What Kind of Twins Are They

WHAT KIND OF TWINS ARE THEY?

35th Annual Perinatal Day Conference 3 November 2010

JULIAN E. DE LIA, MD, FACOG, FACS WFHC-ST. JOSEPH HOSPITAL MEDICAL COLLEGE OF WISCONSIN Milwaukee, Wisconsin

OBJECTIVES

1. To review factors responsible for higher morbidity and mortality rates in monochorionic (always MZ) twins compared to dichorionic twins. 2. To review the expanding paradigm of twin transfusion syndrome (to which significant maternal abnormalities must be added), and the need for a comprehensive management plan in multiple pregnancies of all types 3. Briefly review the status of fetoscopic placental laser surgery in severe previable twin transfusion of syndrome.

INTRODUCTION: In 2007, approximately 1 in 30 (3.4%) of the 4,316,233 U.S. births (145,388) were multiple [National Center for Health Statistics, National Vital Statistics Reports, vol. 87, no. 24, 2010]. Although the majority (66%) arise from separate embryos, 47,390 are single embryo (monozygous) multiples. Of the latter, the majority (66% or 31,280) share a single monochorionic (MC) placenta. There is no primary prevention for MZ twinning and its complications, some better known are conjoined twins and single amnion twins with umbilical cord entanglement. Assisted reproductive technologies are mainly responsible for the multiple pregnancy epidemic, and surprisingly have MZ twinning rates up to 20X that seen in spontaneous conception [Behr B, et al. J Assist Reprod Genet 2000;17:349]. Five percent of single embryo transfers result in a twin gestation. Some investigators maintain that monozygotic (MZ) twinning should be considered an anomaly in itself, as these twins demonstrate increased morbidity and mortality when compared to dizygous twins [Baldwin VJ. Pathology of Multiple Pregnancy. Springer-Verlag, New York 1994]. When the rates of prematurity, growth discordance, developmental anomalies and handicaps, and mortality in MZ twins are examined closely, the majority occurs in MZ twins with MC placentas [Machin GA. Am J Med Genet 1996;61:216]. Fortunately the majority of MC multiples (≈ 80%) have a normal antepartum course, with 15-20% experiencing pathology related to their chorion status. The significance of chorion type is not universally recognized in clinical obstetrical, pediatric and radiological practice despite decade old warnings, and even pleas to enroll all MC twins in clinical studies [Benirschke K. Obstet De Lia

Gynecol 1961;18:334; Ville Y. Ultrasound Obstet Gynecol 1997;10:82; Malone F. Am J Obstet Gynecol 2003;188:1308]. Typically, residents respond to the title question with fetal presentations, while many physicians/sonographers will be relieved to find a ‘membrane’ indicating diamnionic twins (v. monoamniotic) between the twins, and fail to characterize the placenta as either MC or dichorionic. Several factors underlie this state of affairs: 1) marginalization of clinical pathology in residencies; 2) death or retirement of the most notable placental pathologists of the last century; 3) the paucity of information on the monitoring and management of MC twins ACOG Practice Bulletin #56 (of October 2004) on Multiple Gestation; and 4) the ACOG Committee Opinion #125 on Placenta Pathology unchanged since 1993 [Curtin WM, et al. Obstet Gynecol 2007;109:39]. Until placental type is known in all cases, couples will continue to experience previable pregnancy loss without timely diagnosis and treatment, and physicians caught off guard with sudden catastrophic events in MC twins at term. Ultrasound can accurately identify the presence of multiple fetuses, chorion type, and pathophysiologic disorders in MC twins [Wittman BK, et al. Obstet Gynecol 1981;58:123]. Ultrasound monitoring of MC twins, therefore, should be started as early as possible and repeated at intervals dictated by the clinical situation [Gaziano E, et al. J Mat-Fetal Med 2000;9:89]. This lecture will stress the importance of early determination of chorionicity, and review the pathology associated with MC placentation, so that we and our patients may have opportunities for timely secondary and tertiary prevention and understanding of the associated fetal morbidity and mortality.

PLACENTAL FACTORS: The normal development of MZ twins and their placental type begins at fertilization, and is a function of time to the twinning process. Within the first three days, division leads to two complete, identical embryos that are nourished by separate (dichorionic) placentas. When a zygote takes from four to eight days to divide, the twins share a common placenta (monochorionic) and have two separate amniotic sacs (diamnionic). If the fertilized egg divides in eight to twelve days, the twins share a common placenta and one amniotic sac (monoamnionic). After twelve days (and the appearance of the primitive streak) the twins will be conjoined. Two primary placental factors form the anatomic basis for most clinical pathology seen in MC twins, some of which are unique to these twins such as twin-to-twin transfusion syndrome (TTTS) and acardius syndrome. These are: 1) the presence blood vessel anastomoses (chorioangiopagous vessels) connecting the MC twins’ circulations; and 2) the tendency for shared placenta to be partitioned unequally between the twins. Variations in anastomotic type (A-V, A- A, V-V), size and number, and placental asymmetry produce an intragestational spectrum of complications that may begin with the onset of feto-placental (chorio- allantoic) circulation at 35 days, and end at term in labor (FIGURE 1). The anastomoses most likely occur by chance, while the chorion asymmetry common in MC twins may be caused by the variations in the twin embryoblasts’ orientation to the endometrium at implantation [ibid. Gaziano E, et al.].

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MECHANISIMS OF MC TWIN DEMISE: Of greatest concern to clinicians and patients is the excess perinatal mortality and risk of neurodevelopmental deficits in MC twins [Lopriore E, et al. Am J Obstet Gynecol 2003;189:1314]. For instance, when TTTS presents in the mid-trimester, early reports indicated perinatal mortality rates of 80-100% with or without treatment [Cheshire NC, et al. Obstet Gynecol 1988;71:882]. The mortality in MC twins results from: extremes of asymmetric placental sharing (i.e., donor dies from profound placental insufficiency); co-twin death from sudden transfusion through placental anastomoses into a MC twin that died first; heart failure from circulatory overload in the TTTS recipient; immature/premature birth from the effects of rapid, massive TTTS-related hydramnios (contractions → cervical insufficiency → rupture of membranes) with neonatal death; lethal congenital anomalies associated with MC status; neonatal renal failure from chronic hypovolemia in TTTS donor, or from ischemic necrosis (organs other than the kidney may have lethal injuries as well) after the death of a co-twin; and sudden acute transfusions in labor at term.

MECHANISMS OF MC TWIN MORBIDITY: Cardiac, renal and neurological disorders are not uncommon in MC twins, and these are often discordant despite identical karyotypes. The pathophysiology of neurologic deficits in MC twins includes: hemodynamic instability or fluctuations in blood pressure or blood volume through direct (A-A, V-V) anastomoses [Grafe MR. Pediatr Pathol 1993;13:15]; nutritional insufficiency causing qualitative alterations in brain myelination [Ulfig N, et al. Pediatr Neurol 1998;19:287]; ischemic brain injury after death of a MC co-twin fetus [Glinianaia SV, et al. Arch Dis Child Fetal Neonatal Ed 2002;86:9]; the chronic anemia and hypotension in the donor, and polycythemia and hyperviscosity in the recipient characteristic of chronic TTTS; the effects of premature birth [Blickstein I. Dev Med Child Neurol 2002;44:352]; and developmental defects from insults during embryonic development (e.g., MC twins with or without TTTS present at mid-gestation, and one fetus already has hydrocephalus) [Skibsted L, et al. Ugeskr Laeger 1999;161:5687]. The placental paradigm for malformation or loss of preformed structures is not well recognized by many genetic counselors. Additionally, placental type is not monitored consistently in birth defect registries. Practically every anomaly ever described has been observed (typically discordant) in MC twins [Glinianaia SV, et al. Hum Reprod 2008;23:1306].

DIAGNOSIS OF TTTS: The diagnostic criteria for TTTS include evidence of MC placentation (single disc, thin inter-fetal membrane septum, like-sex twins), and the presence of polyhydramnios/oligohydramnios sequence (POS) with or without growth disparity and or signs of cardiac decompensation in the recipient fetus.

CLINICAL UNCERTAINTIES OF TTTS: There is little disagreement that something should be done to treat this menacing problem of contemporary obstetrics. However, one can be reluctant to make therapeutic recommendations

3 De Lia while TTTS is still characterized as poorly understood, enigmatic and subject to debate among clinicians regarding the underlying pathophysiology and diagnostic criteria. Although anastomotic vessels are consistently present in MC twin placentas, which allow for mixing of the fetuses’ blood, only a minority develop TTTS. Other concerns are raised in reports of: absent fetal hematocrit and weight differences classically described in TTTS [Carroll SG, et al. Ultrasound Obstet Gynecol 1997;9:398]; wide and unpredictable clinical fluctuations, with the disease as likely to improve as worsen [Luks FI, et al. Fetal Diag Ther 2004;19:301]; failure to demonstrate transfusion of blood or other substances between the twins in vivo [Bruner J, et al. Am J Obstet Gynecol 1993;169:925.]; and difficulty relating TTTS case outcome directly to placental findings [Bendon RW. Pediatr Pathol Lab Med 1995;15:363]. This latter study found placenta features to be complexly rather than directly related to clinical outcome, although an exception was twin chorion asymmetry where weight discordance was > 20% at ratios of 60:40 or greater. Bendon also reported TTTS-specific cardiomegaly in only 20% of autopsied recipients, and polyhydramnios not proportional to excess of transfused blood, both of which point to factors other than significant transfusion of blood in the fetal deaths.

MATERNAL FACTORS IN TTTS: We believe that many of the persistent uncertainties and concerns can be explained by incorporating two maternal factors to the current placental paradigm of TTTS: metabolic abnormalities and cervical insufficiency. The mother has been basically ignored in TTTS. Several recent monographs on TTTS therapy failed to mention any maternal issues or their management [Bebbington M. Semin Fetal Neonatal Med 2010;15:15; Chescheir NC. Obstet Gynecol 2009;113:717; Luks F, et al. J Pediatr Surg 2005;40:1063; Stamilio D, et al. Am J Obstet Gynecol 2010;203:3]. The recognition of a more complex TTTS pathophysiology should result in less maternal morbidity and improved fetal outcomes when using comprehensive treatment plans.

Maternal metabolic abnormalities - There is limited information on maternal metabolism in complicated multiple gestations. In one series of 100 patients undergoing laser surgery for TTTS in the midtrimester (mean 21.2 weeks), virtually all mothers were anemic (hematocrit mean 27.3%, range 21-34) and hypoproteinemic (albumin mean 2.6 g/dl, range 1.7-3.0) [De Lia JE, et al. Twin Research 2000;3:113]. These metabolic abnormalities have been consistently observed in an unpublished like number of TTTS patients subsequently managed at WFHC-St. Joseph. The degree of anemia and hypoproteinemia may not be evident in ambulatory patients, who have hemoconcentration from dehydration and effects low colloid osmotic pressure (COP) when studied. In addition, despite important target weight gain goals in multiple gestation [Luke B, et al. Am J Obstet Gynecol 1993;169:588], TTTS is a special circumstance where weight gain may be a poor indicator of true maternal nutritional status.

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Maternal protein-calorie malnutrition may provide insight into some of the enigmatic fetal manifestations of TTTS, as well as increased risks for maternal morbidity in multiple gestation when compared to singleton.

Fetal Effects - Recipient fetuses in TTTS have elevations in total protein and albumin [Weiner CP, et al. Fetal Diag Ther 1994;9:283]. If maternal protein levels are depressed from the effects of malnutrition, the absorption of water by the recipient through the placenta from the mother may be enhanced. The volume of amniotic fluid, and classification of TTTS as mild to severe (or even fatal from membrane rupture or labor in the face of massive polyhydramnios), may depend partly on maternal nutritional status. The importance of this relationship between the fetuses and mother in TTTS was stressed 40 years ago [Kloosterman, GJ. Ned T Verlosk 1963; 63:395], but few investigators have given it much attention. At any given fetal COP and hematocrit (which may not be the critical TTTS variant), the speed and volume of amniotic fluid produced by the recipient may be directly related to variations in low maternal COP. Hypoproteinemia will reduce maternal circulating blood volume, and with it the supply of nutrients to the fetus [Karsdorp V, et al. Eur J Obstet Gynecol Repro Biol 1994;57:117; Dandrea J, et al. Exp Physiol 2002;87:353]. If MC twins are > 20% discordant, the growth restricted twin has lower cord plasma essential and non-essential amino acids when compared to its co-twin or concordant twin controls [Bajoria R, et al. Am J Obstet Gynecol 2001;185:1239]. Reduction in uterine blood flow will likely compound the effects of placental insufficiency on growth in a MC twin with a small placenta share.

Maternal Effects - Maternal anemia and hypoproteinemia imply that normal increments in plasma and red cell volume are deficient in mid-gestation TTTS. With low COP, maternal weight gain occurs from the accumulation of extravascular water (compounding weight gain from polyhydramnios), giving a false clinical impression of nutritional competence, as indicated by ‘appropriate’ weight gain. Poor or slow weight gain before 24 weeks in twin gestation in general, is significantly associated with poor intrauterine growth and higher morbidity [ibid. Luke B, et al.]. Albumin is responsible for the majority of plasma COP, although hydrostatic pressure, capillary permeability and lymphatics determine whether fluid passes from the intravascular space to cause edema of pregnancy or of pathologic significance such as pulmonary edema. In one study of desaturation events in women receiving intravenous magnesium therapy for premature labor, multiple gestation was the only one of 14 independent variables associated with low maternal oxygen saturation [Thorp JA, et al. Obstet Gynecol 1997;89:963]. The mean COP for the group at 27.4 weeks (which must have consisted of both MC and dichorionic twins) was less than normal for gestational age. The excess maternal extravascular water amassed while ambulatory (which is virtually impossible to quantitate in individual cases), may be mobilized during hospital-imposed bed rest and contribute, along with the administration of intravenous fluids, to the risk of pulmonary edema.

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Attempts to treat dehydration in patients with abnormally low COP may be impossible and risky. Besides, a Cochrane Database Review failed to show any advantage to hydration over bed rest alone for pre-term labor [Stan C, et al. Cochrane Database Syst Rev 2002;2:CD003096]. Although uterine contractions have a complex and incompletely defined physiology, with dehydration possibly involved, we believe that uterine irritability may continue until circulating blood volume (and improved uterine blood flow) is restored by correcting nutritional deficiencies [Binienda Z, et al. Am J Obstet Gynecol 1989:160:746]. Uterine contraction frequency is significantly higher for twin gestations than singletons throughout the latter half of pregnancy, especially between 1600 and 0359 hours when intravascular blood volume may be most reduced in ambulatory patients [Newman RB, et al. Am J Obstet Gynecol 2006;195:1564]. Patients often report considerable thirst from dehydration in the face of excess body water; so oral intake should be monitored closely and even restricted. Patients (we believe this should be all mothers of multiples) should be weighed on hospital admission for any reason and daily thereafter to detect accelerating weight gain, factoring in any amniotic fluid removal or increases. With progressive weight gain, intravenous fluids may have to be limited further, while urinary output should not be used as a guide for fluid intake. If a surgical procedure or delivery follows, the anesthesiologists must be made aware of the probability of hemoconcentration, anemia and hypoproteinemia.

Maternal consequences of protein-calorie malnutrition and anemia

- Extravascular fluid accumulation (peripheral edema) confounding estimation of actual weight and gestational weight gain - Hemoconcentration confounding diagnosis of anemia and malnutrition in ambulatory patients - Decreased circulating blood volume - Decreased uterine blood flow - Greater risk of supine hypotension/tachycardia during anesthesia - Sensitivity to intravenous crystalloids and tocolytics - Greater risk of pulmonary edema - Ballantyne (mirror) syndrome - False impression of surgery-related hemorrhage requiring transfusion, exploratory surgery, or pregnancy termination - Chronic dehydration - Uterine irritability/preterm labor

Cervical insufficiency in TTTS: In untreated TTTS, pregnancy loss occurs most often from polyhydramnios-induced pre-term labor or premature rupture of the membranes. It is likely that cervical insufficiency (CI) is intermediary in this process. TTTS is one clinical setting at high risk for CI due to the burden of multiple fetuses, polyhydramnios and associated high intra-amniotic pressure [Meagher S, et al. Aust NZ J Obstet Gynaecol 1995;35:22], and uterine irritability

6 De Lia enhanced by chronic dehydration and malnutrition. Since the diagnosis of TTTS can be made either early in the pathophysiologic process (i.e., mild differences in amniotic fluid volumes), or late where the uterus is found massively enlarged, cervical ultrasound may help identify those patients destined to deliver while specific therapies are being directed to the twins or their placenta. For instance, the volume of amniotic fluid drained after completion of laser surgery has correlated directly to risk of miscarriage or extremely premature delivery within the first four postoperative weeks [Zikulnig L, et al. Ultrasound Obstet Gynecol 1999;14:380]. Although there are few specific reports on cervical assessment in TTTS, cervical length is the strongest predictor of risk for preterm twin delivery [Goldenberg RL, et al. Am J Obstet Gynecol 1996;175:1047], and also in TTTS treated by laser [Robyr R, et al. Ultrasound Obstet Gynecol 2005;25:37] particularly when length is less than 20 mm. The rate of spontaneous delivery prior to 33 weeks in 464 twin pairs seen for routine care in one center rose exponentially below 25 mm [Skentou C, et al. Ultrasound Obstet Gynecol 2001;17:7]. Coincidental cervical insufficiency can explain some pregnancy loss, especially those that occur early from ruptured membranes or preterm labor following invasive TTTS treatments, which may have been considered complications of specific therapies [Pistorius LR, et al. Fetal Diagn Ther 1999;14:337]. Additionally, by detecting and treating CI, outcome statistics reported in the past for all TTTS treatment methods may improve. The recent addition of cervical evaluation in our center has shown CI in as many as 25% of previable TTTS cases seen for laser surgery [De Lia JE, et al. Am J Obstet Gynecol 2002;187:517]. These patients had therapeutic or rescue cerclage placed either before transport (usually in conjunction with a large volume amnioreduction), in combination with placental laser surgery while at our center, or in the weeks immediately after returning to their referring physicians.

TREATMENT METHODS FOR TTTS

NUTRITIONAL SUPPLEMENTATION AND HORIZONTAL REST: Nutritional supplementation and horizontal rest are discussed together as both may be necessary to ameliorate the effects of maternal metabolic abnormalities in midgestation TTTS. Previable TTTS fetuses are in the midst of a critical period of nutrition, but have mothers depleted of nutritional reserves from both increased demands and past digestive disorders (nausea, vomiting, etc.) [Luke B. Clin Obstet Gynecol 2004;47:146]. Our recommendations for nutritional supplementation and bed rest are currently empirical pending further studies. Patients are counseled on the use of commercially available canned liquid products (e.g., Ensure High Protein, Boost High Protein, etc.) to supplement regular meals. Dietary interventions in first trimester MC gestation was associated with lower TTTS stages, fewer invasive treatments, and lower twin birth weight discordance when compared to a non-supplemented group [Chiossi G, et al. Am J Perinatol 2008;25:667]. Although there is no evidence, either

7 De Lia supporting or refuting the use of bed rest at home or in hospital, to prevent preterm birth [Crowther CA. Cochrane Database Syst Rev 2001;2:CD000110], the levels of maternal hypoproteinemia in TTTS suggests that any potential adverse effects horizontal rest could have on women and their families, are outweighed by the benefits of improved circulating blood volume and uterine blood flow. Reappearance of umbilical artery end-diastolic velocity has been observed in some cases after maternal volume expansion [ Karsdorp V, et al. Obstet Gynecol 1992;80:679].

THERAPEUTIC CERVICAL CERCLAGE: With coincidental CI in TTTS, a decision must be made whether to discontinue tocolysis and induce of labor, or perform rescue cerclage. The cerclage operation becomes progressively more difficult technically with worsening degrees of CI, especially if chorioamnion is visualized within a dilated canal. Membranes may be at or through the external Os. It may be necessary to pass a Foley catheter with a 30 cc balloon through the cervix to displace the membranes, so that a high adequate purchase of tissue can be made with the McDonald suture. When membranes were at or beyond a dilated external os in singleton gestation, subjects randomized to bed rest alone were more likely to deliver before 34 weeks (7 of 16 v. none) and experience more neonatal NICU admission or death (8/16 v. 1/19), when compared to therapeutic cerclage [Althuisius SM, et al. Am J Obstet Gynecol 2003;189:907]. Emergency cerclage for a short cervix at the time of laser surgery can significantly improve pregnancy duration and perinatal survival [Salomon LJ, et al. Prenat Diagn 2008;28:1256].

REDUCTION AMNIOCENTESIS: Therapeutic reduction amniocentesis has been the most widely available and practiced therapy for TTTS. It relieves maternal discomfort and respiratory difficulties, and prolongs TTTS pregnancies by reducing the risk of spontaneous rupture of the membranes [Urig MA, et al. Am J Obstet Gynecol 1990;163:1522]. By reducing intrauterine pressure, which may be as high as 39 mmHg (normal upper limit ~10), it can restore placental thickness and positively affect utero-placental perfusion and flow through vascular anastomoses [Bower SJ, et al. Am J Obstet Gynecol 1995;173:502]. The procedure does not correct the vascular basis of TTTS, so rates of fetal distress remain high regardless of amniotic fluid volume [Pinette MG, et al. Obstet Gynecol 1993;82:841], as does risk of ischemic somatic injury after single intrauterine demise. Recent comparisons to laser surgery, which can destroy the vascular anastomoses, indicate a somewhat higher incidence of neurologic morbidity in TTTS survivors after amnioreduction treatment [Fox C, et al. Obstet Gynecol 2005;105:1469; Lenclen R, et al. Am J Obstet Gynecol 2009;201:291.Epub]. Regardless of the widespread call for comparison to other treatment methods, amnioreduction plays a vital role in comprehensive TTTS management. Amnioreduction is used as an adjunct to fetoscopic surgeries (polyhydramnios is one component of the indications, required to safely insert the trocar into the recipient’s sac, and to effectively identify and ablate anastomoses). In the face of

8 De Lia significant polyhydramnios and lower stage TTTS, amnioreduction can provide time necessary to evaluate effects of nutritional therapy, rest and other treatment methods. The procedural risks (infection, rupture of membranes, placental abruption) are low, and like all TTTS treatments, the previously reported adverse events, theoretical rates of complications, and outcome variables must now be rethought in light of possible concurrent CI at amnioreduction [ibid De Lia JE, et al. 2002].

FETOSCOPIC LASER OCCLUSION OF THE CHORIOANGIO- PAGOUS VESSELS: Fetoscopic laser occlusion of the chorioangiopagous vessels (FLOC) has been available since 1988 [De Lia JE, et al. Obstet Gynecol 1990;75:1046]. It was pursued in previable TTTS because of the poor results initially observed with alternative treatments [ibid. Cheshire NC, et al. 1988], the move toward donor feticide despite the potential risks to the recipient with intracardiac injections [Baldwin VJ, et al. Pediatr Pathol.1990;10:79], and the belief that early onset TTTS (< 21 weeks) was more difficult to manage. The operation used existing endoscopic, video and laser technology with minor modifications, to identify and ablate all anastomotic vessels within the vascular equator [De Lia JE, et al. Placenta 1993;14:477]. The goal was to create a ‘functionally dichorionic placenta’ to halt both chronic transfusion between the twins, and sudden transfusion of blood should one fetus die. The procedure consists of inserting a small trocar and sleeve (< 3.5 mm) through the uterine wall opposite the center of the fetuses’ placental surface [De Lia JE. Clin Obstet Gynecol 1996;39:607]. The laser light (neodymium:YAG set at 60 Watts) is delivered via a 400u fiber placed in the side channel of the fetoscope. Since uterine puncture site bleeding is the Achilles Heel of the procedure, efforts are made to complete the separation as quickly as possible ≈ 15 minutes. Longer operative times are needed for higher numbers of vessels, or when the amniotic fluid is stained. Excess amniotic fluid is removed at the end of the procedure. The perinatal outcome for FLOC in severe previable TTTS (mean 20.8 weeks) has been reported from some experienced centers as 68% overall survival, 81% at-least-one survivor, 42-57% where both twins survived, 9.9-13 weeks post-treatment pregnancy duration, in a combined population of 296 patients [Hecher K, et al. Eur J Obstet Gynecol Repro Biol 2000;92:135; De Lia JE, et al. J Perinat Med 1999;27:61]. One of the centers reported 4.3% (4/93) handicap rate in survivors at 14.3 months mean age. Since its introduction, however, several modifications in technique have materially affected survival rates and neuroprotective benefits of FLOC. In a recent meta-analysis of published mortality and morbidity rates in MC twins after FLOC, Rossi and D’addario were troubled by the 40% of donors and 30% of recipients who died, as well as the 9% (range 5-23%) and 10% (0.8-21%) cerebral injury rate in donors and recipients respectively [Am J Perinatol 2009;26:27]. They propose that a first trimester lethal or cerebral injury may occur before the FLOC (usually performed in the second trimester), and that efforts should be made toward first trimester diagnosis and perhaps earlier

9 De Lia intervention. However, we believe the mortality and cerebral injury following FLOC is less enigmatic and explained by factors not apparent in meta-analysis. Since the new reality for the twins begins only if ALL the anastomoses within the vascular equator are ablated, there are indications in the articles included in the meta-analysis that this is not always the case. Several series of postpartum placental examination following FLOC in experienced centers have reported residual anastomoses in 33% to 70% of cases [De Paepe ME, et al. Pediatr Dev Pathol 2004;7:159; Lopriore E, et al. Placenta 2007;28:204; Stirnemann JJ, et al. Am J Obstet Gynecol 2008;198:62]. The second variable not apparent in the meta-analysis is the presence of CI at the time of FLOC, which has been shown to be a significant risk factor for premature delivery (vide supra).

TTTS IN TRIPLET GESTATION: Information on TTTS in higher order mutifetal gestation is limited. TTTS or spontaneous loss before viability complicates up to 30% of dichorionic triplet pregnancies [Chasen ST, et al. Am J Obstet Gynecol 2002;186:765]. The presence of a MC placenta in any multifetal pregnancy, i.e., twins, triplets, or quadruplets, increases the rate of low birth weight, delivery at < 30 weeks, and perinatal mortality 5-8 times [Adegbite AL, et al. J Perinatol 2007;27:15]. In 16 reported triplet TTTS cases we found before our first FLOC triplet case, some of whom had amnioreduction, only 11 of 48 (23%) fetuses survived, two (18%) with major deficits [Leung WC, et al. Obstet Gynecol 2003;101:1107]. Ten cases treated with FLOC have been reported recently at a mean gestational age of 21 weeks [De Lia JE, et al. Am J Perintalol 2009;26:559]. Five were IVF conceptions. All mothers had anemia and hypoproteinemia, and 5 had CI (3 cerclage, 1 long term indomethacin, 1 bed rest only). Twenty-three (77%) of the triplets survived (5 fetal and 2 neonatal deaths) with a mean birth weight of 1,568 g. All 23 survivors are healthy at mean age 68 months (range 6-194). Diemert A, et al. recently reported somewhat similar outcomes in 18 laser cases [Ultrasound Obstet Gynecol 2010;35:71]

INTRAPARTUM-POSTPARTUM MC TWIN ISSUES Delivery and neonatal concerns of MC twins -- Monochorionic twins, whether affected by TTTS or not, must be considered at-risk for sudden transfusion throughout labor and delivery, which may be spontaneous, elective or under emergency circumstances. Twins with uncertain placentation at presentation should be considered MC in the puerperium. Nursery personnel on call for the delivery must be informed of the twins’ chorion status and possibility of chronic or acute transfusion. One or both twins may need volume resuscitation, inotropic support or exchange transfusions. Acute transfusions may reverse the volume status of the presumed donor and recipient, so newborn TTTS twins may have birth weights and color that may be misleading or seem paradoxical. Finally, certain anomalies, especially congenital heart defects (present in up to 12% of recipients) possibly undetected prior to delivery, may complicate resuscitative efforts [Karatza AA, et al. Heart 2002;88:271].

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Placental examination at delivery -- Postpartum placenta examination should document ultrasound impressions of monochrionicity (and therefore monozygosity), the presence of chorioangiopagous vessels, and the degree of placental asymmetry [ibid. Baldwin VJ; ibid. Benirschke K; ibid Bendon RW]. The examination is facilitated by removing the amnions from the chorion surface (this should be noted on the form accompanying the specimen sent to pathology). The respective chorion districts and asymmetry can be approximated by observing the course of each twin’s surface vasculature from their individual umbilical cords to the vascular equator. Qualitative injection studies of the anastomoses require some degree of experience. However, merely sending the specimen to the pathology department may or may not prove informative [Travers H, et al. Arch Pathol Lab Med 1991;115:660]. If any uncertainty persists regarding the pathologist’s examination, a photograph or two of the entire placenta, with the amnion removed from the chorion surface, should be taken at delivery and placed in the records. Recall that ‘twin A’ on ultrasound may not be first born at delivery, who is typically called ‘baby A’ by delivery room and nursery personnel. Finally, at the birth of an anomalous singleton, careful placental examination may reveal evidence of the early demise of a MC co-twin [Pharoah PO, et al. Hum Reprod 2009;24:726].

IMPORTANT POINTS  Twins sharing a single placenta (monochorionic) have more morbidity and mortality than fraternal twins and identicals with separate placentas.  Assisted reproductive technologies (ovulation induction, IVF, etc.) have high rates of both dizygous and monozygous twinning.  Our TTTS paradigm, which starts with the abnormal placental blood vessels, also includes: twins’ proportions or sharing of the single placenta, and both maternal metabolic abnormalities and uterine cervical insufficiency.  Maternal factors have been ignored in fetal therapy, but they explain some of the enigmatic aspects of TTTS pathophysiology and have significant impact on the fetuses and mother.  Maternal protein-calorie malnutrition and anemia my complicate in ALL multiple pregnancies, and must be treated. Early stage TTTS signs may resolve with horizontal rest and nutritional therapy alone.  Complication and failure rates for TTTS treatment methods need to be reassessed in light of coincidental maternal cervical insufficiency.

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 There are differences in the techniques used at various centers for available treatment methods (e.g., laser), which are material and affect outcomes.  Comprehensive treatment plans are necessary rather than single therapy to maximize fetal outcomes in TTTS.  FLOC (laser) should be first line therapy when signs of significant transfusion are present (e.g, recipient has heart thickening or enlargement), or if extreme degrees of discordancy (> 40%) are present with abnormal UA Doppler.  Placental insufficiency, lethal congenital anomalies and acute transfusions in MC twins make 100% fetal survival in any cohort impossible.  Even with close monitoring, placental factors may still cause the sudden death of one or both MC twins within days following reassuring tests.

Figure 1

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