ART: Management of associated conditions

1. Aboubakr Elnashar
ART:
Management of
associated
conditions
Aboubakr Elnashar
Benha University, Egypt

2. I. Medical
1. Habits
2. Psychology
3. PCOS
4. Obesity
5. DM
6. Thyroid disease
7. Hepatitis
8. SLE
9. Thrombophylia
10. Heart disease
11. Hyperprolactinaemia
II. Surgical
1. Endometrioma
2. Hydrosalpinges
3. Fibroid & polyp
4. Cervical stenosis
5. Uterine problems
Aboubakr Elnashar
ASSOCIATED CONDITIONS

3. I. MEDICAL CONDITIONS
1. HABITS
Smoking:
 ↓ conception rate &↑abortion and Gnt dose
 stop before IVF.
Caffeine:
 use ≤ 2mg (one cup of decaf coffee): No deleterious
effect
Aboubakr Elnashar

4. 2. PSYCHO-SOCIAL ASPECTS
Stress, anxiety, and depression
linked to lower IVF outcomes
Psychological intervention improves success
(Sanders et al.1999; Klonoff-Cohen 2001; Smeenk et al.2001; Domar et
al. 2000)
Aboubakr Elnashar

5. 3. OBESITY
Decrease: CPR , LBR
Increase: miscarriage rate, duration and dose of
Gnt
(Rittenberg et al, 2011)
33 studies including 47,967 tt cycles
Unethical to refuse to accept a patient solely
because she is obese
(ACOG, 2014)
Violation of Articles Human Rights
12 (Right to marry and found a family)
14 (Prohibition of discrimination).
Aboubakr Elnashar

6. Before starting IVF cycle:
1. Above 35y: tt rather than unsuccessful
attempts to lose wt. {Age stronger negative effect on
oocyte number, number of mature and fertilized
oocytes, CPR and LBR }(Sneed et al., 2008).
2. Counseling
unbiased manner, avoiding blame and maintaining her
dignity
Impact of: raised BMI on IVF outcome
 wt loss on IVF tt outcome.
 raised BMI on pregnancy
Wt loss should be encouraged
3. Informed consent: I wish to proceed under these
circumstances
Aboubakr Elnashar

7. Management
Preconceptional
Screen for:
DM and optimization of glucose control
Thyroid disease.
Healthy diet and lifestyle
Prenatal vitamins
Aboubakr Elnashar

8. Weight loss:
1. Hypo-caloric diet:
2. lifestyle changes, Exercise program
3. Pharmacologic agents Orlistat (Xenical):
4. Bariatric surgery
 Metformin: not a wt loss drug
 Gonadotopins dose: Increased after exclusion of
PCOS
Aboubakr Elnashar

9. 4. PCOS
Patient preparation
I. Counseling and information
 increased obstetric risk (gestational diabetes, PET and
fetal morbidity) if overweight.
 Potential problems as OHSS and multiple pregnancy.
II. Evaluation:
Screen for DM
III. TT of associated condition:
Cessation of smoking, Weight reduction
IV. Preventive TT:
Doxycyclin: 100mg 1x2x7d., Diflucan or Flucoral one caps.
Flagentyl 4 tablet
Folic acid 0.5mg. Aspirin 75mg /day are continued
Prevention of OHSS in PCOS:
Metformin: given in the period prior to ART
LOD

10. CHOICE OF GONADOTROPINS
Type:
No difference in outcome between ovarian
stimulation with hMG preparations or urinary derived
FSH, in studies using the long protocol of GnRH
desensitization.
(MA: Agrawal et al. 2000)
No significant clinical differences between hMG
and rFSH.
(Nugent et al., Cochrane Data base Syst Rev 2000; van Wely et al, 2003)
hMG, uFSH, and r-FSH: equally effective for
achieving pregnancy in PCOS.
(Al-lnany et al.,2005)

11. STIMULATION PROTOCOLS
GNt dose:
low dose in either a long protocol, or short GnRHa
protocol
50–150 IU
depending on age and other factors
Protocols
1-GnRHa
(Griesinger et al., 2006)
2-GnRHan
(Griesinger et al., 2006)

12. Short or ultra short agonist protocol
should not be proposed
{initial flare-up effect could lead to an excessive
ovarian response}.
Metformin
{reduce risk of OHSS}
(dose 850mg twice daily from the start of
down-regulation to the day of OR).
History of severe OHSS
GnRHan and use a single-shot of agonists for final
oocyte maturation.

13. MONITORING RESPONSE TO STIMULATION
US and E2
1. US: Evaluate whether the dose of GnT is adequate or
not.
1st US
 D4 Stimulation
In PCO
 D 5 or 6 stimulation
In normal responder
Number: 6-8 each ovary
 With diameter: 11- 12 mm Aboubakr Elnashar

14. US in day of HCG
 High risk of OHSS
 Number of follicles >20
 Number of small & intermediate size (10-14 mm)
>15
 No risk of OHSS
 immature follicles are < 15.
{Number of the immature follicles is more important
than the number of mature follicles in predicting
OHSS.
Aboubakr Elnashar

15. 2. E2:
Level:
<1000 pg/ml: No OHSS
>3000-4000 pg/ml: HCG should be withheld
<3500 pg/mL: No OHSS (Asch et al 2005)
3500-5999 pg/mL: 1.5%
6000 pg/mL: 38%
Slope:
Cases with severe OHSS are seen with E2 <1500
pg/ml.
slope of rise of E2 is more accurate (considered if
the value is doubled).
Aboubakr Elnashar

16. Do not trigger ovulation with the intention of fresh
ET in women who have:
E2>3500 pg/ml or
>20 follicles on US
(NICE, 2013)
Aboubakr Elnashar

17. HOW TO TRİGGER THE OVULATİON
1.Decrease HCG dose:
As low as 3300 IU
as low as 2500 IU is effective in PCOS.
(Kashyap et al.,2010)
2000 IU: ineffective, lower successful oocyte recovery
(Kashyab et al, 2010).
does not prevent OHSS
(Kol, Dor, 2009)
There is no clear published evidence that lowering HCG
dose will result in a decrease in the rate of OHSS. (III)
2-GnRHa trigger
-0% incidence of OHSS
(Humaidan et al.,2011)

18. PREVENTION OF OHSS
The incidence of severe OHSS:
significantly higher in PCOS (15%) compared with
normal ovaries (3%).
(Swanton et al., 2010)

19. Primary prevention
1. Prediction of OHSS from history, exam, and US
2. LOD in PCOS
3. Metformin in PCOS
5. Low-dose Gnt in PCOS
6. GnRHan protocol
7. Rec LH to trigger ovulation
8. GnRHa to trigger ovulation
9. IVM of oocytes
10. Replacement of only one embryo
(Rizk B., 2006)
Aboubakr Elnashar

20. 2ndry prevention
1. Withholding hCG ± continuation of GnRHa/GnRHan
2. Coasting or delaying hCG: currently most popular method
3. Use of GnRHa to trigger ovulation
4. Follicular aspiration
5. Cryopreservation and replacement of frozen–
thawed embryos at a subsequent cycle
6. Progesterone for luteal phase
7. Dopamine agonist
8. Albumin: administration at time of retrieval
9. Glucocorticoid administration
10. Aromatase inhibitors
Rizk (2006)
Aboubakr Elnashar

21. 5. DM
 Female:
Preconception counseling
Wt loss and optimal BMI
Tight glycemic control
Risks of miscarriage and teratogenicity
Optimize HBA1c before the start of ART:
If on statin therapy: check serum lipids and stop tt during
ART and pregnancy
COS:
Will affect glycemic contol {change in hormonal milieu and
stress}: check and maintain
OR:
Antibiotics and thromboprophylaxis (if indicated)Aboubakr Elnashar

22. Men
Optimal BMI: control DM, improve ED and T levels
Check androgen status
TT of ED: phosphodiestrase inhibitors
If on statin therapy: {can reduce T levels} check
serum lipids, if normal: stop temporarily
Aboubakr Elnashar

23. 6. THYROID DISEASE
 Before ART:
 First treat hypothyroidism or hyperthyroidism
 Normal menses restored
(Poppe et al, 2007).
 Carbimazole or methimazole: PTU
 Monitor/4w: FT4 at upper 1/3 of normal range
 L-thyroxine tt in Normal TSH before ART
1. Positive TPOAb, and history of miscarriage or
hypothyroidism.
2. TSH is greater than 2.5 mIU/L
(Am Ass of endocrinology, 2013, Grade B)
Aboubakr Elnashar

24. ART in hyperthyroid-treated women:
PTU may need to be reduced
{ increased thyroxine requirements}
TFT should be checked during COS
once PT is +ve
/2-4 w
FT4: upper 1/3 of normal range
Aboubakr Elnashar

25. ART in hypothyroid-treated women:.
LT4 dosage should be increased
1. To obtain TSH < 2.5 mIU/L before COS
{latter procedure increases TH demands}.
2. AITD treated with LT4 and developed OHSS
{E2 increase sharply and markedly:
severe hypothyroidism (TSH, 42 mIU/L)
{Association between OHSS and AITD}.
:increase daily LT4 dosage 4 wk before starting the COH
(Poppe et al, 2008)
3. Pregnancy:
Spontaneous: 30%
After COS: 32% (Davis et al., 2007)
Aboubakr Elnashar

26. 7. SLE
How to promote and safeguard fertility
In SLE
1. CYC
Lowest effective dose
Shortest duration
Gonadal protection if risk of therapy-induced POF.
use a different disease-modifying and steroid-sparing
therapy e.g. Mycophenolate mofetil MMF (Cellcept)
Fertility is more likely to be preserved if
Age ≤ 30 ys
IV pulse course of CYC lasts ≤ 6 months
Cumulative dose ≤ 7 g
No changes in the menstrual cycle during tt
Aboubakr Elnashar

27. 2. Prevention of POF
a. GnRha: leuprolide.
protective against POF when administered
10-14 d before each CYC pulse.
Leuprolide: reduction in E and P levels
:reduce the risk of POF from 30 to 5%
[Somers et al,2005].
Aboubakr Elnashar

28. b. Oocyte storage.
Cryopreservation of gametes before gonadotoxic tt
Aboubakr Elnashar

29. 3. IVF.
Ovarian stimulation using GnRHa:
1. increase levels of oestrogens: increase the risk
of thrombosis
Thrombosis often occurs in the context of overt
OHSS
2. Flare
Aboubakr Elnashar

30. Avoid ART
{high risk of complications for mother and fetus during
pregnancy & puerperium}
1. SLE manifested in acute flares
2. Badly controlled arterial hypertension, pulmonary
hypertension
3. Advanced renal disease
4. Severe heart disease and major previous
thrombotic events
 Before ART:
1. Disease has been silent for at least 6 months
2. BP
3. Urine analysis
4. RFT
5. Pulmonary hypertension to be ruled outAboubakr Elnashar

31. During ART:
1. Ovarian stimulation
 Aggressive should be avoided
 low effective Gnt dose
 Mild ovarian stimulation {avoid high E2}.
Anti-oestrogens (CC or aromatase inhibitors)
 Avoidance of OHSS & multiple pregnancy
2. OR:
If Heparin: to be stopped 12-24 h prior to OR & restarted
6-12 h after
3. ET:
Single
4. Luteal phase support:
Natural P through a non-oral route
{avoid OHSS and first passage effect in liver}
(Huong et al. 2002; Askanase and Buyon 2002; Bellver , 2012)Aboubakr Elnashar

32. APA, Hx of thrombosisAPA, No Hx of
thrombosis
SLE, No APA
1. Warfarin is switched to
heparin therapeutic dose
before ov stim.
2. Heparin to be stopped 12-24
h prior to OR & restarted 6-
12 after
3. Heparin to be continued till
day of preg test & if pregnant
to continue during
pregnancy
4. Aspirin low dose to be added
, but to be interrupted 5-7 d
before OT
1.Heparin:
prophylactic dose
from day of ET
2. Aspirin:
unproven
1. Anti coagulation is not
recommended
2. Anti-inflammatory
(Corticosteroids or
immunosuppressant) to
be introduced or
increased
5. Prophylactic therapy
 Anticoagulant: for thrombosis
 Corticosteroids or immunosuppressant: for lupus
activity) during and after ovarian stimulation
(Huong et al, 2002)
Aboubakr Elnashar

33. 8. HEPATITIS
Hepatitis B
 ICSI:
 in male HBV carriers: safe
 in female HBV carriers: no enough evidence that
it is safe {HBV DNA chromosomal integration is a
potential risk}.
 Risk of vertical transmission is not different from
spontaneous pregnancy.
Aboubakr Elnashar

34. Positive for HBsAg and HBeAg in the absence of
Post Exposure Prophylaxis (PEP): (MMWR 2005)
- 70%-90% of infants get infected
Positive for HBsAg only:
<10% of infants infected
HBV DNA < 108 copies/mL= 0% transmission
HBV DNA > 108 copies/mL= 32% transmission
Viral load should be followed and IVF should be
started at a time of low viral load
(Lutgens et al, 2009)
Aboubakr Elnashar

35. Prevention
Precautions to prevent lab transmission of
infection during sample handling and embryo
cryostorage
When either of the partener is HbsAg, HbeAg and
/or HBV DNA +ve: other partner to be vaccinated
HBV vaccine:
For health care workers, uninfected partners,
people at risk
Immunoprophylaxiis: when the child is born from
HBV positive woman
Aboubakr Elnashar

36. Hepatitis C
Effects on the ovarian response: controversial
Some: no effect
Others: poor ovarian response, increased HMG dose
alteration of granulosa cell function}
Poor IR, PR,
Effect on pregnancy outcome: No effect
In ICSI
Risk of vertical transmission is not different from
spontaneous pregnancy.
Aboubakr Elnashar

37. Risk of V. transmission is enhanced by:
1. High level of HCV RNA titers:
> 106 copies/ml: 36%
<104 copies/ml: No transmission
The viral load should be followed, and IVF to start at low
level of viral load
Vertical transmission (%)Serostatus of the mother
<1HCV RNA-HCV Ab+
11HCV RNA+HCV Ab+
16HCV RNA and HIV Ab+HCV Ab+
Aboubakr Elnashar

38. ICSI:
Safe in seropositive men and women {HCV RNA
cannot integrate into the human chromosome
{virus lacks reverse transcriptase activity}
Prevention:
Precautions to prevent lab transmission of
infection during sample handling and embryo
croystorage
No HCV vaccine available
No immunoprophylaxis is available
Aboubakr Elnashar

39. II. SURGICAL
1. ENDOMETRIOMA
Check: previous surgical or medical tt , ORT
Avoid surgery:
previous history of surgeries
reduced ovarian reserve
If ≥4 cm and surgical tt is not planned:
GnRHa for at least 3 consecutive months before IVF
During OR:
Avoid puncturing or drainage of endometrioma
Give IV antibiotics
Aboubakr Elnashar

40. 2. HYDROSALPINX
Prior to starting IVF:
Salpingectomy
Tubal occlusion
During ovarian stimulation
TV aspiration at OR
Freeze all embryos, surgery for HS and the freeze-thaw
cycle
Laparoscopic salpingectomy should be considered for all women with
hydrosalpinges prior to IVF
(Cochrane Systematic Reviews 2008 )
Occlusion of the proximal tube seems to be equally effective
US guided aspiration of hydrosalpinges during OR improves PR (20
v43%)
(Hammadieh et al , 2008)
Aboubakr Elnashar

41. 3. UTERINE FIBROIDS
Myomectomy
1. SM
2. IM distorting endometrial cavity or ≥5 cm
UAE:
infertility is a relative contraindication
Reproductive outcome is less favorable with UAE
than myomectomy
Aboubakr Elnashar

42. 4. CERVICAL STENOSIS
History
previous surgery
difficult or painful cervical instrumentation
Mock ET
Before the start of IVF to identify cases and plan
action
1. Cervical dilatation:
 at the start of IVF cycles: ET easier and increase PR
{allow time for the endometrium to recover from any trauma,
inflammation or bacterial contamination resulting from
dilatation at time of OR}
at the time of OR: ET easier but does not increase PR
Aboubakr Elnashar

43. 2. Osmotic cx dilatation:
Hygroscopic rods (Dilapan)
Inserted in cx for 4 hours (day 4) in the stimulation
phase
(Serhal et al, 2003)
Laminaria tents for 24 h either at OR or early in
stimulation phase
(Mains et al, 2010)
Aboubakr Elnashar

44. 3. Tramsmyometrial ET: Towako method
Under TVS guidance
overcome the most difficult or impossible cases {bypass the
cervix}: PR similar to easy transcervical transfers
 The echogenic line represents the needle equipped with an
embryo transfer catheter protruding into the uterine cavity.
Aboubakr Elnashar

45. Aboubakr Elnashar

46. 4. Tubal ET:
an alternative in cases with normal fallopian tubes
but requires laparoscopy and GA
5. Hysteroscopic canalization of the cervix:
only for cases associated with amenorhea or
significant dysmenorhea
Operative hysteroscopic shaving of the cx to create
a new canal
(Pabucca et al, 2005)
Aboubakr Elnashar

47. Aboubakr Elnashar