Etiology, management and delivery of

Dora Melicher MA, MD, PhD Department of and Gynaecology

06/12/2019

Department of Obstetrics and Gynaecology Definition and Classification

A multiple is a pregnancy in which more than one develops in the at the same time (: one fetus in utero, the other is extrauterine) Classification Ä number of : Ê Twins, triplets, quadruplets, etc. Ä number of fertilized eggs: zygosity Ê monozygotic, dizygotic Ä number of placentae: chorionicity Ê monochorion, dichorion Ä number of amniotic cavities: amnionicity Ê monoamnion, diamnion

Etiology, management and delivery twins Dora Melicher MA,MD,PhD Classification

Etiology, management and delivery twins Dora Melicher MA,MD,PhD Umstad MP, Calais-Ferreira L, Scurrah KJ, Hall JG, Craig JM. (2019) Twins and Twinning. Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics: Foundations, Chapter 14:387-414. 28 pages. https://doi.org/10.1016/B978-0-12-812537-3.00014-7 Process of Monozygotic Twinning During Postfertilization

Etiology, management and delivery twins Dora Melicher MA,MD,PhD Umstad MP, Calais-Ferreira L, Scurrah KJ, Hall JG, Craig JM. (2019) Twins and Twinning. Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics: Foundations, Chapter 14:387-414. 28 pages. https://doi.org/10.1016/B978-0-12-812537-3.00014-7 Incidence

Ä Hellin’s Law: 1:85[n-1] ÊTwins: 1:85 ÊTriplets: 1:852 ÊQuadriplets: 1:853 , etc.

Ê This rule applies only to spontaneously conceived multiple ¦(drug-induced ovulation or assisted reproductive technology are not involved)

Etiology, management and delivery twins Dora Melicher MA,MD,PhD Etiology of multiple pregnancies

Ä Dizygotic or fraternal twins: Ê fertilization of two separate oocytes Ê gender: 50% same-sex, 50% different sex Ê etiology and prevalence varies (race, hereditary differences) Ê increasing prevalence (maternal age, infertility therapy) Ä Identical or identical twins: Ê single fertilized oocyte splits in two Ê genetically almost 100% identical fetuses Ê same-sex (including HLA genes) Ê frequency is constant in all races (prevalence 1/250)

Etiology, management and delivery twins Dora Melicher MA,MD,PhD Factors that influence the incidence of multiple pregnancies

Ä maternal age (>35 years, <18 years) Ä maternal parity Ä genetic factors Ä race/geographic area (Afro-American >> White> Asian) Ê naturally conceived dizygotic twins accounted for 1.3/1000 births in Japan, 8/1000 births in the US and Europe, and 50/1000 births in Nigeria* Ä maternal weight and height Ê obese (body mass index [BMI] ≥30 kg/m2) and tall (≥65 inches [164 cm]) Ä family history Ä endogenous FSH, GnRH level Ä use of fertility stimulating drugs Ê IVF, ovulation induction, superovulation plus intrauterine insemination

Etiology, management and delivery twins Dora Melicher MA,MD,PhD

Fertil Steril. 2012;97(4):825. and multiple births statistics

Ä Twin births account for ∼ 3% of live births and 97% of multiple births in the United States Ä Growth in the United States over the past 25 years Ê twin births increased from 1/53 infants in 1980 to 1/29 infants in 2014 Ê The number of twin pregnancies increased by 76 percent from 1980 through 2009 and stabilized with a birth rate of 33.7 per 1000 births in 2013* Ê The number of live-born twins rose nearly 50%, the number of live-born multiples more than 400% Ê Over one-third of all twin infants born can be attributed to iatrogenic interventions ¦(in vitro fertilization, ovulation induction, superovulation plus intrauterine insemination)

Etiology, management and delivery twins Dora Melicher MA,MD,PhD *Natl Vital Stat Rep. 2015 Jan;64(1):1-65. www.update.com. The risk of multiple pregnancies

Ä High rate of preterm delivery: Ê less chance of survival Ê Increases risk of life-long disability Ä Twins account for Ê 17% of all preterm deliveries Ê 24% of low birth-weight infants (<2500 g) Ê 26% of very-low-birth-weight infants (<1500 g) Ä fetal malformation (double-frequent) Ä specific diseases

Ä Women with twin pregnancy are 6 times more likely to be hospitalized with complications

Etiology, management and delivery twins Dora Melicher MA,MD,PhD

ACOG practice bulletin. Clinical management guidelines for Obstetrician–Gynecologists. Number 56, 2004 Comparative outcomes of singleton, twin, and triplet pregnancy

Etiology, management and delivery twins Dora Melicher MA,MD,PhD

Martin JA, Hamilton BE, Sutton PD, et al. Births: final data for 2006. Natl Vital Stat Rep 2009; 57:1. Fetal complications

Ä All twins: Ê growth restriction Ê congenital anomalies Ê preterm delivery Ä Ê Twin-twin transfusion syndrome (TTTS) Ê Twin anemia-polycythemia sequence (TAPS) Ê Twin reversed arterial perfusion sequence (TRAP) Ê Selective fetal growth restriction (sFGR) Ê Single fetal demise Ä Ê Intertwin cord entanglement Ê

Etiology, management and delivery twins Dora Melicher MA,MD,PhD Assessment of zygosity and chorionicity

Ä Monozygotic twins: DDD or MDD or MMD or MMM (DCDA, MCDA, MCMA)

Ä Dizygotic twins: DDD or MDD (DCDA) Ä Monochorionic : monozygotic Ä Different sex fetuses: dizygotic Ä Same-sex fetuses and dichorionic placenta: ?? Chorionicity is of high importance !! Ä Monochorionic twins: Ê 3-10-fold perinatal mortality Ê Specific diseases

Etiology, management and delivery twins Dora Melicher MA,MD,PhD Lambda sign and T sign Ä Ultrasound (I. screening) Ê Measurements at the end of the first trimester (11-14 weeks):

Etiology, management and delivery twins Dora Melicher MA,MD,PhD placenta placenta Decision tree of Zygosity

Are the twins the same sex?

Yes No Dizygotic

How many are present?

Monozygotic 1 2 ?

Do the twins have the same blood type?

Yes ? No Dizygotic

Are the zygosity test results identical?

Monozygotic Yes Etiology, managementNo and delivery twins DizygoticDora Melicher MA,MD,PhD Histopathological examination after birth

Dichorionic placenta No anastomoses!

Etiology, management and delivery twins Dora Melicher MA,MD,PhD

Courtesy of Professor Enrico Lopriore, Head of Neonatal Intensive Care Unit, Leiden University Medical Center, Start & Hart 2012, TWINS Madrid 2017 Histopathological examination after birth

Monochorionic placenta always anastomoses!

Start & Hart 2012

Etiology, management and delivery twins Dora Melicher MA,MD,PhD

Courtesy of Professor Enrico Lopriore, Head of Neonatal Intensive Care Unit, Leiden University Medical Center, Start & Hart 2012, TWINS Madrid 2017 Complications – MC twins

Ä Twin-twin transfusion syndrome (TTTS) Ä Twin anemia-polycythemia sequence (TAPS) Ä Twin reversed arterial perfusion sequence (TRAP) Ä Selective intrauterine growth restriction (sIUGR)

Etiology, management and delivery twins Dora Melicher MA,MD,PhD

Courtesy of Professor Enrico Lopriore, Head of Neonatal Intensive Care Unit, Leiden University Medical Center, Start & Hart 2012, TWINS Madrid 2017 Twin-to-Twin Transfusion Syndrome (TTTS)

Ä Arteriovenous vascular connection in the placenta between the two fetal circulations Ä 5-15% of monochorionic twins are affected Ä Acute: in early pregnancy it can result in early fetal loss Ä Chronic: the blood flow through blood vessel anastomoses becomes unbalanced Ä The smaller twin (donor) does not get enough blood while the larger twin (recipient) becomes overloaded with too much blood. Ä If untreated: 60-100% mortality

Etiology, management and delivery twins Dora Melicher MA,MD,PhD TTTS

Ä Diagnosis: Ultrasound Ê monochorionic placenta Ê same-sex fetuses Ê weight discordance (no longer used) Ê discordance with “stuck-twin” Ê Twin oligo - sequence (TOPS) Ä Recipient: hydrops, heart failure Ä Donor: absent end-diastolic flow

Etiology, management and deliverySource: twinstwintwintransfusionsyndrome.weebly.comDora Melicher/diagnosis MA,MD,PhD-of-ttts.html *Malone FD et al. ClinPerinatol 2000; 27: 1033-1046 Staging system in TTTS

Ä Stage I.: donor bladder is visible Ä Stage II: donor bladder is no longer visible Ä Stage III.: abnormal Doppler findings: Ê (absent/backward-diastolic flow in the umbilical artery Ê donor: reverse flow in the ductus venosus, Ê recipient: pulsatile flow in the umbilical vein) Ä Stage IV.: ascites or hydrops in both twins Ä Stage V.: death of one or both twins

Etiology, management and delivery twins Dora Melicher MA,MD,PhD

Quintero RA et al. J Perinatol 1999; 19: 550-555 Treatment of TTTS Ä Conservative management: not recommended Ä Early (2nd trimester) Ê selective Ê termination of the entire pregnancy Ê aggressive management: physical interventions ¦serial amniocentesis ¦septostomy ¦selective laser ablation Ä Mid- to late 3rd trimester Ê less aggressive treatment depending on the severity of the disease

Etiology, management and delivery twins Dora Melicher MA,MD,PhD

Reduction amniocentesis Septostomy (microseptostomy) Selective lase ablation Complications – MC twins

Ä Twin anemia-polycythemia sequence (TAPS) Ê a variant of TTTS in which one twin is anemic and the other twin is polycythemic, but without amniotic fluid volume discordance.

Etiology, management and delivery twins Dora Melicher MA,MD,PhD

Courtesy of Professor Enrico Lopriore, Head of Neonatal Intensive Care Unit, Leiden University Medical Center, Start & Hart 2012, TWINS Madrid 2017 Complications – MC twins

Ä Twin reversed arterial perfusion sequence (TRAP) Ê a rare complication of monochorionic twins in which a living twin perfuses a nonliving (acardiac) twin through patent vascular channels.

Etiology, management and delivery twins Dora Melicher MA,MD,PhD Radiofrequency ablation Complications – MC twins

Ä Selective intrauterine growth restriction (sIUGR) Ê estimated weight of one twin below the 10th percentile or discordance in estimated twin weights greater than 25%

Etiology, management and delivery twins Dora Melicher MA,MD,PhD

Courtesy of Professor Enrico Lopriore, Head of Neonatal Intensive Care Unit, Leiden University Medical Center, Start & Hart 2012, TWINS Madrid 2017 Etiology, management and delivery twins Dora Melicher MA,MD,PhD www.update.com Monoamniotic twins

Ä rare disease (less than 1% of MZ twins) Ä diagnosis made with ultrasound Ê no visible separation membrane Ä high rate of fetal mortality (30-68%) Ä premature birth Ä congenital anomalies Ä complications Ê Intertwin cord entanglement/knots are common Ê acute cord compression is unpredictable Ä delivery at 32 weeks with cesarean section

Etiology, management and delivery twins Dora Melicher MA,MD,PhD Adaptation of the maternal body to multiple pregnancies

Ä Higher levels of β-hCG – more frequent nausea, vomitus Ä Increased plasma volume (50-60%) - relative anemia Ä Increased folic acid and iron requirements - true anemia Ä Hypervolaemia, higher cardiac output (~20%), increased pulse rate Ä Increased uterine volume (compression of abdominal organs, lungs, urinary tract)

Etiology, management and delivery twins Dora Melicher MA,MD,PhD Complications of twin pregnancies

Ä Maternal: Ä Fetal: Ê Preeclampsia, PIH Ê Higher risk of premature birth Ê Ê Higher perinatal mortality, Ê Cervical incompetence morbidity Ê Insufficiency of the placenta Ê Weight discordancy (over 20%) Ê Ê TTTS, TAPS, TRAP, sFGR Ê Ê Intrauterine death Ê (dystocia) Ê Special congenital anomalies Ê Primary and secondary Ê Discordancy for anomalies uterine inertia, Ê Polyhydramnion Ê Prolonged labour Ê Lie and posture abnormalities Ê Postpartum

Etiology, management and delivery twins Dora Melicher MA,MD,PhD Maternal risks and complications

Ä Maternal hemodynamic changes Ê Women carrying twins have a 20% higher cardiac output and 10 to 20% greater increase in plasma volume than women with singleton pregnancy Ä and preeclampsia Ê rates of gestational HT and PE were twice as high in twin compared with singleton pregnancies (13% in twins vs. 5-6 % in singletons for both disorders) Ä Gestational diabetes Ä Acute fatty liver of pregnancy Ä Other Ê pruritic urticarial papules and plaques of pregnancy (PUPPP), intrahepatic cholestasis of pregnancy, iron deficiency anemia, , abruption, thromboembolism Etiology, management and delivery twins Dora Melicher MA,MD,PhD www.update.com Pregnancy-induced hypertension in multiple pregnancy Ä Placental origin Ä more or larger placenta Ä higher risk of placental ischemia Ä maternal and fetal effects Prenatal Surveillance: Ê blood pressure Ê urine analysis Ê body weight gain Ä More frequent visits (every 2nd week) Ä Management: hospitalization (otherwise identical to single pregnancy)

Etiology, management and delivery twins Dora Melicher MA,MD,PhD Gestational diabetes in multiple pregnancy

Ä Placental origin Ä larger placental weight Ä higher levels of placental diabetic hormones Ä Effect (macrosomy, RDS, hypoglycemia) Ä Screening and diagnosis: 75 g OGTT

Etiology, management and delivery twins Dora Melicher MA,MD,PhD Cervical cerclage in multiple pregnancy

Ä Indications for cerclage: Ê Prophylactic (anamnesis) Ê Therapeutic (ultrasound) Ê Emergency (examination) Ä Indications have been significantly reduced! Ê “A 2019 meta-analysis of randomized trials and cohort studies (two randomized trials and four cohort studies) comparing cervical cerclage with no cervical cerclage in twin gestations with normal cervical length Ê did not provide convincing evidence Ê that prophylactic cerclage is an effective intervention for preventing and reducing perinatal death in this population, even in women with a past history of preterm birth.” Ä Cervical cerclage in twin and multiple pregnancy is not recommended!

Etiology, management and delivery twins Dora Melicher MA,MD,PhD Am J Obstet Gynecol. 2019;220(6):543. www.update.com Hospitalization

Ä Advantages: Ê extended bed rest Ê access to diagnostics and treatments Ä Disadvantages: Ê risk of thromboembolism Ê risk for nosocomial infection Ê psychological symptoms Ä Randomized controlled trial Ê The policy of routine hospitalization of women with twin pregnancies up to 26 weeks is not beneficial for the mother and the newborn.

Etiology, management and delivery twins Dora Melicher MA,MD,PhD

Maclennanet al, Lancet 1990; 335: 267-269 Antepartum Management of a multiple pregnancies

Congenital abnormalities Treatment: Ä Concordancy Ä early detection Ä Discordancy Ä regular monitoring of the cervix Ê Options: Ä detection of preeclampsia ¦conservative management Ä diet (proteins, vitamins) ¦termination of pregnancy Ä hospitalization -individualized ¦selective feticide with KCl: Ä Ultrasound every 2-3 weeks » severe anomaly Ä fetal surveillance » dichorionic placenta Ê (CTG, US, BP, color Doppler) » fetus "B" has a disease » (Multifetal Pregnancy Reduction)

Etiology, management and delivery twins Dora Melicher MA,MD,PhD Ultrasound screenings

Etiology, management and delivery twins Dora Melicher MA,MD,PhD Types of intrauterine presentations

Etiology, management and delivery twins Dora Melicher MA,MD,PhD

K. Hanretty, Obstetrics Illustrated, sixth ed., Churchill Livingstone, Edinburgh, 2003. Delivery in multiple pregnancies

Ä Conditions: Ä After the birth of the fetus "A": Ê 2 obstetricians, Ê vaginal examination, amniotomy, most of the fetus Ê 2 neonatologist, should be guided into the pelvis, Ê extra nursing personnel, (birth in 30 min.). Ê anesthesia, Ä Fetus "B" is not in head position: Ê available OP, Ê podalic version and extraction Ê intravenous access or cesarean section. Ä Active management of the third Ä CTG, oxytocin (placental) phase Ä Cesarian Section: Ê Fetus "A" is not in head position or fetus "B" is in transverse position, Ê triplets, quadruplets.

Etiology, management and delivery twins Dora Melicher MA,MD,PhD Etiology, management and delivery twins Dora Melicher MA,MD,PhD www.update.com Collision geminorum “Locked twins”

Etiology, management and delivery twins Dora Melicher MA,MD,PhD

M. Laubach, Y. Jacquemyn, in Obstetric Interventions, A. Grunebaum et al., Eds. (Cambridge University Press, Cambridge, 2017), pp. 91-99. Thank you very much for your attention!

Department of Obstetrics and Gynaecology