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10.1 Epidemiology of Natural Twinning 10.1.1 Actual Trend The cultural modifications in women’s reproductive strate- gies over the past 50 years have drastically influenced the demographic scenario. Higher levels of education and a de- sire for economic and social success, as well as difficulties in finding a permanent job, have played a major role in mod- ifying the reproductive strategies, as evidenced by delayed parenthood and the reduction in family size [1]. In addition to this expected twinning rate due to advancing maternal age, there is also evidence that natural twinning has increased in women who have been exposed to assisted reproduction technologies [2]. 10.1.2 Dizygotic Twinning In humans, multiple pregnancies arise more frequently from fertilization of two separate oocytes (1.2% of pregnancies). The incidence of excessive follicular recruitment is more or less 31% in mothers of dizygotic (DZ) twins. The DZ twin- ning rate is affected by race, genetic factors, seasonality, ma- ternal age and parity, endogenous gonadotropins, fertility drugs and sex of the embryo [3]. The incidence of twin preg- nancy also varies from country to country, the highest rates being reported in Nigeria (5%), and the lowest in Japan. In Italy the best estimate of DZ twinning is 1%. It has been sug- gested that genetic predisposition and malnutrition may play a role in this different frequency. Maternal age up to 35–39 years is linked with increasing twinning rates and this pattern has been attributed to the rise in the level of gonadotropins with age [2]. There is a slight tendency for twins to have been conceived during summer as compared with singletons; and this may reflect the effect of increased light during summer on the pineal gland, resulting in melatonin production, and consequent decreased inhibition of pituitary follicle-stimulat- ing hormone (FSH) release [3]. 10.1.3 Monozygotic Twinning The constant frequency of monozygotic (MZ) pregnancies over time and in different areas, and the lack of association be- tween maternal age and frequency of MZ twinning, suggests that MZ twins are largely determined by genetic mechanisms. In fact an excess of monozygotic twins occurs in mothers who are themselves one of monozygotic twins, whereas there is no evidence for a paternal effect on MZ twinning [2]. 10.2 Epidemiology of Iatrogenic Twinning There have always been some naturally, or spontaneously, oc- curring multiple pregnancies (with twins being more frequent than triplets, and quadruplets or even higher multiples being much rarer). However, the frequency has increased enor- mously since assisted reproductive technologies (ART) have become available. Because of the higher morbidity and mor- tality associated with twins and particularly triplets, every ef- fort should be made to reduce incidence [3]. In Europe, the overall rate of multiple pregnancy in 2002 was 23% com- pared to 26% in 2000. This reduction has been determined by the transfer of fewer embryos, except in Italy where a con- troversial law obliged the transfer of three embryos until it was recently modified. A similar high prevalence of twinning in ART pregnancies was reported in 2006 in the USA (26%), where such a policy had not been universally adopted. In the M.A. Rustico () Obstetrics and Gynaecology Clinical Unit, Buzzi Children’s Hospital Department of Clinical Sciences, University of Milan, Milan, Italy 67 G. Buonocore et al. (eds.), Neonatology. A Practical Approach to Neonatal Diseases. © Springer-Verlag Italia 2012 10 Multiple Pregnancies Maria Angela Rustico, Mariano Lanna and Enrico Ferrazzi

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10.1 Epidemiology of Natural Twinning

10.1.1 Actual Trend

The cultural modifications in women’s reproductive strate-gies over the past 50 years have drastically influenced thedemographic scenario. Higher levels of education and a de-sire for economic and social success, as well as difficultiesin finding a permanent job, have played a major role in mod-ifying the reproductive strategies, as evidenced by delayedparenthood and the reduction in family size [1]. In additionto this expected twinning rate due to advancing maternal age,there is also evidence that natural twinning has increased inwomen who have been exposed to assisted reproductiontechnologies [2].

10.1.2 Dizygotic Twinning

In humans, multiple pregnancies arise more frequently fromfertilization of two separate oocytes (1.2% of pregnancies).The incidence of excessive follicular recruitment is more orless 31% in mothers of dizygotic (DZ) twins. The DZ twin-ning rate is affected by race, genetic factors, seasonality, ma-ternal age and parity, endogenous gonadotropins, fertilitydrugs and sex of the embryo [3]. The incidence of twin preg-nancy also varies from country to country, the highest ratesbeing reported in Nigeria (5%), and the lowest in Japan. InItaly the best estimate of DZ twinning is 1%. It has been sug-gested that genetic predisposition and malnutrition may playa role in this different frequency. Maternal age up to 35–39years is linked with increasing twinning rates and this pattern

has been attributed to the rise in the level of gonadotropinswith age [2]. There is a slight tendency for twins to have beenconceived during summer as compared with singletons; andthis may reflect the effect of increased light during summeron the pineal gland, resulting in melatonin production, andconsequent decreased inhibition of pituitary follicle-stimulat-ing hormone (FSH) release [3].

10.1.3 Monozygotic Twinning

The constant frequency of monozygotic (MZ) pregnanciesover time and in different areas, and the lack of association be-tween maternal age and frequency of MZ twinning, suggeststhat MZ twins are largely determined by genetic mechanisms.In fact an excess of monozygotic twins occurs in mothers whoare themselves one of monozygotic twins, whereas there is noevidence for a paternal effect on MZ twinning [2].

10.2 Epidemiology of Iatrogenic Twinning

There have always been some naturally, or spontaneously, oc-curring multiple pregnancies (with twins being more frequentthan triplets, and quadruplets or even higher multiples beingmuch rarer). However, the frequency has increased enor-mously since assisted reproductive technologies (ART) havebecome available. Because of the higher morbidity and mor-tality associated with twins and particularly triplets, every ef-fort should be made to reduce incidence [3]. In Europe, theoverall rate of multiple pregnancy in 2002 was 23% com-pared to 26% in 2000. This reduction has been determined bythe transfer of fewer embryos, except in Italy where a con-troversial law obliged the transfer of three embryos until itwas recently modified. A similar high prevalence of twinningin ART pregnancies was reported in 2006 in the USA (26%),where such a policy had not been universally adopted. In the

M.A. Rustico (�)Obstetrics and Gynaecology Clinical Unit, Buzzi Children’s HospitalDepartment of Clinical Sciences, University of Milan, Milan, Italy

67G. Buonocore et al. (eds.), Neonatology. A Practical Approach to Neonatal Diseases.© Springer-Verlag Italia 2012

10Multiple Pregnancies

Maria Angela Rustico, Mariano Lanna and Enrico Ferrazzi

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USA the proportion of multiple births attributable to ovula-tion induction or ART is 33%. In triplets and higher-ordermultiple pregnancies this rate must be even higher.

10.3 Placentation

10.3.1 Chorionicity and Zygosity

Two thirds of spontaneous twin pregnancies are dyzygotic(DZ), resulting from the fertilization of two eggs by differentspermatozoa, and are therefore dichorionic (DC). The DCtwin placenta of DZ twins may be composed of separatedisks, or alternatively, the two placental portions may befused. Vascular communications are almost totally absent.The other third of spontaneous twin pregnancies are monozy-gotic (MZ), occurring when one single fertilized egg givesrise to two separate embryos. Of these MZ pregnancies, athird are DC. The other two thirds are monochorionic diamni-otic (MCDA), meaning that a single placenta serves both em-bryos, and that vascular communications connecting the

twins are always present. Between 2 and 5% of monochori-onic (MC) twins are monoamniotic (MCMA). When twin-ning occurs after approximately 12 days from conceptionSiamese twins are generated (Fig. 10.1).

Because of their placental angioarchitecture (Fig.�10.2),MC twins are more susceptible to additional complicationsthan DC twins. In fact, the presence of vascular anastomosis,which mediates unidirectional or bidirectional flow betweenthe two circulations, greatly influences intrauterine develop-ment and plays a crucial role in causing those complicationsspecific to MC twins, leading to a higher morbidity and mor-tality than in DC twins [4].

68 M.A. Rustico et al.

Fig. 10.1 Partition of placentas and chorion, amniotic sac and fetusesas a function from days of conception in monozygotic twinning

Fig. 10.2 Monochorionic placenta

Fig. 10.3 a Dichorionic twins (lambda sign): chorion and decidua be-tween the two sacs. b Monochorionic twins (T sign), only extraembry-onic coelom between the two amniotic membranes

a

b

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In multiple pregnancies, ultrasound is a very accurate tech-nique (100% sensitivity and 99% specificity) for determiningchorionicity (Fig. 10.3). In twin pregnancies, in the first orearly second trimester, ultrasound examination is mandatoryto determine chorionicity in order to assess the obstetric riskwhich is significantly different in DC and MC twins.

10.4 Fetal Complications of Twin Pregnancy

10.4.1 Miscarriage and Fetal Loss

10.4.1.1 Definitions

The World Health Organization in 2008 reported a consensuson definitions concerning miscarriage and fetal loss. Preclin-ical spontaneous miscarriage: a pregnancy diagnosed only bythe detection of HCG in serum or urine, which does not de-velop into a clinical pregnancy. Spontaneous abortion/mis-carriage: the spontaneous loss of a clinical pregnancy asdiagnosed by ultrasound that occurs before 20 completedweeks of gestational age (18 weeks post fertilization) or, ifgestational age is unknown, the loss of an embryo/fetus ofless than 400 grams. Vanishing sac(s) or embryo(s): sponta-neous disappearance of one or more gestational sacs or em-bryos in an ongoing pregnancy, documented by ultrasound.

10.4.1.2 Epidemiology

The “vanishing twin” phenomenon, which has been viewedas part of the general fetal wastage in human reproduction,suggests that while multiple conceptions are not rare events,multiple pregnancies are strongly selected against, especiallyduring the early stages of embryonic development. The inci-dence of miscarriage during the first trimester is estimated tobe between 10 and 20%. The true incidence of vanishingtwins is difficult to assess. Landy and Keith [5] reviewed themajority of pertinent studies, most of which described preg-nancies conceived as a result of ART. Using these data it wasestimated that ~30% of these twins will ultimately result insingletons and <10% will end in a complete abortion.

10.4.1.3 Etiology

It is thought that intrinsic abnormalities within the embryoare the major reasons for failed conceptions or early fetaldeath. The most significant intrinsic factor contributing toembryonic loss is aberrations in the first meiotic division re-sulting in non-dysjunction and aneuploidy. Trisomies 13, 15,16, 18 and 21 account for the most common autosomal tri-somies in spontaneous pregnancy losses. Some authors haveobserved an increased risk of fetal death, and in particular

spontaneous abortion with increasing maternal age, and thereis clear evidence from oocyte donation programmes that thisrisk is associated with the ageing of the oocytes [6].

10.4.1.4 Diagnosis

The diagnosis of miscarriage is made by ultrasound (US) ex-amination. A biochemical pregnancy is considered when im-plantation is revealed on day 16 by blood test, but there is anegative US scan result on day 23 [7].

10.4.2 Fetal Growth Restriction

10.4.2.1 Definition

Intrauterine growth restriction (IUGR) is a sonographic di-agnosis consisting of either an estimated fetal weight belowthe 5th percentile of the intrauterine growth chart for gesta-tional age, or declining abdominal fetal growth below the 5thpercentile, or declining more than 40 centiles from mid-preg-nancy to third trimester. Abnormal uterine Doppler velocime-try and/or an abnormal umbilical Doppler velocimetry areconsidered additional criteria of severity (Italian Society ofUltrasound in Obstetrics and Gynecology). In a twin preg-nancy, a growth discordance of more than 20% in estimatefetal weight is an index of selective growth restriction.

10.4.2.2 Epidemiology

Neonates from multiple gestations are over-represented amongpreterm and low birth weight infants. Multiple pregnanciesweigh less than their singleton counterparts. The prevalenceof small for gestational age newborns in multiple pregnancyis higher than expected in singletons. Although many variablesmay influence the reference standard, the prevalence of smallfor gestational fetuses varies between 12 and 47%.

10.4.2.3 Etiology

For most of a pregnancy, twins grow at the same rate as sin-gletons, regardless of chorionicity, up to at least 32 weeks’gestation. Thereafter, twins show a slower rate of growth [8].The decreased rate may be related to uteroplacental insuffi-ciency. It is thought that, at some point in the third trimester,the placenta can no longer maintain the nutrient requirementof both fetuses. In patients with triplets or high-order multi-ples, this process occurs earlier.

When growth restricted fetuses are diagnosed in a twinpregnancy, one should keep in mind the diverse etiologies ofIUGR (such as genetic/chromosomal problems, fetal anatom-ical anomalies, placental and cord abnormalities, maternal

10 Multiple Pregnancies 69

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complications) rather than assuming that the cause is utero-placental insufficiency, which is more frequent in twins thansingletons. Although IUGR can complicate a pregnancy withgrowth discordance, the latter does not necessarily imply theformer unless growth discordance is less than 20%. It is im-portant to note that IUGR can affect both twins, leading toboth twins being small but not discordant

10.4.2.4 Diagnosis

Knowledge of chorionicity assessed during the first trimesteror by gender discordance is paramount for managing patientswith growth abnormalities. Since fetal growth is a dynamicprocess, serial ultrasound is helpful in the assessment of fetalgrowth in patients with multiple fetuses. In utero growth dis-cordance is most often defined as the difference in sono-graphic estimated fetal weights expressed as a percentage ofthe larger twin’s estimated fetal weight. Growth discrepancymay be mild (<15%), moderate (15–30%), or severe (>30%).This wide range (from 15 to 30%) is the consequence of clin-ical neonatal examination. It might help to note that a studyby Naeye [9] in 1964 showed that the total number of organsand cells is not reduced until growth discrepancy is more than25%. However, in less severe cases, weight discrepancy isdetermined by a smaller volume of cell cytoplasm. A clinicaldiagnosis of growth discordance is better achieved by addinginformation about feto-placental conditions to biometricgrowth curves: for example, amniotic fluid index, Dopplerexamination of the umbilical artery and fetal vessels, com-puterized analysis of fetal heart rate, maternal complicationsthat frequently cause placental insufficiency such as gesta-tional hypertension and preeclampsia.

10.4.2.5 Consequences

IUGR has long been known to be associated with perinatalmorbidity and mortality. Neonatal morbidity such as meco-nium aspiration syndrome, hypoglycemia, polycythemia andpulmonary hemorrhage may affect up to 50% of IUGRneonates. The high prevalence of IUGR in twin pregnanciessuggests that such patients should be included in protocolsrelating to the management of high risk pregnancies.

10.5 Preterm Delivery

10.5.1 Definition

Preterm birth (PTB) is defined as a delivery at less than 37completed weeks’ gestation. This condition can be further di-vided into late preterm (33–37 weeks), moderate preterm(28–32 weeks), and severe preterm (20–27 weeks).

10.5.2 Epidemiology

There is a wide variation in preterm birth rates between coun-tries, mostly because of different iatrogenic practices. Inmany states of the European Union, about half the childrenborn following multiple births were preterm, accounting forbetween 18 and 25% of preterm birth in each country. Theproportion of births before 37 weeks in twins ranges from68.4% in Austria to 42.2% in the Republic of Ireland. Thisreflects different clinical protocols and the consideration oftwin pregnancies being at high risk and providing parentswith leave from work and other social maternal benefits.

10.5.3 Etiology

The etiology of preterm birth depends on multiple factors.The most investigated etiologies both in singletons and twinsare infection and maternal stress. Twin pregnancy with its im-pact on cervical integrity is per se a risk factor for ascendinginfections. Twin pregnancy is also a risk factor for psycho-logical and physical maternal stress. Other minor risk factorsfor preterm birth are: cervical incontinence, uterine malfor-mations, infertility, previous preterm birth or intrauterine fetaldeath, low social status, male fetal sex.

10.5.4 Diagnosis

High risk for PTB should induce clinicians to make a carefulassessment of risk factors and to use appropriate diagnostictests. Among these the evaluation of short cervical length bytransvaginal sonography seems to be the best predictor ofPTB. Infection and other possible direct causes of PTB shouldbe excluded. Fetal fibronectin in vaginal secretions may addto the usefulness of cervical length measurements. A cervicallength ≤25 mm at 18 weeks and ≤22 mm at 24 weeks seemsthe best predictors of preterm delivery.

10.5.5 Prevention

Cervical length measurement, the fibronectin test and the as-sessment of uterine contractions might diagnose impendingPTB, but should not be confused with the cause of PTB. Ef-forts should be made to exclude intrauterine infections andsubclinical chorioamnionitis. Blood and amniotic tests for in-fections and abnormalities of fetal heart rate should be takeinto account. Tocolysis with Atosiban and bed rest may delaydelivery by at least 48 hours, permitting the administration ofcorticosteroids to improve fetal lung maturity. In cases of se-vere infection, delivery may well be the best option combinedwith antibiotic therapy. Opinions about cervical cerclage vary.

70 M.A. Rustico et al.

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10.5.6 Fetal Complications

Prematurity is the main cause of low birth weight, perinatalmortality, and the most frequent determinant of neonatal andinfant mortality and morbidity. The following diseases are fre-quently associated with prematurity: transient tachypnea of thenewborn, respiratory distress syndrome, persistent pulmonaryhypertension, respiratory failure, temperature instability, jaun-dice, feeding difficulties, intraventricular hemorrhage, necro-tizing enterocolitis and brain damage.

10.6 Monochorionic-Related Complications

10.6.1 Twin-to-twin Transfusion Syndrome

Twin-to-twin transfusion syndrome (TTTS) is the best-knowncomplication of MC pregnancies, occurring in approximately10–15% of cases. Although hormonal and hemodynamicmechanisms may be involved, the current interpretation ofTTTS is that it is caused by an imbalance in the exchange ofblood between one twin (the donor), and the other (the recipi-ent) via placental anastomoses, due to a relative excess of uni-directional arterio-venous connections which is not com-pensated by reverse flow through other anastomoses. When asignificant imbalance in blood flow occurs, the donor twin be-comes hypovolemic and oliguric, develops severe oligohy-dramnios and Doppler signs of placental insufficiency. Therecipient twin shows hypervolemia, polyuria and polyhydram-nios, with cardiac overload, leading to hydrops in severe cases[10]. Without treatment, the prognosis is poor, with perinatalmortality up to 90%. In survivors, preterm birth due to poly-hydramnios is a major cause of mortality and morbidity. In thecase of intrauterine death of one twin, the surviving twin has asubstantial risk of neurologic morbidity due to hemorrhage intothe dead co-twin via placental anastomoses [11]. At 4 yearsfollow-up, the incidence of cerebral palsy and abnormal mentaldevelopment is 21% in surviving twins with TTTS [12].

The traditional neonatal criteria for diagnosing TTTS,based on an inter-twin hemoglobin difference (> 5 g/100 mL)and weight discordance (> 20%), do not apply in utero be-cause similar discrepancies in hemoglobin and birthweightare also found in DC and MC twins without TTTS [13].

The diagnosis of TTTS is only made by ultrasound. In atwin pregnancy with a single placental mass, twins of the samegender, and a thin membrane dividing the twins (Fig.�10.3),the crucial ultrasound sign for the diagnosis of TTTS is thecombined presence of polyuric polyhydramnios in one sac(deepest vertical pocket > 8 cm before 20 weeks’ gestation,>10 cm after 20 weeks’ gestation), and oligouric oligohydram-nios in the other (deepest vertical pocket <2 cm) [14].

A classification system is divided into five stages basedon ultrasound criteria. Stage I or II is when the donor bladder

is still either visible or empty, in association with the polyhy-dramnios-oligohydramnios sequence. Stage III is whenDoppler findings are abnormal for either twin. Stage IV andV is when there is congestive cardiac failure and hydrops inthe recipient or the death of one or both twins [15]. This clas-sification has created an impression of a disease with progres-sive deterioration and poorer outcome in the more advancedstages. However, clinical observations have demonstrated thatthe natural history of TTTS is variable and unpredictable. Forthis reason, this classification has recently been challengedbecause it fails to incorporate the cardiac function of the re-cipient twin, in whom there may be myocardial dysfunctioneven in Stage I and II in over 50% of cases, which representadvanced TTTS [16].

TTTS can manifest itself at any time during a pregnancy,but is more common in the second trimester. Considering thepoor survival rate, and the risk of neurological complicationsdue to antenatal or postnatal injury, treatment should undoubt-edly be offered. The Eurofetus randomized trial which com-pared laser coagulation of placental anastomoses with serialamnioreduction, demonstrated that laser coagulation is thebest first-line treatment for TTTS diagnosed before 26 weeksbecause it blocks the vascular connections which are assumedto be responsible for the syndrome [14].

10.7 Single Intrauterine Death

In MC twin pregnancies, the death of one twin, occurring inabout 4% of these pregnancies, presents the co-twin with anincreased risk of mortality and morbidity. The mechanism forthis adverse outcome is blood loss from the dying twin throughplacental vascular anastomoses. This leads to hypovolemia,which may cause the death of the co-twin from hypovolemicshock, or parenchymal damage due to hypoperfusion. Sequelaeinclude ischemic cerebral lesions, periventricular leukomala-cia, renal cortical necrosis, and small bowel atresia. A reviewof the literature of 119 MC twin pregnancies complicated bythe death of one of the fetuses showed 57% healthy survivors,19% perinatal deaths, and 24% survivors with severe sequelae[11]. The risk of an adverse outcome for the surviving co-twindepends on the gestation at the time of intrauterine death, andthe interval to delivery. In early pregnancy, the death of onetwin frequently causes the death of the other fetus, but severesequelae in the survivor are less common than at a more ad-vanced gestation. The same review showed that in healthy sur-vivors there was a longer interval to delivery (mean, 11.1weeks) when compared to pregnancies with perinatal deathsor neurologic sequelae (mean, 5.3 weeks). Immediate deliveryafter a single intrauterine death only adds the risks of prema-turity to the surviving twin. Indeed, damage may occur at themoment of death of the co-twin and therefore may not be pre-ventable. Intrauterine transfusion can be a therapeutic solutionbut, if the critical moment preceding fetal death is missed, there

10 Multiple Pregnancies 71

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is no treatment and conservative management is recommended[17]. Ultrasound of the fetal brain and magnetic resonance im-aging (MRI) 2–3 weeks after an intrauterine fetal death mayprovide useful information for predicting neurodevelopmentaloutcome in the surviving twin.

10.8 Twins Discordant for Fetal Anomalies

An excess of structural anomalies is observed in twins com-pared to singletons. While the frequency of malformations ina DZ pregnancy is similar to that for singletons (2–3%), it istwo or three times higher than in a MZ pregnancy [18]. Thereason for this is unknown, but might be considered to be partof teratogenic process during twinning.

MZ twins are considered identical, but recent observa-tions have reported that this is not the rule, and a number ofdiscordances have been observed for chromosomal anom-alies (such as trisomy 21 and Turner syndrome), single genedisorders, X-linked diseases (such as Fragile-X, Aicardi’ssyndrome) and structural defects. These structural defectsinclude malformations of the brain, abdominal wall anom-alies, and cardiac disorders. The prevalence of cardiac de-fects has been reported as 2.3% in twins without TTTS, and7% in those with TTTS, compared to 1% in the general pop-ulation [19].

Structural malformations which are not genetically deter-mined may of course affect only one of the two MZ twins. Ithas been estimated that both twins are affected in less than20% of cases, whilst in the majority of cases only one twin isinvolved.

In approximately 1–2% of twin pregnancies a seriousanomaly affects only one fetus and clinicians face thedilemma of choosing between expectant management or se-lective termination. The primary goal is to prevent the deathof the normal twin. In monochorionic twin pregnancies, se-lective termination needs to be performed by ensuring com-plete and permanent occlusion of umbilical cord of theabnormal twin, in order to avoid acute hemorrhage from theco-twin into the dying fetus, a process which may lead todeath or organ damage [20]. Bipolar cord occlusion under ul-trasound guidance is still considered the best method for se-lective feticide in these cases.

Based on a cohort of 84 (9.6%) discordant anomalies de-tected by ultrasound or invasive prenatal diagnosis in 870monochorionic twin pregnancies between 1999 and 2009,Table 10.1 shows the type of severe anomaly detected in onefetus that led to selective termination by bipolar cord coagu-lation in 51.2% of cases. During the same period, five twinpregnancies were complicated by concordant anomalies (tri-somy 21, Apert’s syndrome, cystic hygroma with hydrops,bilateral renal dysplasia) affecting both fetuses (0.6 %).

10.9 Twin Reversed Arterial Perfusion (TRAP)Syndrome

Twin reversed arterial perfusion (TRAP) sequence, alsoknown as acardiac twinning, is a rare complication of MCpregnancies which can lead to an unfavorable outcome for thenormal co-twin. The reported incidence is 1/35,000 deliveries,or 1% of MZ twins. In this condition there is a twin withoutany functional cardiac tissue and variable developmental dis-ruption (the acardiac twin). This acardiac twin is perfused bythe normal twin (the pump twin) by arterial blood flowing ina retrograde fashion through a single superficial artery-to-artery placental anastomosis. Poorly oxygenated blood by-passes the placenta, enters the acardiac twin’s circulation atlow pressure, and preferentially perfuses its lower part. Theblood flow returns to the pump twin via a single vein-to-veinconnection [4]. The acardiac twin acts as a parasite and space-occupying mass, being hemodynamically dependent on theother twin. Perinatal mortality rates reported for the pump twinrange from 35–55%.

The primary causes leading to poor perinatal outcome arepreterm delivery (because of the continuing growth of the ac-ardiac fetus) and congestive heart failure (because of the vol-ume of the acardiac twin’s mass needing to be perfused by thenormal heart). The deoxygenated blood circulating back to thepump may also cause chronic hypoxia, growth restriction, andhypoxic ischemic lesions.

In the case of rapid enlargement of the acardiac twin mass,or signs of cardiac overload in the pump twin, blockade of thevascular supply to the parasitic twin is recommended. Possibletreatments include intrafetal ablation procedures such as ra-diofrequency and interstitial laser. Although no single tech-nique has been conclusively shown to be the best, some formof antenatal treatment seems to be beneficial, because there isa reported overall pump twin survival rate of 76%.

In a series of 34 cases of TRAP sequence during the period1999–2009, 15 cases were managed expectantly. In six cases,intrauterine death of both twins occurred before 18 weeks,while one pregnancy was terminated because of an abnormalpump twin. In eight cases, both twins were delivered nearterm. Two babies (where the acardiac fetus was very large, upto 1.5 kg) had a poor neurological outcome and periventricularleukomalacia probably because of the pathophysiology of the

72 M.A. Rustico et al.

Table 10.1 Type of discordant anomalies detected in a series of 84monochorionic twins

Type of discordant anomaly N. (%)

Central nervous system 37 (44.0)Cardiovascular (without TTTS) 12 (14.3)Abdominal wall 8 (9.5)Urinary tract 8 (9.5)Skeleton 3 (3.6)Miscellaneous 10 (11.9)

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condition. Apart from complications related to the invasiveprocedures (4/19), and one case of unexplained intrauterinelate death of the pump twin, 14 of 19 cases (73.6%) who hadin utero treatment are alive and well and free of neurologicalcomplications at postnatal follow-up.

10.10 Monoamniotic Twinning

Monoamniotic (MA) twinning is rare, affecting 2% of allMZ pregnancies. MA twins share the placenta and the amni-otic sac, and are at higher risk of structural anomalies, unex-pected fetal death and perinatal death (ranging from 30 to70%), compared with MCDA twins. The excess of fetal losscan be explained by umbilical cord entanglement (Fig. 10.4),and a crucial cofactor may be an acute exsanguination acrosslarge placental anastomoses. In the largest study reported inthe literature (98 cases) there was a 17% perinatal mortalityrate, and fetal death after 32 weeks occurred in 4% of preg-nancies [21]. Thus the current perinatal mortality rate in MAtwins appears to be lower than previously reported, but it re-mains high and occurs throughout pregnancy. Based on theobservation that the risk of neonatal death associated withpreterm birth at 32 weeks is 1 in 100, the risk for MA twinsat this gestational age appears to be four times lower.

10.11 Laser Treatment In Twin-to-twinTransfusion Syndrome

Since the description of vascular anastomoses affecting allmonochorionic twin placentae, the development of TTTSsyndrome was explained by the hypothesis of unbalancedflow through arterio-venous anastomoses. Thus, the aim ofresearchers has been to treat TTTS by endoscopic laser co-agulation of chorionic vessels in order to interrupt unwantedvascular connections. In the first description, De Lia photo-coagulated all possible anastomotic vessels [22].

Due to a lack of anatomical markers for the identificationof communicating vessels, this technique has been difficultto reproduce, and other approaches have been proposed. Thenon-selective technique requires coagulation of all vesselscrossing the insertion of the inter-twin membrane. The se-lective technique interrupts only those vessels involved inblood exchange between twins, preserves normal cotyledonsand is considered an important development in the treatmentof TTTS [23].

The procedure is performed under local or regional ma-ternal anesthesia. A 3 mm cannula is introduced in the amni-otic sac of the recipient twin under ultrasound guidance usinga percutaneous approach. A 2 mm fiberscope is then passedthrough the cannula, so that the operator can explore the fetalsurface of the placenta to identify the vascular connections.

10 Multiple Pregnancies 73

Fig. 10.4 Monochorionic monoamniotic pregnancy: twins floating inthe same sac (a); entanglement of umbilical cords with colour Doppler(b); true knots between the two cords (c)

a

b

c

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After identifying the anastomosis between an artery and avein arising from the donor twin, coagulation is performedwith a 400 μm laser fibre.

Until recently, serial amnioreduction (AR) was the mostcommon treatment for TTTS. Amnioreduction works by re-ducing the risk of preterm delivery secondary to uterine dis-tension, and possibly also by reopening compensatoryplacental vascular anastomosis. For MC twin pregnanciescomplicated by TTTS before 28 weeks, the International Am-nioreduction Registry reported an overall survival rate at birthof 78%. In survivors, a central nervous system scan was ab-normal in 25% of cases at 1 month of life [24].

In 2004, endoscopic laser coagulation of chorionic vesselswas shown to result in a better neurological outcome than se-rial amniotic reduction. Periventricular leukomalacia (PVL)was 6% vs 14% (p = 0.002) [25]. This is why laser treatmentis considered the best first line option in severe TTTS before26 weeks’ gestation, with 6 months’ survival ranging from 50to 70%. Complications that lead to a repeated procedure (laseror amniotic reduction are reported in less than 5% of cases,and reflect the evidence that there are deeper anastomoses,which cannot be coagulated. Preterm premature rupture ofmembranes (pPROM) has a significant impact on pregnancy

when presenting before 24 weeks, since it may lead to mis-carriage (7–23% of treated pregnancies) [26].

Perinatal survival rates vary from 50% in the first reportedseries to 80% in the most recently reported series (Table 10.2).

Postnatal complications have been described both in ex-recipient and in ex-donor twin after laser therapy. The recip-ient twin, which is hypervolemic, may develop right hearthypertrophy with a tricuspid valve regurgitation leading tovalvular pulmonary stenosis. This cardiac abnormality maypersist after successful laser treatment because myocardialtissue may have been already damaged by persistent over-load. In selected cases, pulmonary stenosis may be so severethat balloon valvoplasty is required after birth. Similarly, se-vere hypovolemia may cause renal insufficiency. In this case,laser treatment can preserve kidney function in the survivingtwin by establishing a normal circulating volume.

For both twins, neonatal morbidity is mainly related toneurological outcome. Most cerebral lesions result from he-morrhagic or ischemic injury. These lesions, which affect10% of survivor twins after laser, are related to unbalancedblood flow and occur before laser treatment of TTTS [27].Cerebral palsy affects nearly 6% of twins after laser; the riskof neurodevelopment impairment increases significantly with

74 M.A. Rustico et al.

Table 10.2 Endoscopic non selective laser coagulation of placental vessels: pregnancy outcome

Authors N. cases GA (weeks) GA (weeks) Overall Live fetuses after procedure (%)procedure delivery survival rate (%) 2 1 ≥1 0

De Lia et al, 1995 [22] 26 20.8 – – 35 35 70 30(18–24)

De Lia et al, 1999 [28] 67 21 – 69 57 18 75 25(18–24)

Senat et al, 2004* [14] 72 20.6 33.3 57 36 40 76 24(15–26) (26–35)

Yamamoto et al, 2005 [29] 175 20 – 54 35 38 73 27(16–24)

Robyr et al, 2006** [30] 101 21 32.1 76 66 22 88 12

Quintero et al, 2000 [23] 71 20.8 32.7 61 39 43 83 17(16–25) (24–39)

Chang et al, 2006 [31] 428 20.1 32 80 66 29 95 5(16–26)

Hecher et al, 1999 [32] 73 20.7 33.7 61 42 37 79 21(17–25) (25–40)

Hecher et al, 2000 [33] 127 20.7 34 68 54 27 81 19(16–26) (23–40)

Huber et al, 2006 [34] 200 20.7 34.3 71 59 24 83 17(16–25) (23–40)

Becker et al, 2006 [35] 31 19.7 32.3 66 – – 81 19(16–26) (26–37)

Barrea et al, 2006 [36] 35 21 30 66 43 46 89 11

Buzzi Hospital 155 20.6 31.6 52 33 39 72 29(2004–2009) (16–27) (23–40)

GA gestational age.* Randomized multicenter study ** Multicenter study.

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prematurity. Neurological outcome worsens when laser treat-ment is performed at advanced gestational age and with aIII/IV Quintero stage of TTTS. The reason is that the fetalbrain may be more vulnerable to injury when the gestationalage at the time of the procedure is higher. Indeed, the rate ofneurological lesions in surviving twins after the intrauterinedeath (IUD) of one twin is considerably lower after laser ther-apy than after spontaneous IUD.

10.12 Cord Occlusion in Monochorionic Twins

Bidirectional flow through vascular anastomoses makesblood pressure in each twin dependent on both circulations:after the spontaneous IUD of one twin, acute hypotension inthe other twin causes death or neurological damage in 50%of cases [11]. In complicated MC pregnancies, the risk of IUDof one twin is so high that selective termination of pregnancy(TOP) can be the last opportunity to save at least one fetus.There is often severe intrauterine growth restriction (IUGR)of one twin with an abnormal umbilical cord Doppler signaland TTTS that persists after treatment (amniotic reduction orlaser), or there may be discordant abnormalities.

Intracardiac injection of chloride potassium cannot beused, as it would in dichorionic twin pregnancies because thetoxic drug could reach the other fetus through anastomosescausing an unwanted fetal death. The safest way to terminateone MC fetus is occlusion of the umbilical cord of the se-lected twin. This can be done by ligation or by bipolar forcepscoagulation, procedures that also prevent unwanted hypoten-sion and hemodynamic changes in the co-twin. Bipolar cord

coagulation appears to be a better option because of a higheroverall survival rate [37]. With a local anesthesia, a 3.3 mmcannula is introduced in the uterine cavity under ultrasoundguidance. Coagulation is obtained by a power of 50 W for30–40 sec with the aim to reduce blood flow in the placentaof the selected fetus.

In a cohort of 113 pregnancies that underwent umbilicalcord occlusion with bipolar coagulation, preterm delivery oc-curred in 33% of cases, with a procedure-to-delivery intervalwhich varied between 1 to 22 weeks (median 11 weeks)(Table 10.3).

As for any other invasive procedure, pPROM before 24weeks is the main complication (8%), and it is associated withabortion in 85% of cases if the procedure is performed before18 weeks. A recent review reported a prevalence of 4–7% ofsevere neurological lesions in surviving MC twins [38]. Thispercentage is lower than expected if compared with neuro-logical morbidity in surviving twins after the spontaneousIUD of the co-twin, which accounts for 22% of cases.

The main problems associated with any invasive intrauter-ine therapeutic procedures are abortion and prematurity fol-lowing pPROM. The possibility of sealing the membranedamage caused by trocars and needles has recently been in-vestigated by the introduction of an amniopatch made ofplatelets and cryoprecipitate. It seems that, if injected intothe amniotic cavity, an amniopatch is able to seal rupturedmembranes in 50–70% of spontaneous pPROM [39]. Thislevel of success is not reached in cases of iatrogenic ruptureof the membranes, where the origin of damage depends onmany confounding factors (i.e., indication for the procedure,experience of the operator, gestational age at the time of theprocedure).

10 Multiple Pregnancies 75

Table 10.3 Cord occlusion in complicated monochorionic twin pregnancies: pregnancy outcome *

Indication N. cases GA (wks) IUD TOP Ab pPROM PD GA (wks) PND Overallat procedure <24 wks <32 wks at delivery surv

median (range) n (%) n (%) n (%) n (%) n (%) median (range) n (%) n (%)

TTTS 45 22.3 (17.1–27) 5 (11) 1 (2) 4 (9) 4 (9) 13 (29) 33 (25–40) 5 (11) 30 (67)

sIUGR 30 21.6 (16–26.6) 2 (7) 0 0 2 (7) 9 (30) 33.5 (23.5–40) 2 (7) 26 (87)

Anomaly 38 22.1 (17–25) 5 (13) 0 3 (8) 3 (8) 8 (21) 37 (25–41) 4 (10) 26 (68)

Total 113 22.1 (16–27) 12 (11) 1 (1) 7 (6) 9 (8) 30 (26) 34 (23.5–41) 11 (10) 82 (73)

TTTS twin-to-twin transfusion syndrome, sIUGR selective intrauterine growth restriction of one twin, GA gestational age, IUD intrauterine death, TOPtermination of pregnancy, Ab abortion, PD premature delivery, pPROM premature rupture of membrane, PND perinatal death.* Fetal Medicine Unit, Buzzi Children’s Hospital, Milan (1999–2009). Unpublished data.

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