IVF made easy

By
Prof Mohamed Yehia
MD FRCOG
• IVF is becoming the main form of assisted reproduction utilized to help the
couple to have a child .
• The number of children born by IVF and ICSI had exploded during the past
few years.
• Up till now more than 8 million babies have been born by this technique .
• Based on CDC’s 2017 Fertility Clinic Success Rates Report, there were
284,385 ART cycles in the United States during 2017, resulting in 68,908 live
births (deliveries of one or more living infants) and 78,052 live born infants in
the U.S., approximately 1.7% of all infants born in the United States every year
are conceived using ART.
• In some countries about 5% of the population are born by IVF.
The Growth of IVF1‒10 Total PubMed Hits for “IVF” in
1,200 Title/Abstract by Year

Number of Cycles (thousands)

1,000
Number of Countries

800

600

400

200

0
1982 1986 1990 1994 1998 2002 2006 2010

 2005: 418,111 cycles

 2006: 458,759 cycles
 Increase of 40,648 cycles (+9.7%)
IVF = in vitro fertilization.
1. Nygren KG et al. Hum Reprod. 2001;16:384‒391; 2. Nygren KG et al. Hum Reprod. 2001;16:2459‒2471; 3. Nygren KG et al. Hum Reprod. 2002;17:3260‒3274; 4. Nyboe
Andersen A et al. Hum Reprod. 2004;19:490‒503; 5. Andersen AN et al. Hum Reprod. 2005;20:1158‒1176; 6. Andersen AN et al. Hum Reprod. 2006;21:1680‒1697; 7.
Andersen AN et al. Hum Reprod. 2007;22:1513‒1525; 8. Andersen AN et al. Hum Reprod. 2008;23:756‒771; 9. Andersen AN et al. Hum Reprod. 2009;24:1267‒1287; 10. de
Mouzon J et al. Hum Reprod. 2010;25:1851‒1862.
Physical or Psychological Treatment
Burden Is a Primary Reason for Dropout 1
Among 384 couples undergoing IVF treatment, 65 (17%) dropped out
Reasons for Dropout
Physical or psychological burden of treatment

Unknown

Relational problems/divorce

Ethical objections to ICSI treatment

after failed IVF treatment
Adoption

Poor embryo quality

Poor response/signs of ovarian aging

Other

Percentage
IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection.
1. Adapted with permission from Verberg MF et al. Hum Reprod. 2008;23:2050‒2055.
Dropouts Negatively Impact Real
Cumulative Pregnancy Rates1
• Data from 4,102 IVF cycles in 2,130 women
70

60 Difference between
expected and real
50 pregnancy rates is
Percent

40 caused by the diminishing

size of the cohort due to
30 dropout frequency
20
10 Dropout rate ECPR RCPR
0
1 2 3 4 5 6
(n=2,130) (n=1,087) (n=518) (n=222) (n=74) (n=36)

Cycles

IVF = in vitro fertilization; ECPR = expected cumulative pregnancy rate; RCPR = real cumulative pregnancy rate.
1. Adapted with permission from Schröder AK et al. Reprod Biomed Online. 2004;8:600‒606.
Problems of todays practice of IVF
• The exhausting un necessary investigations .

• The use of huge doses of induction drugs .

• The use of so many adjuvants .

What are the essential investigations before
first IVF:
Female :
1- assessment of ovarian reserve (AMH or AFC)
2-proper assessment of uterus and endometrium.(vaginal ultrasound)
3- may be prolactin and TSH.
Male
Semen analysis .
If nothing in the history or examination is abnormal these are the
necessary investigations before first IVF
Unnecessary investigations :
• Hormonal assay (E2 –inhibin- progesterone ect)
• Immunological investigation ( ANA- CD56-Cd16 – homocyctine –
clotting factors – vit D , genetic make up etc..)
• Hysteroscopy.

• Male : DNA fragmentation –electron microscopy..

Aim Of Controlled Ovarian Hyper
stimulation

• Maximize chances of success.

• Maximize patients compliance.
• Minimize side effects .
• Minimize cost.
• Decreases time to pregnancy.
Antagonist protocol.
E2>1000 pg/ml

HMG

4 16-18mm ET
OPU
3

2 HMG

menses
Day 5 HMG HCG
Long protocol
Mid luteal

HMG

LHRHa
Luteal support
36h 48h

day21 D1 Pick-up Transfer

HCG
E2,LH, U/S
GnRHa vs GnRH ant.
• Same ongoing pregnancy rate
• Shorter duration of stimulation
• Less FSH requirement
Choice of induction protocol
• The data points that both long and antagonist protocol have similar
pregnancy rates .
• OHSS is markedly reduced using antagonists protocol.
• However Lambalk et al 2017 when accounting for patient type and
excluding low and high responder found that the pregnancy rate with
antagonist was lower (odd ration .89 ,95 CI .82-.96) than agonist
protocol.
Premedication with oral contraceptives.
• Pre treatment with estrogen or progestogens is not recommended .
• Pretreatment with both is not recommended for improving results,
however the use of estrogen and progesterone for scheduling is
probably acceptable (ESHRE 2019)
• Oral contraceptive premedication for both the agonist and antagonist
reduces ongoing and live birth rate . OR (.74 , 95 CI .58-.95).Farquher
et al 2017. however ESHRE restricts this recommendation to
Antagonist protocol.
 Dose
• The usual starting dose is 225 IU except in PCO.
• No value of dosage over 450 units .
• A lower dose is probably not also recommended over conventional
dose for normal responder.
• Higher doses of FSH does not improve outcome of IVF (van Tilborg
2017) even in low responders the cumulative pregnancy rate was not
significant when 450 IU were used Vs. 150 IU.
More oocytes means more euploid blastocysts after 24
chromosome analysis
Euploidy rate is consistent across
the number of MII oocytes
retrieved
34,8%

35,2%

27,6%
Colamaria, Ubaldioralpresentation, ESHRE 2015
More oocytes more embryos/blastocysts more cycles with
frozen embryos

• 6-10 oocytes : 40 % cryopreserved embryos

• 16 oocytes : 70 % cryopreserved embryos.
Baker VL et al. FS 2015
cumulative pregnancy rate per OPU
A measure of success in IVF
Vaughan et al., FertilSteril2017
GnRH antagonist cycle and GnRH agonist trigger to almost
eliminate the risk of OHSS
Which preparation
• Recombinant versus urinary gonadotrophin for ovarian
hyperstimulation in ART (A Cochrane review 2011)
• 42 trials more than 9000 couples , there was no significant difference
in live birth rate or OHSS between either types .
• All gonadotrophins are the same , no effect of basal LH on the choice
of preparation . (ESHRE 2019)
• The cheapest drug will do .
• For practical and production purposes we are moving toward rec. FSH
which preparation:
LH containing preparation appears important in
• Low responders .
• Old patients.

In COS, FSH alone results in higher oocyte number. HMG improves the
collection of mature oocytes, embryos, and increases implantation rate.
On the other hand, LH addition leads to higher pregnancy rate. Meta
analysis by Santi D 2017

• Any specific differences are likely to be too small to justify further

research (high quality evidence). (van Wely 2011)
ESHRE guide line 2019
• “According to the best available evidence, the addition of rLH to rFSH
results in similar live birth rates compared to rFSH alone.
• For the general population, or for low responders and women of
advanced age addition of rLH to rFSH is probably not recommended,
• It could be applied in specific patient groups such as WHO-I
anovulatory patients. Further studies would be necessary to
strengthen this conclusion in GnRH antagonist treated patients.
ELONVA™ (corifollitropin alfa) Reduces
the Number ELONVA
of Necessary InjectionsrFSH1,2 hCG

1 2 3 4 5 6 7 8 9 10
GnRH
antagonist
Luteinizing
Hormone

Direct
gonadotropin
suppression

Time
rFSH = recombinant follicle-stimulating hormone; hCG = human chorionic gonadotropin; LH = luteinizing hormone .
1. Adapted with permission from de Greef R et al. Clin Pharmacol Ther. 2010;88:79‒87.
2. Adapted with permission from Hodgen GD. Contemp Rev Obstet Gynaecol. 1990;35:10‒24.
Follicular flushing:
• No improvement in Clinical pregnancy rate .
• No increase in oocyte yield.
• Increase operative time
• More opiate analgesia (moderate quality evidence). (Wongtrangan
2010)
• May be in very low number oocytes (<3).
Monitoring
• The addition of hormonal panel ( E2, progesterone , LH)to ultrasound
monitoring is probably not recommended . It does not seem to affect
the pregnancy rate or the number of oocyte retrieved .

• It is recommended to have a single measurement of endometrium at

the day of triggering or at collection to councel the patient about the
patient of the potential of lower pregnancy rate .
The case for add on(Adjuvants)
• The mean number of medication per cycle prescribed for patients is
around 20 .
• Most if not all are without scientific evidence or at least without
proper randomized controlled trial.
• To make it even wore patients are subjected to invasive procedure
despite the evidence e g scratch , routine hysteroscopy and immune
therapy .
Adjuvants
• Any type of medication that is given during IVF cycle that aim to increase
response and/or improves pregnancy rate .
• The list is endless e.g
Aspirin
Growth hormone .
DHEA
Heparin
Nitric acid
Argenine .
Co Q 10.
Methyl folate.
Immune modulators( steroid ,intralipid).
Aspirin and Heparin
• (Cochrane review 2015)
• 386 women randomized into heparin or placebo no difference in
pregnancy rate or live birth rate.
• More over A Cochrane review in women with unexplained recurrent
miscarriage in 2014 studying 1228 women without thrombophilia
found that neither Aspirin and or Heparin add any benefit .
• Preterm labour , preeclampsia IUGR , were not significantly different
by any treatment regiment.
Growth Hormone.

• Three meta analysis showed that co- treatment with growth hormone
improves the outcome in poor responders .
• It does not increase the number of oocytes so probably the
improvement is mediated by the effect on the quality of oocytes .
• However the increase is small and does not warranty the use of
extremely expensive drug (de Zielger et al 2011)
• The British fertility Society Practice committee does not recommend
its use .
DHEA
• 17 RCT with a total of 1496 participant .
• Initial results showed a moderate increase in live birth rate .
• When Biased trial were removed no longer significance was detected
(Nagels 2015)
• No difference in miscarriage rate .
• The British fertility Society Practice committee does not recommend
its use .
Uterine Natural killer cells in ART(Saks
2016)
• The potential risks and cost of therapy for NKC out weight any benefit.
• The function of these uterine Natutal killer cells are essentially
unknown .
• Despite the lack of knowledge, expensive and dangerous therapies
are introduced without proper trial .
• Healthcare professional and patients should be very careful to
evaluate the use of immuno-modulators to enhance pregnancy
outcome .
conclusion
• IVF is rapidly becoming the primary option of infertility treatment
thus replacing the extensive investigation and surgeries .
• To maximize its potential and reduce the drop out rate it should be
kept simple and only scientifically proven investigation and treatment
is utilized.
• By today evidence only AMH or AFC , Ultrasound and semen analysis
are needed before starting of a cycle .
• Any HMG preparation will do and antagonist protocol is simpler .
• Cumulative pregnancy rate with utilization of frozen embryos should
be the way to used to measure the efficacy of infertility treatment .
Thank you
Using AMH to choose the protocol
Indications
• Male factor .
• Female factor.
• Combined male and female .
• Unexplained .
More Gonadotrophins = worse endometrium
(in fresh transfer)