer of continuous chorion limiting the villous growth. The intertwin membrane takes off perpendicularly to the placental surface producing the sonographic sign known as “T” sign [3]. With one common amniotic sac without intertwin membrane the pregnancy is monochorionic monoamniotic. Summarized, if the fetuses are separated by chorion, then the pregnancy can be mono-, or dizygotic, while a monochorionic pregnancy is always monozygotic. To determine the zygosity after birth is possible, the gender is one of the most important marker, twins of opposite sex are always dizygotic. Furthermore, a careful examination of the placenta and the intertwin membrane are also essential, while blood group typing form the cord blood samples of the twins may be also helpful. 

Pregnancy outcome of multifetal gestations

All twin pregnancies have higher rates of the following fetal complications than singleton pregnancies. Spontaneous abortion can occure in an increased threeefold chance. Congenital malformations are increased compared to singletons (conjoined twins, acardiac anomaly, neural-tube defects, sirenomelia (fusion of the lower extremities), “twin-to-twin transfusion” , congenital hip dislocation). Twins are more likely to have low birthweight due to restricted fetal growth and preterm birth (60% of twins and 93 % of triplets are delivered preterm). 

Unique complications of multifetal gestation - What are conjoined twins?

Fused or conjoined twins have been referred to as Siamese twins–after Chang and Eng Bunker of Siam (Thailand), who were displayed worldwide by P. T. Barnum. Joining of the twins may begin at either pole and may produce characteristic forms depending on which body parts are joined or shared. Of these, thoracopagus is the most common (Mutchinick, 2011). The incidence of conjoined twins is not well established. According to the fused area, we discriminate ventral and dorsal types. Ventral can be (a) rostral (omphalopagus, thoracopagus, and cephalopagus, (b) caudal (ischiopagus), and (c) lateral (parapagus dirosopus, parapagus dicephalus), or dorsal (i) craniopagus, (ii) rachipagus, and (iii) pygopagus (see in the presentation). Surgical separation of an almost completely joined twin pair may be successful if essential organs are not shared (Spitz, 2003; Tannuri, 2013). Consultation with a pediatric surgeon team often assists parental decision making. 

Which conditions can arise from different vascular anastomoses between fetuses?

Vascular anastomoses between twins are only present in monochorionic twins. Artery-to-artery anastomoses are the most common, although vein-to-vein and artery-to-vein anastomoses can also develop. The anastomoses can be formed superficially and deep on chorionic surface of the placenta. Most of these vascular connections are balanced, and has no consequences, although is an estimated one quarter of monozygotic twins shunt develop between the fetuses and result acardiac twinning, or twin-to-twin transfusion syndrome. 

1-Acardiac twinning, also called twin-reversed-arterial-perfusion (TRAP) sequence has an incidence of 1/35.000 birth, but serious complication. In TRAP there is a normal fetus, serving as a donor, which develops high output heart failure, and a recipient twin who has no heart (acardius) and other organs. In this case a large artery-to-artery and vein-to-vein shunt is created within a single placenta, resulting in a drop of arterial pressure in the recipient, therefore deoxygenated arterial blood enters the recipient’s iliac vessels from its co-twin counterpart. Thus, only the lower body is perfused, and disrupted growth and development of the upper body will follow, resulting acardius acephalus (failure of head growth), or acardius myelacephalus (partially developed head with limbs). Mortality rate is up to 50-75%. 

2-In twin-twin transfusion syndrome (TTTS), also called polyhydramnion-oligohydramnion sequence, where the blood is transfused from donor twin, who will be anemic, growth restricted, pale, and develop oliguria and oligohydramnion, to its recipient sibling, who will be plethoric, circulatory overloaded, will develop polyuria, polyhydramnion and congestive heart failure, at least hydrops. In monochorionic pregnancies with TTTS unidirectional flow in AV- anastomoses develop, therefore deoxygenated blood from the donor is shared through cotyledon by the recipient. After the completion of oxygenation in the chorionic villus the blood leaves the shared cotyledon via placental vein of the recipient. This unbalanced flow eventually results blood volume depletion in donor twin and volume overload in recipient twin. TTTS occurs in 10-15% of MCDA twins, if left untreated, perinatal mortality rate is 80-100%. TTTS manifest between 15-26. weeks. This condition is diagnosed by ultrasound examination and the severity of one can be assessed through the Quintero staging system as presented in the table below: 

Among the survivors, the most serious complication is brain damage, which is common both for the donor and for the recipient. “Cerebral injury in donors is thought to be mainly caused by impaired cerebral perfusion as the result of hypovolemia and intertwin shifts of blood, leading to hypoxic-ischemic insults. Polycythemia and hyperviscosity with subsequent vascular sludging is the presumed mechanism for cerebral injury in recipients” [4]. Selective fetoscopic laser coagulation of intertwin anastomoses is nowadays the only effective treatment option in advanced stages, which can be performed in all stages between 15-26 weeks of gestation. In stage I: expectant management or continuous amniotic fluid reduction is recommended before intrauterine laeser therapy. 

3-Twin anaemia-polycythaemia sequence (TAPS): the pathophysiology is based on the slow transfusion of erythrocytes through fine (<1 mm diameter) arteriovenous-anastomoses. The incicence is 3%, but it may increase to 13-16% after laeser coagulation due to TTTS. The diagnosis is made by ultrasound (measurement of MCA PSV - Middle Cerebral Artery Peak Systolic Velocity). Twin anemia-polycythemia sequence (TAPS) after intrauterine laser ablation has been treated with repeated laeser therapy, in utero fetal transfusion, selective feticide, expectant management, and early delivery. There is no real consensus on the optimal treatment.

4-Selective intrauterine growth restriction (sIUGR): the estimated fetal weight of the smaller fetus is under 10 percentile, or the weight discrepancy between the two fetuses is more than 25%. In the sIUGR is no detectable oligohydramnion-polyhydramnion sequence. 

Antepartum management of twin pregnancy

Some dietary factors may contribute to the in-utero well-being of the fetus. An increased caloric consumption (with 300 kcal/day), iron supplementation (60-100 mg/day), and folic acid 1 mg/day is preferred. Hypertension occures in aproximatively 20% of twin pregnancies, a cautious prenatal care is needed to prevent preeclampsia. Serial ultrasound examination is preferred throughout the whole pregnancy, including biometrial prophyle, umbilical artery flow analysis, amniotic fluid index, cervical lenght measurement, placenta evaluation. 

Prevention of preterm delivery: bed rest is recommended. Routine prophylactic use of tocolytics, cerclage, supplemental progesterone or pessaries in twin pregnancies should be avoided. None of these interventions reduce the risk of preterm birth. However, selective use of each of these interventions may be indicated in specific clinical scenarios.

Labor and delivery

Chorionicity and amnionicity determine the optimal time for delivery of uncomplicated twin pregnancies. For dichorionic/diamniotic uncomplicated pregnancies the recommended planned delivery should be at 38+0 to 38+6 weeks of gestation [5]. Societies suggest delivery of uncomplicated monochorionic/diamniotic twins at 36+0 weeks of gestation or soon thereafter and by 36+6 weeks. Monochorionic/monoamniotic twin pregnancies are delivered between 32+0- and 34+0-weeks’ gestation because of the high prospective risk of stillbirth compared with neonatal death, despite intensive fetal monitoring.

Both amnionicity and fetal presentation at the onset of labour influence the choice of mode of delivery in twin pregnancies. Vaginal delivery is preferred in diamniotic twins where the presenting twin is cephalic at the onset of labour, if appropriate expertise in internal and external presentation and/or vaginal breech delivery is available and there are no standard indications for caesarean section. Cesarean delivery is preferred in diamniotic twins with one non-cephalic twin, monoamniotic twins and pregnancies with standard obstetric indications for cesarean delivery (e.g. placenta previa). At the onset of labour, approximately 80% of first twins are cephalic and 20% are noncephalic [6]. However, the position of the second twin may change intrapartum. Algorithm for the route of delivery in diamniotic twins:

As a general approach a trained obstetrical attendant should remain with the mother throughout the labor. Cardiotocography (CTG) monitoring is essential. And a sonography machine should be available to determine the fetal lie. An intravenous infusion system should be ready (with oxytocin) and blood transfusion should be readily available. As a non-obstetrical team an experienced anesthesia and two neonatologist attendants required. After the delivery of the „A” twin, vaginal examination has to be carried out to assess the fetal lie, presentation and position of the „B” twin. Then the membrane of the „B” fetus needs to ruptured. If the „B” fetus shifts to transverse lie after the delivery of the „A” fetus internal rotation and extraction maneuver have to be carried out, or cesarian section should be performed. If before the delivery of the „B” fetus the placenta is become separated (placental abruption) emergency cesarian section is required. If any of the fetuses are in transverse lie, or if the „A” fetus is in breech presentation cesarian section is recommended. If the „A” fetus is in breech presentation and the „B” is in cephalic presentation the two heads can stuck together in the birth canal (collisio gemellorum).

Prenatal care in case of monochorionic multifetal pregnancies

Early sonographic determination of chorionicity in needed (T-sign and Lambda sign). Sonographic monitoring of the twins throughout the pregnancy (as presented) including amniotic fluid index, regular assessment of the intrauterine growth (fetal biometry), Doppler flowmetry of the umbilical arteries and vein (and the ductus venosus), middle cerebral artery peak systolic velocimetry (MCA PSV).

The prenatal ultrasound monitoring the dichorionic and in the monochorionic pregnancies differ as presented in the figure below: 

Conclusion

Twin pregnancies are considered to be high-risk pregnancies. While dizygotic twins are two separate pregnancies happening at the same time, they are still responsible for poor pregnancy outcomes. On the other hand, monozygotic, and especially monochorionic pregnancies are potentially more dangerous, since in this cases severe and unique complications can develop, such as conjoined twin, TRAP or TTTS.

References: 

[1] Romanski PA, Carusi DA, Farland LV, Missmer SA, Kaser DJ, Walsh BW, Racowsky C, Brady PC. Perinatal and Peripartum Outcomes in Vanishing Twin Pregnancies Achieved by In Vitro Fertilization. Obstet Gynecol. 2018 Jun;131(6):1011-1020. doi: 10.1097/AOG.0000000000002595. PMID: 29742658.

[2] Adashi EY. Seeing double: a nation of twins from sea to shining sea. Am J Obstet Gynecol. 2016 Mar;214(3):311-3. doi: 10.1016/j.ajog.2016.01.185. PMID: 26928147.

[3] Vincenzo D’Addario, Cristina Rossi: Diagnosis of chorionicity: The role of ultrasound, DOI: 10.1016/j.diapre.2013.09.004.

[4] Marjolijn S. Spruijt, Enrico Lopriore, Sylke J. Steggerda, Femke Slaghekke, Jeanine M.M. Van Klink: Twin-twin transfusion syndrome in the era of fetoscopic laser surgery: antenatal management, neonatal outcome and beyond. Pages 259-267

[5] American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics, Society for Maternal-Fetal Medicine. Multifetal Gestations: Twin, Triplet, and Higher-Order Multifetal Pregnancies: ACOG Practice Bulletin, Number 231. Obstet Gynecol. 2021 Jun 1;137(6):e145-e162. doi: 10.1097/AOG.0000000000004397. PMID: 34011891.

[6] Chasen ST, Spiro SJ, Kalish RB, Chervenak FA. Changes in fetal presentation in twin pregnancies. J Matern Fetal Neonatal Med. 2005 Jan;17(1):45-8. doi: 10.1080/14767050400028592. PMID: 15804786.