Avoiding Multiple Pregnancy in ICSI By Prof. Ahmed Abdel Aziz Chairman of Ob/Gyn Department Alexandria University

Overview A multiple pregnancy is a pregnancy involving more than one fetus. The largest multiple pregnancy on record led to the birth of nine offspring.

Overview Twins are the most common type of multiple pregnancy. The incidence of higher-order multiple pregnancies (triplets or greater) has increased >100-folds. Births of single individuals (singletons) rose only 6% in that same time period.

Overview The increase of multiple births is age related. According to the National Center for Health Statistics, over the last 20 years, multiple pregnancies in the United States have increased : 400% among women in their 30s and 1000% in women in their 40s. This trend is due in part to the fact that older women are less able to get pregnant naturally and are more likely to undergo infertility treatment

Miscarriages They are at least twice as common in multiple pregnancies. Hyperemesis gravidarum Pregnancy-induced high blood pressure Hypertension is 3 times more common in multiple pregnancies, and it is more severe. Gestational diabetes. Iron- and folate-deficiency anemias It is generally recommended that women take mg of iron and 1 mg of folic acid supplementation daily to prevent anemia. A high- protein diet is also recommended. Acute polyhydramnios occurs in about 5 - 8% of women who have a multiple pregnancy. Vaginal and uterine hemorrhaging antepartum Preterm labor and delivery The average length of pregnancy is 39 weeks for singletons, 35 weeks for twins, 33 weeks for triplets, and 29 weeks for quadruplets. Multiple pregnancy is, on average, 12 times more likely to be preterm. Prolonged hospitalization and surgical delivery Maternal risks and complications

Fetal Complications Low birth weight wt <2500 gm is considered low, wt < 1500 gm is considered very low. Two-thirds of infants born from a multiple pregnancy are low birth weight and are at risk for significant short-term and long-term health problems as a result.

Fetal Complications Birth defects Monozygotic twins are twice as likely as dizygotic twins to be born with congenital malformations.

Fetal Complications Infant mortality can result from premature delivery in multiple pregnancy. Most infant mortalities in preterm multiple deliveries occur in gestations less than 32 weeks and birth weights below 1500 gm. Respiratory distress syndrome (RSD) accounts for 50% of neonatal deaths resulting from premature birth.

Fetal Complications Cerebral palsy: Infants born from a multiple pregnancy have a higher risk for cerebral palsy and other types of permanent neurological damage.

Overview The financial, emotional and medical costs of multi-fetal pregnancies are extremely high.

Fetal Reduction Fetal Reduction has been employed over the past two decades as a mechanism to reduce the morbidity and mortality of multiple pregnancies. The procedure is successful in over 80% of patients.

Selective Reductions We argue that selective termination in appropriate circumstances (eg, when the ability to carry the pregnancy to viability is very small) is ethically justified because it meets the criterion of least harm and most potential good. Obstetrics & Gynecology :

Fetal Reduction There is technical, ethical, and psychosocial concerns about the proper use of multifetal pregnancy reduction

Fetal Reduction; Types Multifetal reduction is an outpatient procedure that is most successful when performed between 10 and 12 weeks of gestation. It involves using ultrasound to guide the insertion of a needle through the abdomen to inject potassium chloride into one or more of the fetuses. Multifetal reduction can be performed earlier in the pregnancy (between 6 and 8 weeks) using a transvaginal approach and embryo aspiration. There is a chance for spontaneous fetal reduction at this stage, and it is too early in the pregnancy to perform fetal screening for defects.

Impact of fetal reduction on physical and psychological well-being of women. (a) pre-fetal reduction: feeling threatened by the confirmed diagnosis of multifetal pregnancy, facing guilt and conflict of undergoing fetal reduction; (b) undergoing fetal reduction: getting confused due to family's concern about fetal reduction, losing a sense of body boundary intactness, and worrying about the safety of the remaining fetuses; (c) post-fetal reduction: grieving for losing fetus, returning to the course of normal pregnancy. The findings indicate that undergoing fetal reduction impacted the physical and psychological well-being of multifetal pregnant women. Hu Li Za Zhi Dec ;53 (6): Fertil Steril Apr ;87 (4 Suppl 1):S

Fetal Reduction Success rates from fetal reduction have improved as a function of increasing experience, better ultrasound, and lower starting numbers. Genetic diagnosis prior to reduction can improve the overall outcomes. Semin Perinatol Oct ;29 (5):321-9

Fetal Reduction About 4-5% of women who undergo multifetal reduction miscarry the entire pregnancy as a result of the procedure.

Fetal Reduction For all starting numbers, including twins, reduction to a lower number of fetuses : reduces fetal losses, prematurity, and infant mortality and morbidity. Prenat Diagn Sep ;25 (9):807-13

Fetal Reduction The use of chorionic villus sampling (CVS) before reduction has become a good practice to assure the likelihood of normal, remaining fetuses. Evans. Reduction of Twins to a Singleton. Obstet Gynecol 2004.

Non-selective Fetal reduction; Is it a Malpractice ? From a medical point of view, this non evidence- based practice is not following good clinical practice. multifetal pregnancies can be avoided by transferring only one or a maximum of two embryos by in vitro fertilization. Further, ovarian stimulating programs should strictly adhere to protocols aiming at mono-ovulation. J Perinat Med ;34 (5):355-8

Conclusion 1. High order multiple pregnancy has increased >100 folds due to IVF & COH. 2. It has many fetal and maternal complications. 3. Fetal reduction could be justified in these conditions.

Conclusion 4. Fetal reduction is now safe and effctive in most of the cases. 5. CVS before reduction is a good practice to assure normal remaining fetuses.

Conclusion 6. Non selective fetal reduction could be considered a malpractice. 7. Women receiving fetal reduction usually encounter difficult decision and tremendous emotional stress.

Single Embryo Transfer To reduce the multiple pregnancy rate, eSET was introduced as a routine in patients with a high probability to become pregnant.

Single Embryo Transfer In patients < 36 years of age undergoing their first IVF-ICSI. If two embryos showing satisfactory morphology are obtained, one is selected transferred and the other is systematically frozen. Selection for transfer is based on two criteria, i.e. observation of even early cleavage 26 hours after IVF-ICSI and evaluation of embryo morphology score on day 2. Embryo morphology score is based on the presence of four blastomeres and absence of blastomere irregularities and anucleated fragmentation. Last, a prerequisite for SET is an effective freezing program. Gynecol Obstet Fertil Sep ;34 (9):786-92

Single Embryo Transfer A pregnancy rate of 13% per thawing was sufficient enough to obtain a cumulative pregnancy rate after SET (N = 205) and subsequent frozen embryo transfer (FET) similar to the cumulative pregnancy rate obtained after double embryo transfer (N = 394) and subsequent FET (46.3 vs 46.7%, NS). Twin delivery rate were respectively 2,6% after SET and 26,6% after double embryo transfer (P < 0.01). Gynecol Obstet Fertil Sep ;34 (9):786-92

Single Embryo Transfer In reports from Finland and Belgium already 5 years ago, elective single embryo transfer (eSET) was shown to reach almost the same success rates as double embryo transfer (

Single Embryo Transfer In both these Nordic countries around 60% of the transfers are today eSET and the multiple pregnancy rate below 10% with no triplets.

Single Embryo Transfer Between June 2002 and December 2004, all patients (first cycle, female age <38 years) were offered the choice between having one (SET) or two (DET) embryos transferred. Reprod Biomed Online Sep ;13 (3):368-75

Single Embryo Transfer All of the SET patients, and 82% of the DET group, had at least one embryo cryopreserved, (3.9 versus 2.8 embryos). The option of SET was continued for the frozen-thawed embryo transfers. Reprod Biomed Online Sep ;13 (3):368-75

Single Embryo Transfer The pregnancy rate following embryo transfer was significantly lower after SET compared with DET for both fresh (27.6 versus 36.9%; P < 0.05) and frozen-thawed (14.4 versus 23.5%) embryos. Reprod Biomed Online Sep ;13 (3):368-75

Single Embryo Transfer However, the cumulative live birth rates following the transfer of fresh and frozen embryos were identical between the two groups (43 versus 45%), with a high prevalence of twins following DET (34 versus 0% ) Reprod Biomed Online Sep ;13 (3):368-75

Natural IVF A total of 134 controlled natural IVF (nIVF) cycles were reviewed retrospectively and compared with 370 stimulated IVF (sIVF) cycles. The clinical pregnancy rate per embryo transfer following nIVF was 27% and 47% in sIVF cycles for patients aged less than 35. However, natural cycle patients could attempt consecutive cycles with much less impact on their lives, both medically and financially. Reprod Biomed Online Mar ;14 (3):356-9

Natural IVF In patients under 35 years of age, the choice of controlled nIVF reduces the cost and risk to the patient, permitting her to have multiple, consecutive attempts, and cumulatively offers a clinical pregnancy rate which approaches that of sIVF. Reprod Biomed Online Mar ;14 (3):356-9

Embryo Selection In IVF-ICSI cycles with single embryo transfer (SET), SELECTION OF EMBRYO is of crucial importance. The present study aimed to define which embryo parameters might be related to the implantation potential of advanced blastocysts. CONCLUSIONS: Developmental stage on day 5 and fragmentation rate on day 3 were related to the implantation potential of advanced blastocysts and should also be taken into account in the selection of the best advanced blastocyst for transfer. Reprod Biol Endocrinol Jan 26;5 (1):2

The value of early cleavage (EC) is still being debated. The aim of this prospective study was to examine the predictive value of EC assessment performed exactly 26 h after insemination by IVF or (ICSI) in a programme of elective single embryo transfer (SET) Reprod Biomed Online Jan ;14 (1):85-91

The value of early cleavage (EC) is still being debated Significantly higher overall clinical and ongoing pregnancy rates were obtained after transfer of an EC embryo than a non-EC embryo: 49.4 versus 33.3% (P < 0.05) and 42.4 versus 25.9% (P < 0.02) respectively. Reprod Biomed Online Jan ;14 (1):85-91

Preimplantation genetic diagnosis (PGD ) The Belgian legislation imposes single embryo transfer (SET) on women of <36 years in their first treatment cycle to avoid multiple pregnancies The implementation of a SET policy in young women undergoing PGD for monogenic disorders and translocations enables a significant reduction of multiple pregnancies without significantly affecting the delivery rate. Hum Reprod Jan 4; :

Cost-effectiveness of SET Vs DET The objective of this review is to determine which embryo-transfer policy is most cost- effective: elective single-embryo transfer (eSET) or double-embryo transfer (DET) A total of 496 titles were identified through the searches and resulted in the selection of one observational study and three randomized studies...( Hum Reprod Update Nov 10; :

Cost-effectiveness of SET Vs DET DET is also most effective if performed in one fresh cycle eSET is effective only when performed in good prognosis patients and when frozen/thawed cycles are included. Hum Reprod Update Nov 10; :

Cost-effectiveness of SET Vs DET If frozen/thawed cycles are excluded, the choice between eSET and DET depends on how much society is willing to pay for one extra successful pregnancy. Hum Reprod Update Nov 10; :

Optimal time for selecting a single embryo for transfer ;day3 Vs day 5. To determine the best day for the selection and transfer of a single embryo, a prospective, randomized study was undertaken that compared the ongoing pregnancy rate (PR) after single embryo transfer (SET) on day 3 with that after single blastocyst transfer (SBT) on day 5. Results showed an overall significantly higher PR after SBT (32.8%) compared with SET (23.2%), and a PR of 40.8% after SBT versus 25.6% after excellent-quality embryos became available. Fertil Steril Feb 7; : Nicolas H Zech et alNicolas H Zech

Factors affecting patients attitude towards SET and MET OBJECTIVE: To identify factors that influence patient decision making concerning embryo transfer. DESIGN: Prospective analysis. SETTING: In vitro fertilization unit at a tertiary-care, university-affiliated teaching hospital. Fertil Steril Nov 9; :

Factors affecting patients attitude towards SET and MET PATIENT(S): 79 women and 53 men who were referred consecutively for IVF treatment. INTERVENTION(S): Provision of risk information about complications of twin pregnancy. MAIN OUTCOME MEASURE(S): Rated desirability of different transfer options and twin pregnancy, together with standardized measures of depression and infertility stress. Fertil Steril Nov 9; :

Factors affecting patients attitude towards SET and MET CONCLUSION(S): Cautious patients, preferred transfer of fewer embryos. Less-cautious patients may be motivated by beliefs about the influence of age, desires for, and likelihood of twin pregnancy. Information about risks may affect these groups differently and This may require good information to ensure informed consent. Fertil Steril Nov 9; :

Factors affecting patients attitude towards SET and MET Providing risk information increased the desirability of elective single-embryo transfer and decreased the desirability of twin pregnancy among both men and women. Fertil Steril Nov 9; :

Cochrane Review Single embryo transfer significantly reduces the risk of multiple pregnancy, but also decreases the chance of live birth in a fresh IVF cycle. Subsequent replacement of a single frozen embryo achieves a live birth rate comparable with double embryo transfer. Hum Reprod Oct ;20 (10):2681-7

Conclusion SET with maintenance of acceptable pregnancy rates can only be achieved if tools to select normal embryos are at hand(improved morphological criteria, biomarkers and PGD) together with improved cryopreservation procedures. Gynecol Obstet Fertil Sep ;34 (9):786-92

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Is e-SET a cost-effective alternative to DET ? A review of the literature showed only five studies assessing both costs and consequences of strategies involving eSET compared with double embryo transfer. Several limitations in these studies prevent a definitive conclusion on the cost-effectiveness of eSET being reached. BJOG Nov 2; :

INTRODUCTION In several clinics, elective single-embryo transfer (eSET) is applied in a selected group of patients based on age and the availability of a good-quality embryo. Whether or not eSET can be applied irrespective of the presence of a good- quality embryo in the first cycle, to further reduce the twin pregnancy rate, remains to be elucidated. Hum Reprod Apr 7; :

METHODS In patients <38 years two transfer strategies were compared, which differed in the first cycle only: group A (n = 141) received eSET irrespective of the availability of a good- quality embryo, and group B (n = 174) received eSET when a good-quality embryo was available while otherwise they received double embryo transfer (DET; referred to as eSET/DET transfer policy). In any subsequent cycle, in both groups the eSET/DET transfer policy was applied. Hum Reprod Apr 7; :

RESULTS After completion of their IVF treatment (including a maximum of three fresh cycles and the transfer of frozen-thawed embryos), comparable cumulative live birth rates (62.4% in group A and 62.6% in group B) and twin pregnancy rates (10.1 versus 13.4%) were found. Hum Reprod Apr 7; :

CONCLUSIONS The transfer of one embryo in the first cycle, irrespective of the availablity of a good-quality embryo, in all patients <38 years, is not an effective transfer policy for reducing the overall twin pregnancy rate. Hum Reprod Apr 7; :

Prefences of Subfertile women regarding e-SET Additional IVF cycles are acceptablble, Lower pregnancy rates are not. If elective single ET lowers pregnancy chances with 1%, 3%, or 5%, the percentage of women preferring elective single ET drops to 34%, 24%, and 15%, respectively. If four, five, or six cycles with elective single ET are needed to match the success rate of three cycles with double ET, the percentage of women with a preference for elective single ET drops from 46% to 40%, 36%, and 35% respectively. Fertil Steril Apr 6; :

Prefences of Subfertile women regarding e-SET With identical pregnancy rates after elective single embryo transfer (ET) and double ET strategies consisting of three cycles of IVF or intracytoplasmic sperm injection (ICSI) plus transfers of thawed/frozen embryos if available, 46% of the women undergoing IVF/ICSI favor elective single ET. Fertil Steril Apr 6; :

Embryo Selection METHODS: Overall, in 203 cycles with SET, developmental characteristics of 93 implanted (group A) and 110 non-implanted (group B) advanced blastocysts of good quality were compared. The following developmental parameters were assessed in the two groups: normal fertilization, developmental stage on day 5, number of blastomeres on day 2 and on day 3, fragmentation rate on day 3, compaction on day 4 and cleavage pattern on day 2 and day 3. Reprod Biol Endocrinol Jan 26;5 (1):2

Embryo Selection RESULTS: Expanded blastocysts compared to full blastocysts have higher implantation potential (56.5% vs. 29.3%, p<0.05). In group B, a higher proportion of advanced blastocysts showed between 10% and 50% anucleated fragments on day 3 than in group A

preimplantation genetic diagnosis (PGD) METHODS: A retrospective analysis of PGD cycles for monogenic disorders and translocations in women <36 years on their first treatment cycle.RESULTS:There was no significant difference in the delivery rates between the DET and the SET groups (33.9% versus 27.4%, respectively). Multiple pregnancies were avoided when SET was performed. When monogenic disorders and chromosomal translocations were separately evaluated, no significant difference in the delivery rate after SET was observed. Hum Reprod Jan 4; :

Twin-to-singleton reduction ? Until recently, multifetal pregnancy reductions to a singleton were rare. Physicians had doubts about the justification to go "below twins." However, physicians know that spontaneous twin pregnancy losses average 8 – 10%. Also, with experience, multifetal pregnancy reduction has become very safe. Data suggest that the likelihood of taking home a baby is higher after reduction than remaining with twins. We propose that twin-to-singleton reductions might be considered with appropriate constraints and safeguards. LEVEL OF EVIDENCE: III Obstet Gynecol Jul;104(1):102-9.