1. Multiple Gestation: Complicated Twin, Triplet, and High-Order Multifetal Pregnancy Clinical Management Guidelines for Obstetrician-Gynecologists Number 56, October 2004 R1 변정미

2. Purpose of this document Since 1980 65% increase in frequency of twins 500% increase in triplet and high-order births ← increased use of ovulation induction agents and assisted reproductive technology(ART) In 2002, multifetal gestations ≥ 130,000 infants in the US Although multifetal births account for only 3% of all live births, they responsible of a disproportionate share of perinatal morbidity and mortality all survivors of preterm multifetal birhts have an increased risk of mental and physical handcap.

3. Purpose of this document To address the risks associated with these pregnancies Present on evidence-based approach to management when possible

4. Background Infant and Maternal Morbidity Infant 1/5 of Triple pregnancy & ½ of quadruplet pregnencies ≥1 child with a major long-term handicap (eg. Cerebral palsy) Triple pregnancies : cerebral palsy ≥ 17 times of singleton pregnancies Twin pregnancies : ≥ 4times of singleton pregnancies Growth –restricted preterm infants NICU admission ¼ of twin(18days), ¾ of triples(30days), all quadruplets (58days)

5. Background Infant and Maternal Morbidity Maternal maternal morbidity and associated health care costs ↑ period of hospitalization ≥ 6 times Complication : preeclampsia, preterm labor, preterm premature rupture of membranes, placental abruption, pyelonephritis and postpartum hemorrhage Hospital costs ≥ 40%

6. Background Table 1. Morbidity and Mortality in Multiple Gestation CharecteristicTwinsTripletsQuadruplets Average birth weight2,347g1,687g1,309g Average gestational age at delivery35.3wk32.2wk29.9wk Percentage with growth restriction14-2550-60 Percentage requiring admission to neonatal intensive care unit 2575100 Average length of stay in neonatal intensive care unit 18days30days58days Percentage with major handicap-2050 Risk of cerebral palsy4times more than singletons17times more than singletons- Risk of death by age 1year7 times higher than singletons20 timesgigher than singletons-

7. Background Role of Assisted Reproductive Technology In 1980, 37/100,000 triple or more By 2002, 184/100,000 : result of the increased use of ART and ovulation-induction agents during this period one unexpected complication of ART : high incidence of monochorionic twins - one group evaluated 218 ART pregnancies and found the incidence of monochorionicity : 3.2% - other studies : reported an incidence of monochorionicity ranging 1%~5% in association with both ART and ovulation induction

8. Background Role of Assisted Reproductive Technology Monozygotic twinning increase the incidence of high order multiple gestation complicates fetal growth and development and can lead to rare complications(twin-twin transfusion syndrome or acardiac twinning) increases the morbidity of a pregnancy reduction procedure.

9. Background Maternal Age The a prior risk of a poor perinatal outcome in a high-order multiple gestation : increased by the woman’s age Growing proportion of older women successfully undergoing fertility treatment → increase in pregnancies complicated adult-onset disease (HTN, DM, labor abnormalities, cesarean delivery) Increased maternal age →increases the risk of fetal trisomies (eg. Down syndrome)

10. Background Prenatal Diagnosis Amniocentesis Chorionic villous sampling : technically difficult to accomplish in patients with multiple gestation

11. Complications of Pregnancy Gestational Diabetes Hypertension and Preeclampsia Other pregnancy Complication

12. Complications of Pregnancy Gestational Diabetes Incidence twin pregnancies : higher than in singleton pregnancies (3~6%) triplet pregncncies : higher than in twin pregnancies (22~39%) Diagnosis & management of gestational diabetes in multiple gestation remain unexamined - The best time of testing, the ideal number of daily calories, the optimal weight gain, whether women treated with oral hypoglycemic agents for polycystic ovary syndrome should continue taking them. The best form of insulin to use the best method of fetal surveillance and the ideal time for delivery are all currently unknown -

13. Complications of Pregnancy Hypertension and Preeclampsia Preeclampsia twin gestations ≥ X 2.6 times of singleton gestations triplet gestations ≥ twin gestations Significantly more likely to occur earlier and to be severe <35wks : gestational hypertension (12.4times in twin) preeclampsia (6.7times in twin) hypertension with diastolic BP >110 (2.2 times in twin) Multiple gestations by ART : greater risk of develop in hypertensive complications than spontaneous multiple gestations (unknown)

14. Complications of Pregnancy Hypertension and Preeclampsia High-order multiple gestations : more likely to develop atypical preeclampsia - hypertension (50%) edema (38%) proteinuria (19%) epigastric pain (60%) HELLP : hemolysis, elevated liver enzymes, low PLT (56%) Multifetal reduction : may decrease the risk of preeclampsia Management of hypertension complications in high-order multiple gestations has not been studied prospectively Placental abruption : 8.2 times

15. Complications of Pregnancy Other pregnancy Complication acute fatty liver : severe coagulopathy, hypoglycemia, hyperammonemia → can lead to fetal or maternal death → halt the disease process by delivery but postpartum period : complicated by pancreatitis or diabetes insipidus or both Sx : anorexia, nausea, vomiting, malaise → beginning late in pregnancy and developing over several days of weeks → vague and nonspecific → concurrent evidence of preeclampsia (1/3 of affected women) → delayed Dx.

16. Complications of Pregnancy Other pregnancy Complication Pulmonary embolism Factors multiple pregnancy (m/c) cesarean delivery delivery < 36wks BMI (body mass index) ≥25 maternal age ≥35 Treatment Prompt and sustained anticoagulation ( confirmed thrombosis or thromboembolism) - Because the volume of distribution is increased to a much greater degree in multiple gestations than in singleton gestations, it may be difficult to achieve a therapeutic level of anticoagulation –form of anticoagulation chosen should be readily reversible - Because high - order multiple gestations are at significantly increased risk of preterm labor, c/sec and bleeding complications (eg. Abruption)

17. Complications of Pregnancy Other pregnancy Complication others Pruritic urticarial papules and pustules - dermatosis that most commonly affects primigravid women in the 3 rd trimester - starts in abdominal striae * striae : in multiple gestations (m/c) d/t wt. gain, abdominal distension

18. Complications of Pregnancy Multifetal Reduction and Selective Fetal Termination High-order multiple gestation creates a medical and ethical dilemma The risks associated with a quadruplet or higher pregnancy clearly outweigh the risks associated with fetal reduction Perinatal outcome after fetal reduction Noted an overall postprocedure pregnancy loss rate: 11.7% Very early preterm (ig. 25~28wks) delivery rate : 4.5% ┌ Chance of losing either an additional fetus or the whole pregnancy └ Chance of early preterm delivery Increased according to the starting number of fetuses Fetuses ≥6 : lost before 24wks of gestation – 23% delivered at ≥37wks – 20%

19. Complications of Pregnancy Multifetal Reduction and Selective Fetal Termination Fetal reduction of a high-order multiple pregnancy has been associated with an increased risk of intrauterine fetal growth restriction (IUGR) Monochorionicity : complicate the reduction procedure one fetus of a monochorionic twin pair is inadvertently reduced → sudden hypotension and thrombotic phenomena → death of damage of the remaining twin fetus Selective fetal termination is the application of the fetal reduction technique to the selective termination of an anomalous of aneuploid fetus that is part of a multiple gestation The risks of this procedure are higher than those associated with multifetal reduction

20. Clinical Considerations and Recommendations Can preterm labor be predicted in multiple gestation? Are there interventions that can prolong pregnancy in multiple gestation ? How is preterm labor managed in multiple gestation? How should restriction of discordant growth be diagnosed and managed in multiple gestation? How is the death of one fetus managed? Is there a role for routine antepartum fetal surveillance? How is delayed delivery of the second twin managed? How are problems caused by monochorionic placentation managed? Are there special considerations for timing of delivery in multiple gestations? Are there special considerations for route of delivery of multiple gestation

21. Can preterm labor be predicted in multiple gestation? Cervical length Measurement by ultrasonography - Shortened cervix : predictive of preterm delivery in twin pregnancies - Cx length < 25mm (at GA 24wks) : best predictor of delivery before GA 32, 35 and 37wks. twin gestations (m/c) Cervical Length Measurement by Digital Examination - by experienced examiner - Less objective than USG, not allow assessment of the internal os Clinical Considerations and Recommendations

22. Can preterm labor be predicted in multiple gestation? Fetal Fibronectin - high-molecular-weight extracellular matrx glycoprotein - normally found in fetal membranes, placental tissues and amniotic fluid. - in cervical-vaginal fluids>50ng/ml : abnormal → predict preterm delivery in singleton gestations Home Uterine Activity Monitoring Clinical Considerations and Recommendations

23. Are there interventions that can prolong pregnancy in multiple gestation? U.S. 55-57% of all multiple gestations : delivered preterm - 49%-63% of these infants <2,500g 12% of twin pregnancies 36% of triplet pregnancies 60% of quadruplet pregnancies Are bore before GA 32wks Factors of preterm birth - lower and upper genital tract infection - Uterine overdistension - Cervical incompetence - Maternal medical complications, maternal stress - Fetal, placental or uterine abnormalities Clinical Considerations and Recommendations

24. Are there interventions that can prolong pregnancy in multiple gestation? Management Prophylactic cerclage : not prolong gestation or improve perinatal outcome in either study Routine Hospitalization : Bed rest in the hospital does not prolong twin gestation Restriction of Activities and Rest at Home Clinical Considerations and Recommendations

25. How is preterm labor managed in multiple gestation? Tocolytics - β-mimetic therapy : maternal and fetal cardiac stress and gestational diabetes - occur more frequently in multiple gestation even without β- mimectic therapy - Increased risk of developing pulmonary edema- resulting in severe respiratory distress when tocolytic agents, steroids and intravenous fluid are administered together - should be used judiciously Cortiosteroids Not been examined Clinical Considerations and Recommendations

26. How should growth restriction or discordant growth be diagnosed and managed in multiple gestation? Discordant fetal growth (common in multiple gestation ) Definition : a 15~25% reduction in the estimated fetal weight of the smaller fetus when compared with the largest Causes structural or genetic fetal anomalies, discordant infection, an unfavorable placental implantation, umbilical cord insertion site, placental damage (ie. Partial abruption ) complication related to monochorionic placentation site ( ie. Twin-twin transfusion syndrome ) - occur more frequently in high-order multiple gestations Expected in multiple gestations especially those resulting from ovulation induction or the implantation of ≥3 embryos when the fetuses are not genetically identical and may be of different sexes. Clinical Considerations and Recommendations

27. How should growth restriction or discordant growth be diagnosed and managed in multiple gestation? Associated with - structural malformations - stillbirh - IUGR, preterm delivery, cesarean delivery of nonreassuring fetal heart tracing - Umbilical arterial pH <7.1 - admission to the NICU, respiratory distress syndrome, neonatal death<7days of delivery If 2 fetuses are discordant but both have normal estimated weights and grow appropriately of their own growth curves → not indicate a pathologic process Clinical Considerations and Recommendations

28. How is the death of one fetus managed? Fetal loss cause - 1st-trimester losses : not determined - the later losses : twin-twin transfusion syndrome, severe IUGR, placental insufficiency, placental abruption Fetal monitoring protocol: not predict most of these losses Authorities disagree about the preferred antepartum surveillance method and management once a demise has occurred. Some investigators: advocated immediate delivery of the remaining fetuses If the death is the result of an abnormality of the fetus itself rather than maternal or uteroplacental pathology and the pregnancy is remote from term – expectant management Clinical Considerations and Recommendations

29. The most difficult cases : those in which the fetal demise occurs in 1 fetus of a monochorionic twin pair ← 100% of monochorionic placentas contain vascular anastomoses that link the circulations of the 2fetuses the surviving fetus is at significant risk of sustaining damage caused by the sudden, severe and prolonged hypotension that occurs at the time of the demise or by embolic phenomena that occurs later. How is the death of one fetus managed?

30. There may not be any benefit in immediate delivery (esp. if the surviving fetuses are very preterm and other wise healthy) → pregnancy to continue may provide the most benefit. DIC (disseminated intravascular coagulopathy) remains a theoretical risk, rarely occurs → Fibrinogen and fibrin degradation product levels can be monitored serially until delivery and delivery can be expedited if DIC develops Clinical Considerations and Recommendations

31. Is there a role for routine antepartum fetal surveillance The most effective fetal surveillance system : Not known Nonstress test(NST), fetal Biophysical profile(BPP) At present, antepartum fetal surveillance in multiple gestation is recommended in all situations in which surveillance would ordinarily be performed in a singleton pregnancy (eg. IUGR, maternal disease, decreased fetal movement) Clinical Considerations and Recommendations

32. How are problems caused by monochorionic placentation managed? Twin-Twin Transfusion Syndrome In the 2 nd trimester (m/c) Etiology : the result of uncompensated arteriovenous anastomoses in a monochorionic placenta, which lead to greater net blood flow going to one twin at the expense of the other Effect - Donor twin : anemic & growth restricted - appears “stuck” to one spot in the uterus because the lack of anmiotic fluid in its sac precludes movement - Recipient twin : plethoric and much larger, hydramnios - rapidly lead to premature rupture of membranes, preterm labor or early mortality (d/t heart failure in either of the fetuses) Clinical Considerations and Recommendations

33. How are problems caused by monochorionic placentation managed? Therapy - therapeutic amniocenteses of the recipient twin’s amniotic sac is most frequently used →favorably changing intraamniotic pressure and, thus, placental intravascular pressure, allowing redistribution of placental blood flow and normalization of amniotic fluid volume in each sac. - abolishing the placental anastomoses by endoscopic laser coagulation or selective feticide by umbilical cord occlusion ( only for very early, severe cases) - immediate delivery : gestational age is such that survival is Clinical Considerations and Recommendations

34. How are problems caused by monochorionic placentation managed? Rare Complications Acardiac or acephalus twin - heart failure (d/t abnormal division of the zygote at the time of twinning) : Pump twin is supplying blood flow to both its own body and that of its abnormal twin, death from heart failure is a common complication - Tx : Close monitoring with consideration of early delivery or selective feticide of the abnormal co-twin by umbilical cod occlusion if heart failure develops conjoined twin (at the head, thorax, abdomen, or spine and often share organs ) - Tx : directed by their chance of long-term survival - close monitoring, c/sec delivery Clinical Considerations and Recommendations

35. Are there special considerations for timing of delivery in multiple gestations ? The nadir of perinatal mortality for twin pregnancies occurs at approximately 38 completed weeks of gestation and 35 complete weeks of gestation for triplets Quadruplet and other high-order multiple gestation is not known Fetal and neonatal morbidity and mortality ↑ : Twin >GA37wks, triple>GA35wks If the fetuses are appropriate in size for gestational age with evidence of sustained growth and there is normal amniotic fluid volume and reassuring antepartum fetal testing in the absence of maternal complication (ie. Preeclampsia, gestational diabetes) → the pregnancy can be continued. Clinical Considerations and Recommendations

36. Are there special considerations for timing of delivery in multiple gestations ? If the woman is experiencing morbidities that would improve with delivery but do not necessarily mandate delivery (eg. Worsening dyspnea, inability to sleep, severe dependent edema, painful superficial varicosities) → delivery may be considered at these gestational age. Determination of fetal pulmonary maturity before delivery may be necessary for twin and other multiple gestations if prenatal care was late, if the woman desires a scheduled delivery, or if the pregnancy is complicated by preterm labor or preterm premature rupture of membranes Several reports - noted that GA>31-32wks the biochemical markers of pulmonary maturity (lecithin/sphingomyelin ratio or fluorescence polarization immunoassay) are higher in twin pregnancies than in singleton pregnancies at comparable gestational ages Clinical Considerations and Recommendations

37. Are there special considerations for route of delivery for multiple gestations? Determined by the position of the fetuses, the ease of fetal heart rate monitoring and maternal and fetal status Data are insufficient to determine the best route of delivery for high-order multiple gestations There are retrospective case series that validate vaginal delivery as a potential mode of delivery, especially for triplet gestations But delivered by c/sec Clinical Considerations and Recommendations

38. Summary of Recommendations The following recommendations are based on limited of inconsistent scientific evidence (Level B) Tocolytic agents should be used judiciously in multiple gestation Women with high-order multiple gestations should be queried about nausea, epigastric pain and other unusual 3 rd -trimester symptoms because they are at increased risk to develop HELLP syndrome, in many cases before symptoms of preeclampsia have appeared. The higher incidence of gestational diabetes and hypertension in high-order multiple gestations warrants screening and monitoring for these complication.

39. Summary of Recommendations The following recommendations are based primarily on consensus and expert opinion (Level C) The national Institutes of Health recommends that women in preterm labor with no contraindication to steroid use be given one course of steroids regardless of the number of fetuses Cerclage, hospitalization, bed rest, or home uterine activity monitoring have not been studied in high order multiple gestations, and, therefore should not be ordered prophylactically. There currently is no evidence that their prophylactic use improves outcome in these pregnancies Because the risks of invasive prenatal diagnosis procedures such as amniocentesis and chorionic villus sampling are inversely proportional to the experience of the operator, only experienced clinicians should perform these procedures in high-order multiple gestation.

40. Summary of Recommendations Women should be counseled about the risks of high order multiple gestation before beginning ART Management of discordant growth restriction of death of one fetus in a high-order multiple gestation should be individualized, taking into consideration the welfare of the other fetus (es)