Multiple births—the delivery of twins, triplets, or more—is common with fertility treatments. During the use of assisted reproductive technology (ART)—such as in vitro fertilization (IVF)—multiple births primarily result from transfer of more than one embryo during the procedure

1. Dr. Laxmi Shrikhande
MD; FICOG; FICMCH;FICMU
 Director-Shrikhande Fertility Clinic, Nagpur
 Senior Vice President FOGSI 2012
 National Corresponding Editor-Journal of OB/GY of India
 Peer Reviewer-The Journal of OB / GY of India
 Publications-Eleven National & seven International
 Presented Papers at FIGO,SAFOG,AOFOG,AICC RCOG
 Editor-FOGSI Focus on SUI
 Received Best committee award of FOGSI
 Received Bharat Excellence award

2. Multiple pregnancy after
ART
Dr Laxmi Shrikhande
Director-Shrikhande Fertility Clinic,
Nagpur, INDIA

3. Why so much concern?
• undesirable complication of ovulation induction
and/or ovulation enhancement
• constitute an important health problem due to
high perinatal risks and increased health costs.

4. Is it different from
natural multiple gestation??
• retrospective analysis
• 106 IVF group and 256 spontaneous twin pregnancies
• The mothers in the IVF group were significantly older than those in the
control group (32±4 years vs 28±4 years, P<0.05).
• The incidence rates of gestational hypertension and gestational
diabetes in the IVF group were significantly higher than in the
control group (P<0.05).
• No significant differences were observed for neonatal physical development,
the incidence of birth defects, and the incidence and mortality of perinatal
diseases (P>0.05).
CONCLUSIONS:
• Twins conceived by IVF have similar outcomes as spontaneously
conceived twins in the perinatal period.
• However, special attention is needed to monitor the levels of blood
pressure and blood glucose for pregnant women with twins conceived by
IVF during prenatal checkups.
Zhongguo Dang Dai Er Ke Za Zhi. 2015

5. Obstetric and perinatal outcomes of twin pregnancies
conceived following IVF/ICSI compared with
spontaneously conceived twin pregnancies
• retrospective study
• of all viable dichorionic-diamniotic (DCDA) twin pregnancies (n=539)
• The ART conceived group were on average 4 years older (36.8±4.23 vs
32.3±4.93 years) and more frequently nulliparous (73.7%; n=126 vs
36.1%; n=133) than their SC counterparts (p<0.001).
• There was no significant difference in maternal antenatal complications.
• ART twins were twice as likely to be delivered by caesarean
section (CS) (OR 2.35; 95% CI 1.76-3.14).
• There was no significant difference in the rates of preterm birth or
NICU admission according to mode of conception.
• ART conceived twins were almost twice as likely to be delivered
moderately preterm (32-33(+6)) (OR 1.98, 95% CI 1.21-3.23) and
were more likely to have RDS and neonatal hypoglycaemia
CONCLUSIONS:
• However, for those that do conceive twins, they can be advised that
assisted conception conveys no significant disadvantage over
naturally conceived twin pregnancies.
Eur J Obstet Gynecol Reprod Biol. 2014

6. Features of multiple pregnancies
obtained by in vitro fertilization
• A total of 401 spontaneous multiple pregnancies and 128 IVF multiple
pregnancies were included in the study.
• Rate of multiple pregnancies for live births and IVF rate were 3.8% and
0.79%, respectively.
• The mean maternal age was 30.1 years (21-43) in the IVF group and 27.9
years (13-43) in the spontaneous group (P < 0.05).
• The cesarean delivery rate was 100% in the IVF group and 78% in the
spontaneous group (P = 0.002).
• Premature rupture of membranes rate was 9.8% in the IVF group
and 3.6% in the spontaneous group (P < 0.05).
CONCLUSIONS:
• We found maternal age, premature rupture of membranes and cesarean
delivery rate significantly high in the IVF group.
• No significant differences were found between spontaneous and IVF
multiple pregnancies in terms of demographic features, hospitalization stay
and rate, admission to neonatal intensive care unit, mortality and congenital
malformation.
Pediatr Int. 2014 Oct;56(5):735-41

7. Prevention is better than cure!!!
• All efforts should be made to assure a singleton
birth when treating infertility.
• Tight rope walk for IVF consultants
• Risk of multiple pregnancy vs the success
rate/cycle
Reprod Biomed Online. 2014

8. IUI-When to cancel the cycle

9. How many embryos???
• Elective single embryo transfer (eSET) is
advocated in most European countries.
• In Belgium and Sweden, eSET is mandatory for
couples with a good prognosis.
• However, despite clinical recommendations and
policy statements, patients in clinical practice
frequently do request for the transfer of multiple
embryos in order to have twins.
Ann Med Health Sci Res. 2015 Jan-Feb;5(1)

10. Elective single versus double embryo transfer:
live birth outcome and patient acceptance
in a prospective randomised trial
• 199 women <38 years of age undergoing their first IVF
treatment in a private centre were included in a
prospective open-label randomised controlled trial.
• Of 98 patients selected for eSET, 40% refused and
preferred eDET even after having been well informed
about its benefits.
Reprod Fertil Dev. 2014

11. Number of embryos for transfer
following IVF / ICSI
• Multiple embryo transfer during IVF increases multiple pregnancy
rates causing maternal and perinatal morbidity.
• Single embryo transfer is now being seriously considered as a
means of minimising the risk of multiple pregnancy.
• However, this needs to be balanced against the risk of jeopardising
the overall live birth rate.
• Fourteen RCTs were included in the review (2165 women).
Thirteen compared cleavage-stage transfers (2017 women) and two
compared blastocyst transfers (148 women): one study compared
both.
Cochrane Database Syst Rev. 2013

12. Number of embryos for transfer
following IVF / ICSI
AUTHORS' CONCLUSIONS:
• In a single fresh IVF cycle, single embryo transfer is
associated with a lower live birth rate than double embryo
transfer.
• However, there is no evidence of a significant difference in the
cumulative live birth rate when a single cycle of double embryo
transfer is compared with repeated SET (either two cycles of fresh
SET or one cycle of fresh SET followed by one frozen SET in a
natural or hormone-stimulated cycle).
• Single embryo transfer is associated with much lower rates of
multiple pregnancy than other embryo transfer policies.
• A policy of repeated SET may minimise the risk of multiple
pregnancy in couples undergoing ART without substantially reducing
the likelihood of achieving a live birth.
• Most of the evidence currently available concerns younger women
with a good prognosis.
Cochrane Database Syst Rev. 2013

13. Clinical effectiveness of elective single versus
double embryo transfer:
meta-analysis from randomised trials
• eight eligible trials (n=1367).
• A total of 683 and 684 women randomised to the single and double
embryo transfer arms, respectively,
• The overall live birth rate in a fresh IVF cycle was lower after single
(181/683, 27%) than double embryo transfer (285/683, 42%)
CONCLUSIONS:
• Elective single embryo transfer results in a higher chance of
delivering a term singleton live birth compared with double embryo
transfer.
• Although this strategy yields a lower pregnancy rate than a
double embryo transfer in a fresh IVF cycle, this difference is almost
completely overcome by an additional frozen single embryo transfer
cycle.
• The multiple pregnancy rate after elective single embryo transfer is
comparable with that observed in spontaneous pregnancies.
BMJ. 2010

14. ET practices in the United States
• Retrospective cohort analysis
• Of 134,381 ART transfer cycles performed in 2012, 51,262 resulted in live
births, of which 13,563 (26.5%) were multiple births: 13,123 twin and 440
triplet and higher order births.
• Almost half of these multiple births resulted from the following four cycle
types:
– two fresh blastocyst transfers -less than 35 years ,
– two fresh blastocyst transfers among donor-oocyte recipients ,
– two frozen/thawed ETs among patients less than 35 years
– More than half of triplet or higher order births resulted from the transfer
of two embryos among frozen/thawed autologous transfers).
CONCLUSION-
• A substantial reduction of ART-related multiple (both twin and triplet or
higher order) births in the United States could be achieved by single
blastocyst transfers among favorable and average prognosis patients less
than 35 years of age and donor-oocyte recipients.
Fertil Steril. 2015 Apr;103(4):954-61

15. ASRM guidelines
A. Patients under the age of 35 who have a favorable prognosis should be offered a
single-embryo transfer and no more than two embryos (cleavage stage or
blastocyst) should be transferred . If two embryos are transferred, the patient(s)
must be counseled regarding the risks of multifetal pregnancy and the counseling
should be documented in the patient's permanent medical record.
B. For patients between 35 and 37 years of age who have a favorable prognosis, no
more than two cleavage stage embryos should be transferred. All others in this
age group should have no more than three cleavage stage embryos
transferred. If extended culture is performed, no more than two blastocysts
should be transferred to women in this age group.
C. For patients between 38 and 40 years of age who have a favorable prognosis, no
more than three cleavage stage embryos or two blastocysts should be
transferred. All others in this age group should have no more than four cleavage-
stage embryos or three blastocysts transferred.
D. For patients 41–42 years of age, no more than five cleavage-stage embryos or
three blastocyts should be Transferred.
Fertil Steril. 2013

16. ASRM guidelines
E. In each of the above age groups, for patients with two or more
previous failed fresh IVF cycles or a less favorable prognosis, one
additional embryo may be transferred according to individual
circumstances.The patient must be counseled regarding the risks of
multifetal pregnancy. Both the counseling and the justification for exceeding
the recommended limits must be documented in the patient(s)'s permanent
medical record.
F. In women >43 years of age, there are insufficient data to recommend a limit
on the number of embryos to transfer.
G. In donor-egg cycles, the age of the donor should be used to determine the
appropriate number of embryos to transfer, but when the donor is <35
years of age single embryo transfer should be strongly considered.
H. In frozen-embryo transfer cycles, the number of good quality thawed
embryos transferred should not exceed the recommended limit on
the number of fresh embryos transferred for each age group.
Fertil Steril. 2013

17. Beyond the ASRM transfer guidelines:
how many cleavage-stage embryos are safe
to transfer in women ≥43 years old?
• Retrospective cohort.
• A total of 567 cycles in 464 patients aged 43-45 years, whose IVF
cycles were characterized by transfer of five to eight cleavage-stage
embryos were identified
• Live birth rates per transfer were 14.4%, 9.4%, and 1.3% for
women aged 43, 44, and 45 years, respectively. In 43-year-old
women, 2.9% (2/69) of pregnancies were triplet gestations (one
selective reduction and one spontaneous reduction).
• Twin birth rate was 16.3%, 6.7%, and 0 (of all live births) for ages
43, 44, and 45 years, respectively.
• There was no higher order multiple births.
Fertil Steril. 2014 Dec;102(6):1626-32

18. Beyond the ASRM transfer guidelines:
how many cleavage-stage embryos are safe
to transfer in women ≥43 years old?
• Women aged 43 and 44 years having five or more embryos
transferred experienced higher clinical pregnancy rates (PRs) than
those patients receiving a transfer of three or four embryos.
• Clinical outcomes for patients undergoing transfer with six or more
embryos were not better than those undergoing transfer with five
embryos.
CONCLUSION(S):
• Transferring five or more day 3 embryos may be a safe option for
patients ≥43 years of age, as it is associated with an overall low
rate of multiple gestations.
• Having more than five embryos available for transfer on day 5 is
associated with improved IVF outcomes.
• Whether this benefit is from the additional embryo(s) for transfer or
the inherently better prognosis of such patients remains to be
determined.
Fertil Steril. 2014 Dec;102(6):1626-32

19. Twins even after SET???

20. Twins even after SET???
• To compare monozygotic twinning (MZT) rates in patients undergoing
blastocyst or cleavage-stage ET.
• Retrospective cohort.
• Autologous, fresh IVF cycles resulting in a clinical pregnancy
• There were a total of 9,969 fresh transfer cycles resulting in a pregnancy
during the study period.
• Of these pregnancies, 234 monozygotic twin pregnancies were identified
(2.4%).
• Of all transfers, 5,191 were cleavage-stage and 4,778 were blastocyst-stage
transfers.
• There were a total of 99 MZT identified in the cleavage-stage group
(1.9%) and 135 MZT in the blastocyst ET group (2.4%), which
was significant.
• When controlling for patient age, time period during which the cycle took
place, the number and proportion of six- to eight-cell embryos, and
availability of supernumerary embryos, there was no longer a
difference in MZT rate between blastocyst and cleavage transfer.
Fertil Steril. 2015 Jan;103(1):95-100

21. What makes them split?
Identifying risk factors that lead to
monozygotic twins after IVF
• Of 6,223 gestations, 131 MZTs were diagnosed (2.1%
incidence; 2.0% in autologous and 2.7% in donor IVF cycles),
10 were dichorionic, and 121 were monochorionic.
• Controlling for all risk factors, young oocyte age, extended
culture (noncleavage embryos transferred on/after day 4),
and year of IVF treatment cycle were significantly associated
with MZT.
• day 3 assisted hatching correlated more with
dichorionic MZT, whereas extended culture and
advanced day 5 embryonic stage correlated with
monochorionic MZT.
Fertil Steril. 2014 Jul;102(1):82-9

22. Incidence and zygosity of twin births
following single fresh or frozen ET
• A total of 4701 patients in a large private IVF unit who
gave birth following SET with a fresh or frozen embryo
with complete follow-up.
• Of 137 viable twins at the 7-week ultrasound, 109 were
delivered as twins
Wider implications of the findings:
• As many as 1 in 5 twins born after SET may be the
result of a concurrent natural conception.
• Couples therefore need to be counselled regarding the
relative benefits and risks of intercourse in assisted
reproduction technology cycles where spontaneous
conception is possible
Hum Reprod. 2014 Jul;29(7):1438-43

23. Management
• Selective fetal reduction
• Same as that for non ART twins
• Vaginal infection
• Steroids
• Good monitoring
• Multidisciplinary approach

24. Summary
• Is it different?
• Is it preventable?
• How to prevent?
• Is eSET is solution to
all the problems?
• How to balance ??
ASRM guidelines

25. Take Home Message
• All efforts should be made to assure a singleton
birth when treating infertility.
• Tight rope walk for IVF consultants
• Risk of multiple pregnancy vs the success
rate/cycle
Reprod Biomed Online. 2014