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6/7/2017
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Multiple Pregnancies, Multiple Headaches
Roxane Holt, MD
University of Chicago Medicine
Objectives
• Determine chorionicity in twins.
• Diagnose complications specific to monochorionic diamniotic gestations
• Monitor twin pregnancies with ultrasound techniques
Why are we so concerned about twins?
1% of live births
10‐15% of perinatal death
23% of low birth weight babies
25% of most NICU census
Expenditure: x6 singleton
Ananth, C.V., K. Joseph Ks, and J.C. Smulian, Trends in twin neonatal mortality rates in the United States, 1989 through 1999: influence of birth registration and obstetric intervention.Am J Obstet Gynecol. 2004; 190:1313‐21.
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Mean GA of delivery
Number of fetuses Weeks of gestation
1 40
2 36
3 33
4 29 1/2
Cerebral palsy
5% to 10% of all cerebral palsy cases occur in twins which is more than 4‐times the observed frequency in the general population
Topp, M., et al., Multiple birth and cerebral palsy in Europe: a multicenter study. ActaObstet Gynecol Scand. 2004;83: 548‐53.
Twins in the USA
https://www.washingtonpost.com/news/speaking‐of‐science/wp/2015/12/28/twin‐birth‐rates‐hit‐an‐all‐time‐high‐in‐the‐united‐states/?utm_term=.8cc16e480628. accessed 6/5/2017.
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Twins in the USA
https://www.cdc.gov/nchs/data/nvsr/nvsr64/nvsr64_12.pdf. Accessed 6/5/2017
Increasing multiples
Rate of monozygosity = 3‐times higher in pregnancies conceived after ART, compared to spontaneous conceptions
Derom, C., et al., Increased monozygotic twinning rate after ovulation induction.Lancet, 1987;1(8544):1236‐8.
The role of ART
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Twins
• Etiology
• Diagnosis
• Placentation
• Complications
• Aneuploidy screening
• Cervical Length
• Selective reduction/termination
• Antenatal testing
Twins – Etiology
• Monozygotic: 30%, sporadic, similar throughout the world (1:250 pregnancies)
• Dizygotic: 70%, increases with maternal age (>30), parity, ovulation induction, more common in some families, some ethnicities
Nigeria: The Yoruba have the highest rate of twinning in the world, at 45–50 twin sets per 1,000 live births. ? Due to high consumption of a specific type of yam containing a natural phytoestrogen
Chorionicity/AmnionicityWhat?
Days Post Concept Stage Placentation
1‐2 Morula DC/DA(separate placentas)
3‐4 Morula DC/DA(fused placenta)
4‐8 Blastocyst MC/DA
8‐13 Blastocyst MC/MA
>13 Blastocyst Conjoined
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Etiology
Classification
Dizygotic (70%)
Monozygotic (30%)
DiC‐DiA(8%)
MonoC‐DiA(20%)
MonoC‐MonoA(1%)
43% of same‐sex twins are monozygotic
Cameron AH. The Birmingham twin survey. Proc R Soc Med. 1968;61:229–234
If your patient asks: fetuses are the same gender, does it mean they are identical?
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Accuracy of Diagnosis
• Before ultrasound 25‐50%
• Indicated ultrasound 75%
• Routine ultrasound 90%
Twins ‐ Diagnosis
• Routine scan
• Clinical suspicion
• Reproductive technologies
• Note: number of sacs, yolk sacs, fetuses, location of placenta, presence and type of membrane, heartbeat
Chorionicity/AmnionicityWhy?
• Mortality x 3‐4 in monochorionic twins
• Twin‐twin transfusion
• Cord entanglement
• Conjoined twins (1/50,000 births)
• Co‐twin death
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Perinatal mortality
Type of twinning Mortality
DiC‐DiA 8.9%
MonoC‐DiA 25%
MonoC‐MonoA 50‐60%
Conjoined twins ?90%
Twins‐mortality
Chorionicity/AmnionicityWhen?
1st Trimester
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Chorionicity/AmnionicityHow?
• Dividing Membrane
• Placenta
• Fetal Sex
Hertzberg BS, Kurtz AB, Choi HY, et al. Significance of membrane thickness in the sonographic evaluation of twin gestations. AJR. 1987;148:151
Diagnosis of chorionicity
• Dichorionic membranes• Typically well defined
• Definite measurable width (usually greater than 2mm)
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Twins: sonographic determination of Chorionicity/Amnionicity (I)
Early Pregnancy• Number of sacs• Number of fetuses/sac• Width/number of membranes• Location of yolk sac• Number of placentas• Twin peak or lambda sign (10‐14 weeks)
Diagnosis of chorionicity
Sepulveda, W., et al., The lambda sign at 10‐14 weeks of gestation as a predictor of chorionicity in twin pregnancies. Ultrasound Obstet Gynecol. 1996;7:421‐3
Early in pregnancy ultrasound imaging can distinguish between MC and DC twin pregnancies with more than 90% accuracy (lambda or twin peak sign vs. T sign)
The lambda (twin peak) sign
• Extension of placental tissue into the base of the inter‐twin membrane
Bessis, 1981.Finberg HJ. The "twin peak" sign: reliable evidence of dichorionic twinning. J Ultrasound Med. 1992 Nov;11(11):571‐7.Sepulveda W, Sebire NJ, Hughes K, Odibo A, Nicolaides KH. The lambda sign at 10‐14 weeks of gestation as a predictor of chorionicity in twin pregnancies. Ultrasound Obstet Gynecol. 1996 Jun;7(6):421‐3.
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The lambda (twin peak) sign (cont.)
• Best at 10‐14 weeks
• Lambda sign present: >90% predictive value for dichorionicity
• T‐sign present: sens = 100%
spec = 98.2% for prediction of monochorionicity
Twin peak T‐sign
"Multifetal Pregnancy." Williams Obstetrics, Twenty‐Fourth Edition Eds. F. Gary Cunningham, et al. New York, NY: McGraw‐Hill, 2013,
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8w3d 12w6d 18w1d
Lambda sign
T‐sign
T‐sign
8w4d 11w6d 18w3d
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Twins: sonographic determination of Chorionicity/Amnionicity (II)
•DC‐DA• 2 separate rings/sacs• 2 placentas• Opposite sex (DZ)• Positive twin peak/lambda (99% accurate)• Thick membrane, 4 layers
Twins: sonographic determination of Chorionicity/Amnionicity (III)
•MC‐DA (70% of MZ)• Single placenta• Same sex• Thin, elusive membrane• T sign
Twins: sonographic determination of Chorionicity/Amnionicity (IV)
•MC‐MA• 1% of all monozygotic twins• Single embryo splits at day 8‐10• High perinatal mortality (cord accidents)• Ultrasound
• Same sac (no membrane)• One yolk sac
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MC/MA
13 weeks
Twins: sonographic determination of Chorionicity/Amnionicity (V)
• Later Pregnancy• Fetal Sex• Number of placentas• Membrane width (< or > 2mm)• Lambda sign
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Twins: sonographic determination of Chorionicity/Amnionicity (VI)
Gender
Opposite
DZ (DC)
Same
# Placentas
1
DC or MC
Twin peak (10‐14 wks)
+
DC
Ø
MC
2
DC
Anomalies Unique to Multiple Gestations
• Conjoined twins• 1 per 33,000‐165,000 births and 1 per 200,000 live births
• Zygote splits after 13‐15 days
• Most Common (>50%):
• Thoracoomphalopagus (ie, joined at the chest, abdomen, or both) ‐ 74%
• Thoracopagus or xiphopagus (ie, joined at the chest) ‐ 40%
• Omphalopagus (ie, joined at the abdomen) ‐ 34%
Complications Unique to Multiple Gestations
• “Vanishing‐twin” syndrome
• Growth discordancy
• Twin‐twin transfusion syndrome: TTTS
• Twin‐reversed arterial perfusion sequence: TRAP (Acardiac twin is previous, less scientific, but still used nomenclature)
• Fetal anomalies
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Twins – Complications
“50% of 1st trimester multiple gestations result in the birth of a singleton”
Varan, 1979
Vanishing Twin
• Sac smaller than normal
• Irregular margins
• Crescent shaped
• Incomplete trophoblastic ring
http://www.earthporm.com/25‐animal‐twins‐tough‐tell‐apart. Accessed 6/1/2017
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Growth discordancy
•Constitutional•Genetic•Placental
Early Growth Discordancy
• Difference in CRL may be 1st sign of chromosome abnormality, major congenital anomaly or imminent demise (Cheek, 1992; Weisman, 1994)
• <8 weeks, >3mm difference is associated with 50% risk of demise of smaller twin (Dickey, 1992)
• Use the larger twin CRL to determine gestational age.
• Label the twins and be consistent
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Monochorionic Twins
• ↑ a er IVF poten al causes• Lower maternal age• Ovulation induction• Length of embryo culture• Cultivation media conditions• Manipulation of zona pellucida• Hereditary factors• Ovarian function
Knopman JM, Krey LC, Oh C, Lee J.What makes them split? Identifying risk factors that lead to monozygotic twins after in vitro fertilization. Fertil Steril. 2014 Jul;102(1):82‐9. Sobek A Jr et al. High incidence of monozygotic twinning after assisted reproduction is related to genetic information, but not to assisted reproduction technology itself. Fertil Steril. 2015 Mar;103(3):756‐60.
Monochorionic twins ‐ Risks
• Twin‐Twin Transfusion Syndrome ‐ TTTS
• Twin Anemia Polycythemia Sequence ‐ TAPS
• Twin reversed arterial perfusion ‐ TRAP
• Selective Fetal Growth Restriction ‐ FGR
• Discordance for fetal anomalies
• Death of a twin
Twin‐twin transfusion syndrome
• 10‐15% monochorionic twins
• 50% perinatal mortality in monochorionic twins
• Unbalanced AV shunt
• Mortality = 40‐100% if untreated, 15‐50% handicap
• Donor: small, oligohydramnios
• Recipient: large, polyhydramnios
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Quintero’s stages
Quintero, R.A., Twin‐twin transfusion syndrome. Clin Perinato. 2003;30: 591‐600.
TTTS
Polyhydramnios (>8cm) Oligohydramnios (<2cm)
What doppler velocimetry is used?
• Umbilical artery doppler velocimetry‐Absent or reversed flow
• Ductus venosus‐reversal of a wave
• Umbilical vein‐pulsatile flow
Khalil A, Rodgers M, Baschat A, Bhide A, et al. ISUOG Practice Guidelines: role of ultrasound in twin pregnancy. Ultrasound Obstet Gynecol. 2016 Feb;47(2):247‐63.
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Can we predict TTTS?
• Inter twin CRL discrepancy + isolated increased nuchal translucency: present x 3 more frequently in cases of TTTS
• TTTS: more common when abnormal DV blood velocity waveform detected during the 11‐13+6 week exam
Sebire, N.J., et al., Early prediction of severe twin‐to‐twin transfusion syndrome. Hum Reprod. 2000; 15: 2008‐10.Matias, A., C. Ramalho, and N. Montenegro, Search for hemodynamic compromise at 11‐14 weeks in monochorionic twin pregnancy: is abnormal flow in the ductus venosus predictive of twin‐twin transfusion syndrome? J Matern Fetal Neonatal Med. 2005;18: 79‐86
TTTS: treatment
• Conservative‐Stage I• Amnioreduction‐laser not available or after 26 weeks
• Amniotic septostomy
• Selective feticide‐bipolar diathermy, Radiofrequency ablation, or laser of umbilical cord
• Laser obliteration of placental anastomoses• Acceptable for stage I• Recommendation stage II
TAPS
Twin Anemia‐Polycythemia Sequence• Large inter‐twin hemoglobin differences in the absence of
amniotic fluid discordance• Few, minuscule AV placental anastomoses (diameter <1mm) with
a slow blood transfusion from donor to recipient, leading
gradually to highly discordant Hb levels
Slaghekke F, Kist WJ, Oepkes D, Pasman SA, Middeldorp JM, Klumper FJ et al. Twin anemia-polycythemia sequence: diagnostic criteria, classification, perinatal management and outcome. Fetal Diagn Ther 2010; 27(4):181-190.
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TAPS
• Affects 3‐5% monochorionic twins after 26 weeks
• Affects up to 16% monochorionic twins after fetoscopic laser for TTTS
• Diagnosed by discordance in fetal middle cerebral artery peak systolic velocity (MCA‐PSV) measurements
• Optimal treatment, timing, and surveillance have not been determined.• Choose and be consistent
Bahtivar MO, Emer SP, Dashe JS, Wilkins‐Huag LE. The North American Fetal Therapy Network consensus statement: prenatal surveilance of uncomplicated monochorionic gestations.Obstet Gyneco. 2015 Jan;125(1):118‐23.Tollenaar LS, Slaghekke F, Middeldorp JM, Klumper FJ et al. Twin Anemia Polycythemia Sequence: Current Views on Pathogenesis, Diagnostic Criteria, Perinatal Management, and Outcome. Twin Res Hum Genet. 2016 Jun;19(3):222‐33.
• Not well known (only case reports and small series)• Vary according to severity• May range from double intrauterine fetal demise to two healthy neonates without major morbidity at birth besides large intertwin hemoglobin differences
• Most: severe anemia in donor requiring blood transfusion, and severe polycythemia in recipient requiring partial exchange transfusion.
• Cases of severe cerebral injury in TAPS have also been described
TAPS‐Perinatal outcome
Growth discordancy in MC twin
• Inter‐twin crown‐rump length (CRL) difference greater than 10% : increases the risk for discordant fetal growth or TTTS
• CRL difference of less than 10%: excellent prognosis in terms of perinatal outcome
Tai, J. and W.A. Grobman: The association of crown‐rump length discordance in twin gestations with adverse perinatal outcomes. Am J Obstet Gynecol. 2007; 197: 369 e1‐4.
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• Disproportionate sharing in conjunction with abnormal vascular connections
• Two definitions• One fetus <10% EFW with or without intertwin discordancy
• Intertwin discordancy >25%
• OK to use 20% weight differential to identify women at risk
• Routine growth scans Q4 weeks
• After diagnosis, doppler velocimetry Q1‐2 weeks
Selective Fetal Growth Restriction
Khalil A, Rodgers M, Baschat A, Bhide A, et al. ISUOG Practice Guidelines: role of ultrasound in twin pregnancy. Ultrasound ObstetGynecol. 2016 Feb;47(2):247‐63.Bahtivar MO, Emer SP, Dashe JS, Wilkins‐Huag LE. The North American Fetal Therapy Network consensus statement: prenatal surveilance of uncomplicated monochorionic gestations.Obstet Gyneco. 2015 Jan;125(1):118‐23.
Monochorionic twins – Death of One Fetus
• Co‐fetal death: 12‐25%
• Neurological morbidity: 25%
• Survivor follow up• Delivery usually not indicated
• Serial growth ultrasounds
• MCA doppler velocimetry to screen for anemia Q2‐4 weeks
• Neuroimaging 4‐6 weeks after event
Monochorionic twins – Death of One Fetus
Khalil A, Rodgers M, Baschat A, Bhide A, et al. ISUOG Practice Guidelines: role of ultrasound in twin pregnancy. Ultrasound Obstet Gynecol. 2016 Feb;47(2):247‐63.
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Monochorionic Antenatal testing
• Q2 week US for MVP, bladder visualization beginning at 16 weeks
• Anatomy ultrasound and fetal ECHO at 18‐22 weeks
• Q4 week growth after anatomy scan
• Doppler velocimetry‐be consistent
MonoC‐monoA complications
1) unequal sharing of the placenta (discordant fetal growth with IUGR, metabolic compromise and death)
2) chronic unidirectional blood shunting through placental vascular anastomoses (TTTS or twin reverse arterial perfusion [TRAP] and death)
3) conjoined twinning and cord entanglement (can also lead to death)
Sherer, D.M., Adverse perinatal outcome of twin pregnancies according to chorionicity: review of the literature. Am J Perinatol. 2001;18:23‐37.
MonoC‐monoA
"Multifetal Pregnancy."Williams Obstetrics, Twenty‐Fourth Edition Eds. F. Gary Cunningham, et al. New York, NY: McGraw‐Hill, 2013,
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8 weeks
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Twin Reverse Arterial Perfusion (TRAP), a.k.a. acardiac twin
• Due to unidirectional arterio‐arterial placental anastomosis
• Responsible for secondary fetal cardiac hypoplasia and amorphicdevelopment: one twin pumps blood for both fetuses of a MC twin pregnancy.
• TRAP occurs in both MCMA and MCDA twin pregnancies
• Overall pregnancy loss rate estimated at 50% (due to high output cardiac failure and preterm delivery)
• Can be diagnosed in 1st trimester
Kamitomo, M., et al., First‐trimester findings associated with twin reversed arterial perfusion sequence. Fet Diagn Ther. 2004;19:187‐90.
TRAP sequence (Acardia)
• One twin has absent, rudimentary or nonfunctioning heart
• 5 types. Most common (60‐75%): acardius acephalus. • Head is absent, trunk and limbs +/‐ developed.
• Pathophysiology: a to a anastomoses between umbilical arteries, early in embryogenesis.
• One twin becomes “pump”, other “perfused” by retrograde, deoxygenated blood. Lower body gets “better” blood and develops preferentially.
TRAP sequence (Acardia)
• Most common (75%)• Monochorionic‐diamnionic
• Less common (25%)• Mono‐mono
• Trisomy in 10% of “pump” twin
• “Pump” twin at risk of CHF
• Complications: polyhydramnios, preterm labor
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Acardiac twin
Risk of Chromosomal Abnormalities
• MZ twins: almost always genetically identical, thus risk of each fetus = singleton age‐related risk
• DZ twins: each twin has independent risk • Approximately 2x age‐related risk
Risk of Chromosomal Abnormalities
• ART/ICSI associated with increased risk of aneuploidy.
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Aneuploidy Screening
• More and more pregnancies in women > 35
• ↑ Incidence of multiple gestations
• Risk of one twin, the other or both, to have trisomy 21 is 80% higher than singleton at same maternal age (risk comparable to patient 2‐4 years older)
Aneuploidy screening options with ultrasound
• First trimester screening
• Nuchal translucency must obtained in both fetuses
• Not useful if there is a vanishing twin.
Diagnostic testing
• CVS or amniocentesis
• Loss rate—2‐3.5% vs 1.5‐3.1%
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Do all monozygotic twins have same karyotype?
Heterokaryotypia ‐ a discordance in karyotype due to either an early postzygotic chromosomal rescue in one fetus or a mitotic error that leads to one trisomic fetus with a normal co‐twin
Cheng, P.J., et al., Monozygotic twins discordant for monosomy 21 detected by first‐trimester nuchal translucency screening. Obstet Gynecol. 2006;107:538‐41
Malformations in Twins
• Birth Defects x 2 Singletons
• MZ >> DZ
• Cardiac (PDA, single ventricle, VSD), CNS, facial clefts, GI abdominal defects
• Monochorionic twins have 5% risk of cardiac malformationfetal ECHO
Fetal Anomalies
• Twin “A”: 7.3%
• Twin “B”: 9.4%
• (2.5% in singletons)
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Management of Pregnancy with 1 Anomalous Twin
• Continuation
• Termination
• Selective Reduction
Selective Reduction
• Fetal Abnormality• Chromosomal (50%)
• Structural (43%)
• Other (7%)
Eddleman, AJOG, 2002
Eddleman KA, Stone JL, Lynch L, Berkowitz RL. Selective termination of anomalous fetuses in multifetal pregnancies: two hundred cases at a single center. Am J Obstet Gynecol. 2002 Nov;187(5):1168‐72.
• 8 unintended (4%)• 4/164 twins
• 4/32 triplets
• No losses in 4 quads
• Mean GA at delivery = 37.1 weeks
Pregnancy Losses after Selective Reduction
Eddleman KA, Stone JL, Lynch L, Berkowitz RL. Selective termination of anomalous fetuses in multifetal pregnancies: two hundred cases at a single center. Am J Obstet Gynecol. 2002 Nov;187(5):1168‐72.
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Fetal Reduction
• Initially to reduce high order multiples
• Usually to twins
• Increasingly to singleton
Outcome ‐ Loss
• Complete loss rate: 4.7%
• 46% of losses >8 weeks
• Chance of loss• 1% within 4 weeks
• 1.5% 4‐8 weeks
• 2.1% > 8weeks
Stone J, Ferrara L, Kamrath J, Getrajdman J, Berkowitz R, Moshier E, Eddleman K. Contemporary outcomes with the latest 1000 cases of multifetal pregnancy reduction (MPR). Am J Obstet Gynecol. 2008 Oct;199(4):406.e1‐4.
Outcome – Loss (cont.)
Starting # fetuses
2
3
4
6+
Loss rate (%)
2.1
5.1
5.5
11.0
Stone J, Ferrara L, Kamrath J, Getrajdman J, Berkowitz R, Moshier E, Eddleman K. Contemporary outcomes with the latest 1000 cases of multifetal pregnancy reduction (MPR). Am J Obstet Gynecol. 2008 Oct;199(4):406.e1‐4.
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Outcome – GA at Delivery
Mean GA: 36.2 weeks
Decrease in PTD when reduced to singleton compared to twins
Stone J, Ferrara L, Kamrath J, Getrajdman J, Berkowitz R, Moshier E, Eddleman K. Contemporary outcomes with the latest 1000 cases of multifetal pregnancy reduction (MPR). Am J Obstet Gynecol. 2008 Oct;199(4):406.e1‐4.
Reduced vs. Non‐Reduced Twins
• Decreased risk of PTB <37 weeks
Gupta S, Fox NS, Feinberg J, Klauser CK, Rebarber A. Outcomes in twin pregnancies reduced to singleton pregnancies compared with ongoing twin pregnancies. Am J Obstet Gynecol. 2015 Oct;213(4):580.e1‐5. Haas J,Sasson AM, Barzilay E,Tovi SM, Orvieto R, Weisz B et al. Perinatal outcome after fetal reduction from twin to singleton: to reduce or not to reduce? Fertility and Sterility, 2015 Feb; 103(2): 428‐32.
Uncomplicated DC/DA Twins
Khalil A, Rodgers M, Baschat A, Bhide A, et al. ISUOG Practice Guidelines: role of ultrasound in twin pregnancy. Ultrasound Obstet Gynecol. 2016 Feb;47(2):247‐63.
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Uncomplicated MC
Khalil A, Rodgers M, Baschat A, Bhide A, et al. ISUOG Practice Guidelines: role of ultrasound in twin pregnancy. Ultrasound Obstet Gynecol. 2016 Feb;47(2):247‐63.
Cervical length in twins
• 21 studies (16 in asymptomatic women and 5 in symptomatic women) with a total of 3523 women
• CL ≤20 mm at 20‐24 weeks: most accurate in predicting PTB <32 and <34 weeks (pooled sens, spec, + and ‐ LR of 39% and 29%, 96% and 97%, 10.1 and 9.0, and 0.64 and 0.74, respectively).
• CL ≤25 mm 20‐24 weeks: pooled + LR of 9.6 to predict preterm birth <28 weeks’ gestation.
• Most twins are delivered by 37 weeks
Conde‐Agudelo A, Romero R, Hassan SS, Yeo L:Transvaginal sonographic cervical length for the prediction of spontaneous preterm birth in twin pregnancies: a systematic review and metaanalysis. Am J Obstet Gynecol. 2010; 203: 128 e1‐12.
Identical quads