ART (Assistec Reproductive Technology) and Twins: Special Issues

"I want to have twin babies after IVF"-
This is sometimes asked by the women undergoing IVF. We have to understand,

1. Twin is a complication and it's not a desired outcome
2. Twin pregnancy carries high risk to the mother and the babies
3. The chance of twin pregnancy is higher after any fertility treatment, particularly after IVF. Even when a single embryo is transferred, it can result in twin pregnancy (identical twin).

Honoured to have delivered a talk on "ART and Twins: Special Issues" in the "Double Delight: Masterclass on Multifetal Pregnancy" organized by the Indian Society of Perinatology and Reproductive Biology (ISOPARB) Kolkata Chapter on 30 August 2025.

1. ART and Twins: Special Issues Dr Sujoy Dasgupta MBBS (Gold Medalist, Hons ) MS (OBGY- Gold Medalist) DNB (New Delhi) MRCOG (London) Advanced ART Course for Clinicians (NUHS, Singapore) M Sc, Sexual and Reproductive Medicine (South Wales, UK) Clinical Director, Genome Fertility Centre, Kolkata Managing Committee Member, BOGS, 2025-26 Executive Committee Member, ISAR Bengal, 2024-26 Clinical Examiner, MRCOG Part 3 Examination Winner, Prof Geoffrey Chamberlain Award, RCOG World Congress, London, 2019 Delivered, Dr Kamini Rao Oration, AICOG, 2024 Published original articles (9), case reports (4) and review articles (4) in various National and International journals. Contributed to chapters in 8 books . Peer-reviewer in in various National and International journals.

2. Twin: complications Twin is a complication NOT an expected outcome

3. IVF: High risk for preterm delivery Cavoretto P, et al. Risk of spontaneous preterm birth in singleton pregnancies conceived after IVF/ICSI treatment: meta-analysis of cohort studies. Ultrasound Obstet Gynecol. 2018;51(1):43-53.

4. IVF twin vs IVF singleton The mean gestational age at delivery was lower in twin deliveries (34.9 ± 3.1 weeks) as compared to singleton deliveries (36.8 ± 3.2 weeks,  P  < 0.001 ). 1 The overall incidence of maternal complications was higher in twin pregnancies (29.3% vs. 21.3 %,;   P  = 0.003 ). 1 The mean birth weight of babies was significantly lower (2.02 ± 0.58 kg vs. 2.71 ± 0.68 kg;  P  < 0.001) and the incidence of stillbirth plus neonatal death was higher (7.5% vs. 4.6%,  P  = 0.01) in the twin group as compared to the singleton group. 1 Gupta R, et al. Maternal and Neonatal Complications in Twin Deliveries as Compared to Singleton Deliveries following  In vitro  Fertilization. J Hum Reprod Sci. 2020;13(1):56-64.

5. IVF Twin vs spontaneous twin Overall, maternal and perinatal outcomes were similar in the two groups. 1 The rate of CS was slightly, but not significantly, higher in IVF pregnancies. 1 Antenatal hospitalization (56% vs 28%, p=0.045) and corticosteroid use (72% vs 44%, p=0.041) were significantly higher in the IVF group. 2 Elective caesarean was more frequent in IVF pregnancies (80% vs 48%, p=0.021). 2 NICU admissions (36% vs 22%) and neonatal complications were more common, though not statistically significant. 2 Composite postpartum and neonatal morbidity was higher in IVF-conceived pregnancies. 2 Vasario E, et al. IVF twins have similar obstetric and neonatal outcome as spontaneously conceived twins: a prospective follow-up study. Reprod Biomed Online. 2010;21(3):422-8. Pallavi P, et al. Twin Pregnancies by IVF and Spontaneous Conception: A Prospective Analysis of Clinical Outcomes. J Contemporary Clinical Practice. 2025;11(6):576-583.

6. MCDA after IVF vs Spontaneous MCDA Overall fetal and neonatal survival was significantly lower in the IVF/ICSI group than in the spontaneous-conception group (79%  vs  90%;  P  = 0.001 ). 1 In the IVF/ICSI group, compared with the spontaneous-conception group, loss of one or both twins occurred twice as often (29%  vs  14%;  P  = 0.001) and there was a higher risk of second-trimester miscarriage (8%  vs  1%;  P  = 0.002 ). 1 MCDA twins conceived after IVF/ICSI have lower overall survival rates and higher rates of second-trimester miscarriage than do spontaneously conceived MCDA twins. 1 1. Couck I, et al. Monochorionic twins after in-vitro fertilization: do they have poorer outcomes? Ultrasound Obstet Gynecol. 2020;56(6):831-836.

7. Contribution of IVF to twin Double embryo transfer (DET) MZ twin after single embryo transfer (SET)

8. SET ≠ Elective SET ( eSET )

9. Monozygotic twin after IVF The incidence of MZ twins was higher after ART than that after natural conception. 1 To avoid the complication of a twin pregnancy Single frozen embryo Single cleavage-stage embryo Particularly for people at high risk. 1 Chen N, et al. Risk factors associated with monozygotic twinning in offspring conceived by assisted reproductive technology. Hum Reprod Open. 2023;2023(4):hoad035.

10. Ma S, et al. Comparisons of benefits and risks of single embryo transfer versus double embryo transfer: a systematic review and meta-analysis.  Reprod Biol Endocrinol  2022; 20, 20

11. Ma S, et al. Comparisons of benefits and risks of single embryo transfer versus double embryo transfer: a systematic review and meta-analysis.  Reprod Biol Endocrinol  2022; 20, 20

12. Risk factors for twin after DET Increased risk Age <35 Two good quality embryos High education GnRH agonist cycle Decreased risk Female age over 35- 9.5% vs 25.1%, aRR  = 0.38 (0.27. 0.55). Poor-type endometrium - 19.2% vs 27.5%, aRR  = 0.75 (0.58. 0.96). One good-quality embryo or none good-quality embryo- 26% vs 12.8% vs 9.3%, aRR  = 0.56 (0.45. 0.70), aRR  = 0.44(0.26. 0.74). Chen P, et al. Risk factors for twin pregnancy in women undergoing double cleavage embryo transfer. BMC Pregnancy Childbirth  2022;22,264.

13. Arguments against eSET eSET → reduces twin pregnancies eSET → reduces pregnancy chances → compensated by decreased maternal and especially neonatal risks from avoided twin pregnancies Perinatal outcomes: IVF twins > spontaneously conceived singletons and twin > IVF singletons Differences stable over time Overall obstetrical outcomes significantly improved. With no risk excess, eSET significantly reduces IVF pregnancy chances without compensatory benefits eSET unnecessarily prolongs their time to pregnancy and increasing their medical cost eSET is NOT recommended unless patients do not wish to conceive twins or have medical contraindications to conceiving twins Gleicher N, et al. Risks of spontaneously and IVF-conceived singleton and twin pregnancies differ, requiring reassessment of statistical premises favoring elective single embryo transfer ( eSET ).  Reprod Biol Endocrinol . 2016; 14 ,25.

14. IVF twin vs two consecutive singleton pregnancies The need for a second pregnancy to achieve equal outcome (2 children), resulting treatment delays, increased efforts and costs In absence of any guarantees that a second successful singleton pregnancy/delivery will ever be accomplished, invalidates eSET as a routine procedure eSET offers neither patient-friendly nor cost-effective treatment options for IVF, except where patients object to twins or have medical contraindications Gleicher N, Bard DH. Mistaken advocacy against twin pregnancies following IVF. J Assist Reprod Genet. 2013;30(4):575-9.

15. Who want more than one child Most risk assessments of twin pregnancies after fertility treatment have used spontaneous conceptions data If published data are corrected accordingly to achieve statistical commonality of outcome (i.e., one child in singleton versus two children in twins), twin pregnancies no longer demonstrate a significantly increased risk profile and/or cost for mothers or individual offspring . IVF twins→ 40% lower outcome risks than spontaneous twin conceptions. For infertile patients who want more than one child, twin deliveries represent a favourable and cost-effective treatment outcome that should be encouraged, in contrast to the current medical consensus Gleicher N, Barad D. Twin pregnancy, contrary to consensus, is a desirable outcome in infertility. Fertil Steril . 2009;91(6):2426-31.

16. Argument against DET DET may decrease the chance of later pregnancies if only one of the embryos implants, because a further cycle will be delayed until after delivery DET should only be considered after failed treatment cycles and with lower quality embryos . Obstetric risks are even greater in ageing women Meldrum DR, al. Prevention of in vitro fertilization twins should focus on maximizing single embryo transfer versus twins are an acceptable complication of in vitro fertilization. Fertil Steril . 2018;109(2):223-229.

17. Can funding affect eSET vs DET? Danish recommendation for eSET - should be routine except in cases with low prognosis (e.g. women ≥ 40 years of age, >4 unsuccessful IVF embryo transfers, or decreased embryo quality). This effort reduced the twin birth rate to 5% Denmark- couples <40 yrs, ≤3 IVF cycles, including surplus FET cycles, are fully reimbursed , and costs for medication are partly reimbursed above a self-payment of 1000 dollars Similar progress is more difficult to achieve in locations where the costs of fertility care are borne by the couple themselves. Meldrum DR, al. Prevention of in vitro fertilization twins should focus on maximizing single embryo transfer versus twins are an acceptable complication of in vitro fertilization. Fertil Steril . 2018;109(2):223-229.

18. Higher age- DET vs eSET ? Wang Y, et al. Absolute Risk of Adverse Obstetric Outcomes Among Twin Pregnancies After In Vitro Fertilization by Maternal Age. JAMA Netw Open. 2021;4(9):e2123634.

19. Why eSET in older women? Twin pregnancies conceived via IVF had higher absolute obstetric risks in each maternal age compared with IVF-conceived singleton pregnancies or non–IVF-conceived twin pregnancies . Promotion of the e-SET strategy is needed to reduce multiple pregnancies following IVF technologies. Twin pregnancy IVF Advanced maternal age → independently associated with adverse obstetric outcomes, and their coexistence may lead to the aggravation of obstetric risk. Wang Y, et al. Absolute Risk of Adverse Obstetric Outcomes Among Twin Pregnancies After In Vitro Fertilization by Maternal Age. JAMA Netw Open. 2021;4(9):e2123634.

20. eSET vs Fetal reduction (ESHRE, 2025) The transfer of ≥2 embryos with the intention of performing foetal reduction in case of multiple embryo implantation instead of e-SET is NOT recommended - considering the high risks of the procedure.

21. Reduction of IVF twin to singleton? Retrospective cohort study of 3600 dichorionic twin pregnancies after IVF-ET. The reduced group included 71 women with transvaginal elective fetal reduction between 7 and 8 weeks of gestation. The take-home baby rate was significantly lower in the reduced group (83.1% vs 92.8%,  P  = 0.004). The total miscarriage rate was significantly higher in the reduced group (12.7% vs 6.2%,  P  = 0.04). Although preterm delivery rate was lower in the reduced group ( P  < 0.001), over 90% were over 32 weeks, whereas the proportions were equal in the reduced group. Luo L, et al. Is it worth reducing twins to singletons after IVF-ET? A retrospective cohort study using propensity score matching. Acta Obstet Gynecol Scand. 2019;98(10):1274-1281.

22. DET vs eSET - Obst complications in singleton A higher risk of neonatal death was found in singletons after DET vs SET (OR, 2.67 [95% CI, 1.28-5.55]. 1 In frozen embryo transfers, DET was associated with a higher risk of low birth weight (OR, 1.64 [95% CI, 1.19-2.25]. 1 Among blastocyst transfers, DET was associated with very preterm birth (RRR, 2.64 [95% CI, 1.50-4.63] and low birth weight (OR, 1.83 [95% CI, 1.29-2.60]. 1 These results indicate a higher risk of adverse outcomes following DET, even when the result is a singleton birth, vs singletons born after SET. 1 Rodriguez- Wallberg KA, et al. Obstetric and Perinatal Outcomes of Singleton Births Following Single- vs Double-Embryo Transfer in Sweden. JAMA Pediatr . 2023;177(2):149-159.

23. “I want a twin pregnancy” The majority of twin pregnancies that occur after IVF from good prognosis patients are from patients who request that two embryos are transferred despite our recommendations to consider SET. Shenoy CC. et al. Impact of patient preference on rate of double embryo transfer and resultant twin gestation. Fertil Steril . 2017; 107(3),e47 -e48

24. Role of patient education Increased eSET use or preference after patients were educated on the risks of multiple pregnancy and success rates associated with different types of ART procedures, when combined with clinic policies that supported single blastocyst transfers or provided options for insurance. Sunderam S, et al. Effects of patient education on desire for twins and use of elective single embryo transfer procedures during ART treatment: A systematic review. Reprod Biomed Soc Online. 2018;6:102-119.

25. Recommendations

26. NICE, 2013

27. RCOG Scientific Impact Paper, 2018 HFEA set a maximum multiple birth rate target for clinics, which started at 24% in 2009 and reduced gradually over 4 years to no more than 10% of all live births. IVF clinics were requested to develop their own ‘multiple birth minimisation strategy’. HFEA has removed the maximum multiple birth rate of 10% as a licence condition for IVF

28. ASRM, 2025 PGT (A) maybe a tool to reduce the rate of multiple gestations, especially in women >37 years of age . In women ≤42 years, transferring a single euploid blastocyst resulted in pregnancy rates similar to those of transferring 2 untested blastocysts while dramatically reducing the risk of twins If an IVF program notes a particularly high implantation rate for cleavage-stage embryos among their patients aged 41–42 years, they should adjust their clinic-specific range for the number of embryos to transfer downward.

29. Women with a favourable prognosis (ASRM, 2025) Transfer of a euploid embryo should be limited to one , regardless of patient age. Age <35, strongly encouraged to receive a SET, regardless of the embryo stage. Age 35-37, strong consideration should be made for a SET. Age 38-40, no more than 3 untested cleavage-stage embryos or 2 blastocysts Age 41-42, no  more than 4 untested cleavage-stage embryos or 3  blastocysts . Age ≥43, insufficient data to recommend a limit on the number of embryos to transfer when the patient uses her own oocytes .

30. Special cases (ASRM, 2025) In each of the preceding age groups, patients who do not meet the criteria for a favourable prognosis may have an additional embryo transferred according to their individual circumstances The patient must be counselled regarding the additional risk of twin or HOMP. If otherwise favourable patients fail to conceive after multiple cycles with high-quality embryo(s) transferred, the physicians and patients may consider proceeding with an additional embryo to be transferred. Patients with a coexisting medical condition- SET In the rare cases in which the number of embryos or blastocysts transferred exceeds the recommended limits, both the counselling and the justification must be documented in the patient's permanent medical record.

31. Special cases (ASRM, 2025) In donor- oocyte cycles, the age of the donor should be used to determine the appropriate number of embryos to transfer. SET should be strongly recommended in all surrogates. In surrogates, at a minimum, on the basis of the age of the woman who produced the oocytes  (either the intended parent or oocyte donor). In FET cycles, on the basis of the age of the woman when the embryos were  cryopreserved

32. Summary of ASRM recommendations

33. ESHRE, 2025 Consider medical risks (maternal , foetal, and neonatal); direct costs (related to obstetric care of multiple pregnancies and paediatric care) and indirect costs (due to sick leave days, over-the-counter medication, and loss of productivity because of an ill child) The GDG recommends that information on possible psychosocial complications should be provided to patients at the treatment planning stage. Patients must sign an additional consent form if >1 embryo is transferred

34. DET vs eSET does NOT depend on (ESHRE, 2025) Previous unsuccessful ART treatments Duration of infertility Previous pregnancy/live birth Female age Ovarian response Criteria related to the endometrium Time-lapse morphokinetics Preimplantation genetic testing Embryo age- cleavage/ blastocyst Embryo quality Donor/ surrogate

35. ART Law of India, 2022

36. Management Luteal phase support- like other cases of IVF Scanning and other investigations- just like other cases of twin Aneuploidy screening- Mention IVF Age of the oocyte -donor Delivery- timing, indications and route- like other cases of twin No special indications of C section 1 Wang Y, et al. Absolute Risk of Adverse Obstetric Outcomes Among Twin Pregnancies After In Vitro Fertilization by Maternal Age. JAMA Netw Open. 2021;4(9):e2123634.

37. Prevention of preterm labour in IVF twin Cervical Cerclage Progesterone

38. Cerclage in IVF twin   A retrospective case-control study in eastern India Cases (15) - IVF twins with normal cervical length in whom cervical cerclage was done Control (15) - no-cervical cerclage Excluded- cerclage done for history, ultrasound indicated, uterine anomalies, and MCtwins . The mean age of participants, mean gestation age at delivery , and birth weight in cases and control were 35.27 ± 5.98 years (min: 23; max: 45), 32.40 ± 5.54 years (min: 25; max: 44); 34 weeks 2 days ± 3.28 (min: 31; max: 37), 33 weeks 5 days ± 1.66 (min: 25; max: 37); 1961.33 ± 340 gram, 1899.33 ± 437.48 gram, respectively with no statistical significant difference (p = 0.186, p = 1, p = 0.668, respectively) Routine transvaginal cerclage is not effective in twin IVF pregnancies with normal cervical length for preventing preterm births. IVF twin women usually present at a late age and their birth weight are also low. Samant M, et al. The Effectiveness of Routine Cerclage in In Vitro Fertilization (IVF) Twins. Cureus . 2024;16(7):e65328.

39. Cerclage in IVF Twin Cervical cerclage mechanically aims to prevent cervical dilatation and is likely to be effective only for true cervical incompetence , which is rare. In the absence of clinical indicators of incompetence , clinical studies do NOT show benefit for prophylactic cerclage in multiple pregnancy . Shortening of the cervix is associated with pre-term delivery, but ultrasound surveillance for cervical shortening followed by cerclage does not appear to be offer any benefit either, and may even be detrimental. Gee H et al. Multiple Pregnancy after IVF: To Cerclage or not to Cerclage ? 2012

40. IVF-Conception ≠ Cerclage deficiency

41. Vaginal Progesterone in IVF Singleton vs Twin A single-centre prospective placebo-controlled randomized study was performed. Either treatment with daily 400 mg vaginal natural progesterone or placebo, starting from mid-trimester up to 37 weeks or delivery. There was a significantly lower preterm birth rate in singleton pregnancies in the natural progesterone arm (OR 0.53, 95% CI 0.28–0.97 ). No significant difference between both arms in twin pregnancies (OR 0.735, 95% CI 0.36–2 ). Aboulghar MM, et al. The use of vaginal natural progesterone for prevention of preterm birth in IVF/ICSI pregnancies. Reprod Biomed Online. 2012;25(2):133-8.

42. Rectal progesterone in IVF twin Double-blind, placebo controlled, single center, RCT. Women with dichorionic twin gestations, having an IVF/ICSI Randomized to receive natural rectal progesterone (800 mg daily) vs placebo, starting early from 11 to 14 weeks, regardless of cervical length and had no previous history of preterm birth or known Mullerian anomalies. Progesterone administration was NOT associated with a significant decrease in the spontaneous preterm birth rates before 37 weeks (73.5% vs 68%,  P  = 0.551), before 34 (20.6% vs 21.6%,  P  = 0.649), before 32 (8.8% vs 12.4%,  P  = 0.46) & before 28 (4.9% vs 3.1%,  P  = 0.555) weeks. Aboulghar MM, t al. The effect of early administration of rectal progesterone in IVF/ICSI twin pregnancies on the preterm birth rate: a randomized trial. BMC Pregnancy Childbirth. 2020;20(1):351.

43. Yet to know

44. Summary IVF twin- higher risk of obstetric complications? eSET is the standard of care Management- not significantly different from other twin

45. 45 This PPT will be available at: https:// www.slideshare.net/SujoyDasgupta1 Mail ID- [email protected] ORCID ID- 0000-0002-8116-9312 Thank you ISOPARB