Chairperson: Haryana Chapter Of ISAR ,2011-2015 Executive member ISAR 2016-2017 Associate RCOG Director: LOOMBA HOSPITAL AND IVF CENTRE , Ambala Cantt. HARYANA since 1988 Ex consultant at central hospital ,Arar, Saudi Arabia Ex senior resident Ganga Ram Hospital New Delhi. Graduate from GOMCO ,Patiala.1985.Awards: President’s gold medal at university level.Affiliations: ASRM,RCOG,FOGSI,ISAR,ACOG,,IAGE, ASPIRE,Foetal Medicine Foundation regular attendee at many national and international conferences. Achievements: First IVF/ART centre in haryana in 2003 Trained at CLEVELAND CLINIC U.S.A in IVF/ICSI Trained at HARVARD in advanced ultrasound in fetal medicine Advanced laparoscopy training at Kiel, Germany.Specialised : Infertility/ART, Fertility related Fields Laparoscopic surgeries, Fetal medicine Recurrent pregnancy loss

www.loombahospital.com

Dr.Poonam LoombaM.D.

loombapoonam@gmail.com

www.loombaivf.com

Twin Pregnancy

Poonam Loomba, M.D. Loomba Hospital and IVF Centre Ambala Cantt.

Background of this discussion

Although multifetal births account for only 3% of all live births, they are responsible for a disproportionate share of perinatal morbidity and mortality

Survivors of preterm births have an increased risk of mental and physical handicap.

Maternal morbidity increases.

Hospital costs increase by 40%

NICU Admissions :1/4th of twins for 18 days .

In naturally-conceived multiple gestation, the prevalence of dizygotic twinning varies with ethnicity (1.3 per 1,000 in Japan, 8 per 1,000 in the U.S. and Europe, and 50 per 1,000 in Nigeria)

Dizygotic twinning is also associated with increasing maternal age, greater parity, and a maternal family history of twinning .

Monozygotic twinning is relatively constant (4 per 1,000 live births) although genetic predisposition may have some influence.

Kodhini:Seeing double in India’s Twin town by Jordi Pizzaro

Role of ART in Twin Pregnancy?

National ART Registry of India 2013/2014• 2013: Self cycles: 72.24% S /24.79% T• 2014: Self cycles: 71.65% S /25.46%T

• 2013: Donor eggs: 61.34% S/32.13%T• 2014:Donor eggs: 61.52%S/32.78%T

• 2013:ED: 60.94%S/26.99%T• 2014:ED:60.73%S/30.73%T

• 2013:Surrogacy:76.98%S/21.3%T• 2014:Surrogacy:71.75%S/26.50%T

The incidence of twins among births from SO and ART is more than 20 times greater than for births resulting from natural conception, and that of high-order multiple gestation is more than 100 times higher { ASRM File}

Multiple follicular development is the dominant risk factor for dizygotic twinning and high-order multiple gestations in OI and SO cycles, and it can be difficult to prevent . It also increases the risk of monozygotic twinning by two- to threefold .

Transfer of more than one embryo .

The risk of monozygotic twinning may be increased by approximately twofold in conventional IVF cycles and increases further in ART cycles involving ICSI ,extended cultures.

A 2009 Cochrane review of four studies with a total of 524 patients concluded that available data were insufficient to determine whether assisted hatching increased the risk of monozygotic twinning .

Any relationship with type of drugs used for OI/ SO?

• Clomiphene

• Gonadotropins

Dose of clomiphene was positively related to pregnancy rates and birth rates, but not to multiple birth rates, abortion or ectopic pregnancies. Doses >100 mg/day were responsible for 16% of births and 11% of multiple births. Doses >100 mg were required for pregnancy in 27% of women who weighed >90 kg (198 lb), compared to 11% who weighed 45–59 kg (100–131 lb) (Table I). Doses of 25 mg were enough for pregnancy in 3% of women.

Twin births occur in ~10–12.3% of clomiphene pregnancies, according to information from series comprising ≥1000 births. In the original study conducted during the 1960s (Macgregor et al., 1968)

Multiple pregnancies were unrelated to clomiphene dose in our series and also in that of Groll (1984), who analysed the outcome of 700 clomiphene pregnancies from his practic

ASRM FACT SHEET

When using injectable gonadotropins alone or with IUI, up to 30% of pregnancies are associated with multiple implantations (twins or more), which only occur in 1% to 2% of naturally occurring pregnancies. The increased risk of multiples is due to the number of eggs that are stimulated during an ovulation induction cycle or due to the number of embryos transferred in an IVF cycle. While most multiple pregnancies are twins,

Higher incidence of MZT after IVF. Monochorionic-diamniotic implantations were increased, whereas monochorionic-monoamniotic were not. The MZT risk factors included young age and extended culture, but not zona penetration or cryopreservation.

Of the 441 clinical intrauterine pregnancies, 314 (71.2 percent) resulted from the conception of singletons, 88 (20.0 percent) of twins, 22 (5.0 percent) of triplets, 10 (2.3 percent) of quadruplets, 5 (1.1 percent) of quintuplets, and 2 (0.5 percent) of sextuplets. Low-order pregnancies (si

Norbert Gleicher, M.D., Denise M. Oleske, Ph.D., Ilan Tur-Kaspa, M.D., Andrea VidaliM.D., and Vishvanath Karande, M.D.N Engl J Med 2000;

A correlation matrix revealed that the peak serum estradiol concentration and the total number of follicles were directly correlated with the incidence of high-order multiple pregnancy (for peak serum estradiol concentration: r=0.24, P<0.001; for total number of follicles: r=0.26, P<0.001). Age was inversely correlated with the incidence of high-order multiple pregnancy (r=–0.14, P=0.008). There was no correlation between the number of follicles 16 mm or more in diameter and the incidence of high-order multiple pregnancies.

The inadequate health insurance plans/reimbursement for ART

encourages the transfer of more number of embryos in order to increase probability of pregnancy in couples with

limited financial resources

A couple with one failed IVF Cycle. They had opted for SET but this time they want more number of embryos .

Age of woman is 36yrs

What are the components of Pre IVF Counselling?

• Maximum number you can transfer• Finances/social,cultural, religious values• Family support• Diet and Nutrition• Cryopreservation• Miscarriage rate• Fetal reduction• Complications of multiple pregnancy• Multidisciplinary approach• Referral to tertiary care centre

Fill in the blanks1.Dizygotic twinning occurs from ……. eggs and

……. Sperms and constitute …………. of all twins2.Monozygotic twinning occurs from …….. egg

and …….. Sperm and constitute ………… of all twins

3.Zygosity refers to………… and Chorionicity refers to…………………

4.World’s first IVF Twins were born in …………………5 Lambda sign is diagnostic of .............................

32 yr female conceived in first IVF Cycle .Twin Pregnancy.

Came at 13 wks with report of abnormal biochemical markers .Was advised to discontinue pregnancy.

Couple is educated.

35 Yr female had twin pregnancy in third IVF Cycle.

11-13 wks scan reported as normal NTT in both fetuses NB was not

seen in one of the fetuses.Couple is well educated .

Screening in twins by biochemistry alone is considered problematical by some (Cuckle, 1998), .

Whilst NT can be used successfully to screen in twins with a similar detection rate and false positive rate to that in singleton pregnancies, the combination of both first-trimester NT and maternal serum biochemistry can improve the overall detection rate to around 80% (Spencer, 2000)

Screening in twin pregnancies requires adjustment of the calculated MoM to account for the presence of two fetuses. In general, for free β-hCG, this should be by dividing the observed corrected MoM by 2.023. For PAPP-A two different factors are required −2.192 in dichorionic twins and 1.788 in monochorionic twins. Kevin Spencer1,2*, Karl O. Kagan2,3 and Kypros H. Nicolaides Prenat Diagn 2008; 28: 49–52

In monochorionic (and so monozygotic), both fetuses will be affected or unaffected. Since the amount of cffDNA is approximately double that of a singleton pregnancy, cffDNA aneuploidy testing will not only be possible but probably more effective than in singletons.

In dichorionic, , maternal plasma DNA testing would, in theory, not be as straightforward.

Two studies of small series of twin pregnancies have suggested that shotgun sequencing-based approaches are able to detect fetal trisomies in twin pregnancies. It is also possible to determine the zygosity of twin pregnancies using targeted sequencing from maternal plasma. The application of NIPT to twin pregnancies is still at a very early stage of development The complexity introduced by twin pregnancies suggests that, prior to cffDNA testing, a good quality ultrasound scan would be a valuable first step .

RCOG 2014

BackgroundPrenatal Diagnosis

AmniocentesisChorionic villous sampling

: technically difficult to accomplish in patients with multiple gestation

Role of TVS in first trimester

Chorionicity assessmentbefore 10 weeks?

• Number of Yolk Sacs• Number of GSAC• Number of amniotic sacs in chorionic cavity

After 10 weeks?

• Sex discordance• No of distinct placenta• Twin peak/lambda sign-results from echodense

chorionic villi between the two layers of chorion at its origin from the placenta.(100% PPV for DC placentation)

• T sign:MCDA placentation• Epsilon sign:TCTA placentation• Membrane thickness:cutoff 2mm

Diagnosing anomalies(excluding nt)• Anencephaly• Large encephalocoels• Holoprosencephaly• Cystic hygroma• Omphalocoel/gastrochisis(size of

protruding ant abd mass>7mm and persistence beyond 12weeks)

• Amniotic band syndrome• Conjoined twins

Role of ultrasound in 2nd trimester

Role of ultrasound in third trimester

Twins and preterm birth

Can preterm birth be predicted in Twin pregnancy?

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

Am JOBG:2016 Feb;214(2):277.e1-7. doi: 10.1016/j.ajog.2015.08.065. Epub 2015 Sep 9.Transvaginal cervical length scans to prevent prematurity in twins: a randomized controlled trial.Gordon MC1, McKenna DS2, Stewart TL3, Howard BC4, Foster KF5, Higby K6, Cypher RL3, Barth WH7.

This is a multicenter, randomized, controlled trial of 125 dichorionic or monochorionic/diamniotic twin pregnancies without prior preterm birth <28 weeks. The study group (n = 63) had TVCL and digital exams

monthly from 16-28 weeks and were managed with a standard algorithm for activity restriction and cerclage. The control group (n = 62) had monthly digital

cervical examinations but no routine TVCL ultrasound examinations. The primary outcome was gestational age at delivery. Secondary outcomes included percentage of deliveries <35 weeks, and

maternal and neonatal outcomes. Routine second-trimester transvaginal ultrasound assessment of cervical length is not associated with improved outcomes when incorporated into the standard management

of otherwise low-risk twin pregnancies.

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

Other high risk factors for PTB

• Prev h/o PTB ,PPROM,RPL• Diabetes• Obesity• Polyhydramnios

32 yr F ,Twins in 2nd IVF Cycle.TVS for length of cervixDone.

At 22 wks Short cervix < 2.5 cm .Couple is well educated and informed.

Interventions• Bed Rest:Crowther 2010• Prophylactic CC:Dor et al 1982• USG indicated CC :Berghella et

al 2005• Vaginal Progesterone:Norman

et al 2009• Intra muscular

Progesterone:Durnwald et al 2011

• Tocolysis:Yamasmit et al 2005

• NO• No

• No

• No

• No

• No

Author’s conclusion In unselected women with an uncomplicated twin gestation, treatment with progestogens (intramuscular 17Pc or vaginal natural progesterone) does not improve perinatal outcome. Vaginal progesterone may be effective in the reduction of adverse perinatal outcome in women with a cervical length of ≤25 mm; however, further research is warranted to confirm this finding.

Effectiveness of progestogens to improve perinatal outcome in twin pregnancies: an individual participant data meta-analysis. BJOG 2015

A randomised controlled double-blind clinical trial of 17-hydroxyprogesterone caproate for the prevention of preterm birth in twin gestation (PROGESTWIN): evidence for reduced neonatal morbidity. BJOG 2015

ONCLUSIONS:Intramuscular 17OHPC therapy did not reduce PTB before 37 weeks of gestation in unselected twin pregnancies. Nonetheless, 17OHPC significantly reduced neonatal morbidity parameters and increased birthweight.

RCOG Green top guidelines 2011

• In Singleton pregnancy with h/o PTB or RPL in second trimester ultrasound indicated cervical cerclage can be offered if length of cervix is <2.5cm

Cervical cerclage in twin preg

• The insertion of a history- or ultrasound-indicated cerclage in women with multiple pregnancies is not recommended, as there is some evidence to suggest it may be detrimental and associated with an increase in preterm delivery and pregnancy loss.

Steroid cover

• Dosage

• When to give

• Once or twice

Serial ultrasounds for monitoring length of cervix

• How frequent?

• What Route?

Prevention of PPROM

• Endo cervical cultures/Screening for BV/Chlamydia/Gonorrhoea

• HVS Cultures

• Antibiotics/Metronidazole

41 yr old female .Comes at 23 wks.Conceived with donor oocytes.

Discordant growth from early GA. Normal 11-13 wks scan. Oligohydramnios in one sac with growth restriction in both

fetuses .

How do you define discordant growth? What else would you like to check on her so as to

explain her the possible prognosis of this pregnancy?• Best method for fetal surveillance?• What if one fetus dies in utero?• With efficient surveillance till what GA you can

prolong pregnancy?

• Discordant fetal growth is defined as 15-25% reduction in the EFBW of the smallest fetus compared to the largest(Talbot et al 1997).>18%

• Accurate assignment of chorionicity: Monochorionic.

• AFI• Biometry and the percentile of GR• Doppler waveform of FUA,MCA ,DV Flow• Urinary Bladder• In case of death of one fetus in utero there are

12% chances of Iufd of second twin.

Complications of MP• Increased maternal morbidity • Fetal and neonatal morbidity and mortality.• Preeclampsia,• Gestational diabetes• Preterm labor and delivery• Growth restriction/Discordant growth/fetal demise • Cholestasis, • Dermatoses,• Excess weight gain,• Anemia, • Hyperemesis gravidarum,• Exacerbation of pregnancy-associated gastrointestinal symptoms (reflux,

constipation) .• Chronic back pain,• Intermittent dyspnea,• Postpartum laxity of the abdominal wall, and umbilical hernias also occur frequently• Perinatal morbidity and mortality associated with multiple gestations relates directly

to the consequences of preterm birth .

• 39yr female with secondary infertility.• Conceived with FTET in second IVF Cycle.• Triplets reduced to twins.• c/o itching .Blood test reported as : Total Se Bilirubin - 1.32mg/dl Direct 0,77mg/dl Indirect 0.55mg/dl SGOT 62.69IU/L SGPT 90.01IU/LAlkaline phosphatase 1117.48U/L

• 30 yr F twins from donor eggs.• 24 wks...B.P. 130/90 .RFT/LFT ...normal range.• Comes at 26wks with :

• H/o Oliguria since 5-6 days,excessive oedema of face and legs and feet since two days.Urine output <200ml in 24 hrs.

• B.p.170/110.Blood work showed only low TSP Low Albumin. 24 hr urinary proteins high.

• Role of Low dose aspirin and Heparin?

Risk of TED

Strategies to limit risks of multiple births?

• eSET• Limit the number of ET ,guiding factors being

maternal age,prognostic factors,quality of embryos.• Highly efficient cryopreservation protocols for IVF

Clinics.• National registry for keeping record of all OI/SO in

order to assess actual proportion of twins attributable to ART

• National health insurance schemes for ART Procedures.

Factors affecting application of e SET

• 1.Desire to achieve higher preg per transfer• 2.Selection of best embryo and best mother• 3.Economic pressure on patients restricting

number of cycles taken• 4.Good protocols for cryopreservation• 5.Other socioeconomic,religious and cultural

factors

Double the gigglesDouble the grinsDouble the Trouble WhenYou are blessed with twins