The Embryos to Transfer in IVF/ICSI

- Acknowledgement

We would like to acknowledge the Egyptian health council committee of national Egyptian guidelines

Chair of the panel

Professor Mohammed Yehia.

Scientific group members

Professor Gamal Abu El Serour , professor Abdel Megid Ramsy, professor  Hisham Salah Professor Omar Shabaan Dr Mohamed Elsherbiny  Dr Amgad Monir and Dr Wafaa Bengamin

- Abbreviations

ASRM: American Society of reproductive medicine.

DET : double embryo transfer.

eSET: Elective single embryo transfer.

ESHRE: European Society of human reproductive and the and Embryology.

ET: Embryo transfer.

FET frozen embryo transfer.

HOM: high order multiple pregnancy.

IVF: in vitro fertilization.

LBR :live birth rate.

MPR :multiple pregnancy rate.

SART: Society for assistive reproductive technology.

TA-USG: Trans abdominal ultrasound .

PGT : preimplantation genetic testing.

PGT-A : preimplantation genetic testing aneuploidy .

- Scope

This guideline predominantly covers the recommendations for safe and effective embryo transfer after IVF to achieve the highest possible life birth rate without subjecting the patient to the risk of multiple pregnancy. It also aims to examine different evidence  based procedures and the different steps that should be used during the embryo transfer procedures. It also examines many of the procedures that should be abandoned because there is no evidence to support their practice.

- Executive Summary

● It is recommended that clinicians should perform single embryo transfer (strong recommendation).

● Medical SET is indicated for women in whom multiple pregnancy represents an a priori increased risk compared to the overall population such as women with congenital uterine anomalies (e.g. septate uterus), bad obstetric history (e.g. previous premature birth <32 gestational weeks) and severe systemic diseases (e.g. insulin-dependent diabetes).(strong recommendation).

● Elective single embryo transfer should be used in cases with PGTA (strong recommendation) .

● It is recommended to encourage eSET in good-prognosis patients although a maximum of two embryos is allowed after proper counseling. In cases of DET, a written consent explaining the risks of multiple pregnancies should be signed. (conditional recommendation).

➡️Good prognosis patients include:

● Females <38 years of age should be strongly encouraged to transfer one embryo especially if they meet the criteria of good prognosis. Emphasis on eSET is highly recommended if the female age is <35 years  (strong recommendation).

●  Females between 38 and 40 years are allowed to transfer two embryos, however, eSET can still be encouraged especially if they have good prognosis. (strong recommendation).

● Females 41-42 years of age should receive no more than two embryos. (strong recommendation).

● In FET cycles, the decisions should be based on the age of the woman when the embryos were cryopreserved. (strong recommendation).

● Trans-abdominal  ultrasound guidance during embryo transfer is recommended as it improves clinical pregnancy rate and live-birth rate. (strong recommendation).

● It is  recommended to use a soft embryo transfer catheter as it improves the pregnancy rate in fresh and Frozen cycles. (strong  recommendation).

● Anesthesia during embryo transfer  does not improve pregnancy rates. Given that there are added risks associated with anesthesia, routine anesthesia is not recommended in IVF-embryo transfer. ( strong recommendation).

● It is recommended to place  the catheter tip in the upper or middle (central) area of the uterine cavity, greater than 1 cm from the fundus as this decreases embryo expulsion and optimizes pregnancy rates. (Conditional recommendation).

● It is not recommended to prescribe antibiotics with embryo transfer. (conditional  recommendation).

● Bed rest is not recommended after embryo transfer as it does not increase pregnancy rates (Strong recommendation).

● No enough evidence to recommend routine removal of cervical mucous from the cervix before embryo transfer (conditional recommendation).

● There is No specific time to recommend removal of   the embryo transfer catheter after embryo transfer. (conditional recommendation).

- Introduction

Embryo transfer is the last and one of the most important steps in IVF procedures . It entails deposition of fertilized and divided embryo (s) inside the uterine cavity. Over the years many changes have occurred regarding the number and technique of embryo transfer. It has been shown repeatedly that the results of IVF in the same institution differ dramatically in pregnancy rate depending upon that clinician performing the procedure. A survey of sorts demonstrated that essentially all practitioners are allowed to perform embryo transfer if they desire no matter what their skill level is.

- Scope and purpose

This guideline predominantly covers the recommendations for safe and effective embryo transfer after IVF to achieve the highest possible life birth rate without subjecting the patient to the risk of multiple pregnancy. It also aims to examine different evidence based procedures and the different steps  that should be used during the  embryo transfer procedures. It also examines many of the procedures that should be abandoned because there is no evidence to support their practice.

This is the first guideline in Egypt for regulation of IVF practice. Multiple embryo transfer is widely practiced in Egypt with a consequent high multiple twin and HOM rate. Both the clinician and the patient are responsible for that. The transition from no legislation to eSET cannot be taken abruptly. A gradual move to the limitation of the number of embryos to transfer is needed. The aim is the reduction of MPR to below 15% within the coming 4 years, with an ultimate goal of bringing it down below 10% in a second step. Patient's autonomy to consider placement of more than one embryo is respected, however, this requires a full discussion of the ethical and medical considerations, ensuring that a patient is able to make a fully informed decision. This guideline is meant to assist practitioners to properly counsel patients to take the right decision about the number of embryos to transfer.

- THE TARGET AUDIENCE

This guideline is directed towards healthcare professionals who are involved in the process of patient counseling and guidance regarding the  IVF/ICSI  procedures and the number of embryos to transfer. It includes reproductive medicine specialists, gynecologists, obstetricians, reproductive nurses, embryologists and neonatologists.

- Methods

A comprehensive search for guidelines was undertaken to identify the most relevant guidelines to consider for adaptation.

Inclusion/exclusion criteria followed in the search and retrieval of guidelines to be adapted: 

The following characteristics of the retrieved guidelines were summarized in a table:

All retrieved Guidelines were screened and appraised using AGREE II instrument (www.agreetrust.org) by at least two members. the panel decided a cut-off point or rank the guidelines (any guideline scoring above 50% on the rigor dimension was retained)

These Guidelines were adapted mainly from” performing the embryo transfer: a guide” Practice committee of the American Society of Reproductive medicine 2017,“1ESHRE guidelines: number of embryos to transfer during IVF/ICSI” developed by the ESHRE guideline group on the number of embryos to transfer in 20242 and “Guidance on the limits to the number of embryos to transfer” developed by the Practice Committee of the American Society for Reproductive Medicine and the Practice Committee of the Society of Assisted Reproductive Technology in 20213.

According to WHO handbook for Guidelines we used the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to assess the quality of a body of evidence, develop and report recommendations. GRADE methods are used by WHO because these represent internationally agreed standards for making transparent recommendations. Detailed information on GRADE is available on the following sites:

Table 1 Quality of evidence in GRADE

- Recommendation

1.Number of embryos transferred

It is recommended that clinicians should perform single embryo transfer (strong recommendation- high grade evidence) ^4,9

Conditions of compulsory eSET

●  Medical SET is indicated for women in whom multiple pregnancy represents an a priori increased risk compared to the overall population such as women with congenital uterine anomalies (e.g. septate uterus), bad obstetric history (e.g. previous premature birth <32 gestational weeks) and severe systemic diseases (e.g. insulin-dependent diabetes).(strong recommendation- high grade evidence) ^4,9

Preimplantation genetic testing (PGT)

PGT and particularly PGT-A is associated with a higher implantation rate regardless of the age, and double euploid embryo transfer may be associated with a higher MPR.^5.6 Low- to moderate-quality evidence shows that eSET of euploid embryos minimizes the risk multiple pregnancies without affecting LBR.^7,8 The ASRM guideline recommends the transfer of one euploid embryo regardless of the female’s age.⁹

Conditions of preferred eSET with a maximum of two embryos allowed

Good prognosis patients include:

● In FET cycles, the decisions should be based on the age of the woman when the embryos were cryopreserved. (strong recommendation- high grade evidence) ^4,9 .

2.Ultrasound guided embryo transfer

Trans-abdominal  ultrasound guidance during embryo transfer is recommended as it improves clinical pregnancy rate and live-birth rate. (strong recommendation- high grade evidence ) ^35,36 .

One of the most critical steps in the process of in vitro fertilization (IVF) is the embryo transfer. Studies have consistently demonstrated that embryo transfer pregnancy rates differ depending upon the clinician performing the procedure³¹.

Three randomized controlled trials compared TV-US versus TA-US ^32,34comparing 93 TV-US and 93 TA-US, found no differences in implantation rates, clinical pregnancy rates and live birth rates between the two approaches.

The patient should attend the ET procedure with a full bladder. This straightens the angle between the uterine cervix and uterine body ^35,36 and facilitates visualization using the transabdominal US scan. A straighter cervical canal and smaller inclination of the uterine body facilitate the effortless insertion of an ET catheter into the correct spot in the uterine cavity ³⁷. It was suggested in a large study by ³⁸ that performing ET with a full bladder increases the clinical pregnancy rate.

3. Type of catheter

● It is  recommended to use a soft embryo transfer catheter as it improves the pregnancy rate in fresh and Frozen cycles. (strong  recommendation- high grade evidence ) ^39,41

NB. Soft catheter is defined as any embryo transfer catheter with a soft inner catheter. 

The pooled data of two randomized control trials and two cohort trials showed that pregnancy rates are higher using soft catheters for embryo transfer compared with firm catheters (RR 1.36, 95% CI 1.16–1.59) ^39,41.No soft embryo transfer catheter is clearly superior and that commercially available soft catheters perform similarly. Personal choice and cost can guide differential use of one soft catheter over the other (ASRM practice committee 2017) Data not enough to recommend a certain type of soft catheters.

4. Anesthesia during transfer

●  Anesthesia during embryo transfer  does not improve pregnancy rates. Given that there are added risks associated with anesthesia, routine anesthesia is not recommended in IVF-embryo transfer. ( strong recommendation -high grade evidence ) ^{42 .}

Large cohort study conducted by vander Van and colleagues 1988, showed a pregnancy rate of 18% in the embryo transfers without anesthesia, and 19% in the embryo transfers with anesthesia. In this larger comparison, general anesthesia did not have a beneficial impact on pregnancy rate ⁴².

5. Site of embryo placement

● It is recommended to place  the catheter tip in the upper or middle (central) area of the uterine cavity, greater than 1 cm from the fundus as this decreases embryo expulsion and optimizes pregnancy rates. (Conditional recommendation -moderate grade evidence ) ^44,45.

Avoiding touching the uterine fundus is one of the most important factors leading to a successful transfer. However the depth of the catheter inside the uterus and how far from the fundus should the embryo should be placed in the uterus was the subject of 4 randomized trials ^43,46 . Coroleu et al 2002 ⁴³ studied  a total of 180 consecutive patients undergoing ultrasound-guided embryo transfer were randomized to three study groups according to the distance between the tip of the catheter and the uterine fundus at the moment of the embryo deposition in the lumen of the endometrial cavity: group 1: 10 +/- 1.5 mm; group 2: 15 +/- 1.5 mm; group 3: 20 +/- 1.5 mm. the pregnancy rate higher in group 2 and 3 .Again in 2015 the same finding were found by Kwon et al ⁴⁵, Francoet al 2004⁴⁴ in a randomized controlled study found no difference in implantation rate and pregnancy rate when the embryo was placed in  the upper vs lower half of the endometrial cavity . while Kwon et  al 2015⁴⁵ found no difference whether it was put  2 cm from the fundus vs the uterine cavity midpoint .

Abdelmassih et al 2007⁴⁷studied the effect of introducing the outer sheath inside the cavity and found that leaving the sheath outside the internal os increases the pregnancy rate.

6. Antibiotics before embryo transfer

● It is not recommended to prescribe antibiotics with embryo transfer. (conditional  recommendation - moderate grade evidence )⁴⁹.

350 patients were randomized  by  Brook et al 2006 ⁴⁸ to receive either prophylactic antibiotics or no antibiotics. The antibiotic used was amoxicillin and clavulanic acid on the day before and the day of transfer. The catheter tips were cultured after the transfer. While the antibiotics significantly reduced catheter contamination rates, the clinical pregnancy rates between the two groups were not different.

Kroon et  al 2012⁴⁹ performed systematic review and found no additional data to  justify using antibiotic therapy before transfer with respect to increasing the life birth rate.

In women with symptoms of infection, it is recommended to perform specific microbiological testing and take appropriate actions ⁵⁰.

7.  Bed rest after transfer

Bed rest is not recommended after embryo transfer as it does not increase pregnancy rates (Strong recommendation- high grade evidence) ^51,52.

Meta Analysis included 14 studies, none of them showed any benefit of bed rest of any duration. Three RCTs between 1997 and 2004 included 712 patients randomized to different periods of bed rest and showed no benefit of any of the following durations: 1 hour vs 24 hours (N1⁄4378), 20 minutes vs 24 hours (N1⁄4182), and immediate ambulation vs 30 minutes (N1⁄4152) .⁵¹

In contrast to the studies that have shown no benefit, one well-designed recent RCT demonstrated possible harm . Two hundred-forty patients undergoing their first IVF cycle were randomized to either 10 minutes of bed rest or immediate ambulation. This study demonstrated that the live-birth rates were significantly (P=.02) higher in the no bed rest group (56.7%) when compared to 10 minutes of rest (41.6%)⁵².

8. Removing mucus from the cervical canal

▪  No enough evidence to recommend routine removal of cervical mucous from the cervix before embryo transfer (conditional recommendation -very low grade evidence ) ^53,55

Removing the cervical mucus might prevent clogging of the catheter tip , retraction of the embryos or displacing the mucous inside the uterine cavity which might affect the implantation . However manipulating the cervix can increase uterine contractility which decreases implantation ^53,55.

Moini et al 2011 ⁵³did a randomized trial on mucous aspiration prior to ET. Five hundred patients were included and a significant difference was found both in the pregnancy rate and delivery rate (39vs 22% and 33.6 vs 17.4).However Craciunas et al 2014 ⁵⁴ compiled eight RCTs involving 1,715 women which were systematically analyzed. A meta-analysis from the available moderate to low quality trials provides very little evidence of an overall benefit of cervical mucus removal before embryo transfer for women undergoing IVF/ICSI.

A Cochrane review on cervical mucous flushing prior to ET by Derks et al 2009 did not find any improvement in pregnancy rate with flushing⁵⁵.

9. Timing to remove the catheter after deposition of the embryos.

▪  There is No specific time to recommend removal of   the embryo transfer catheter after embryo transfer. (conditional recommendation-moderate grade evidence) ⁵⁶

After deposition of the embryo there is evidence from one randomized trial that there is no difference between immediate withdrawal or waiting for 30 seconds  (Martiniz et al 2001)⁵⁶.

Similarly cohort study by Soroga et al 2010⁵⁷ found no difference between waiting 60 seconds versus immediate withdrawal

- Clinical indicators for monitoring

We recommend a strict follow up number of embryos transferred. Also follow up of the documentation of the reason for transferring more than one embryo.

➡️Update of guideline

This guideline will be updated whenever there is new evidence

➡️Research gaps:

There is a need to perform research on the prevalence of multiple pregnancy in Egypt following ART and ovulation induction and to follow up these dates after implementation of these guidelines .

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