TMC FERTILITY CENTRE

Risks and Complications of Infertility Treatment

Dr Surinder Singh
Consultant Obstetrician & Gynaecologist
Infertility & Reproductive Medicine Specialist
Women needing infertility treatment &
ART are generally healthy, yet exposed to
serious medical risks. For fertility
disorders confined to the man, the woman
assuming those risks may be entirely
normal.
 Types of Adverse Events in ART

1. Generic risks with all invasive procedures

- Hemorrhage, damage to adjacent organs, infection

2. Specific treatment used in ART

- OHSS, multiple pregnancies, placentation disorders

3. Personal characteristics of women undergoing ART

- VTE, Cytogenetic AEs, Uterine malformations
AEs Unique to ART

• OHSS
• Multiple pregnancy
• Placentation Disorders
•preeclampsia
AEs Due To Personal Characteristics
• VTE
• Cytogenetic AEs
•Fragile X premutation – fragile X mental retardation
•Turner Syndrome – rupture of aorta in pregnancy

• Uterine malformations
•Previous scar/ fibroids - eSET
 Complications
____________________________________________________________________

• OHSS
• Perinatal morbidity – PE, SGA, IUGR, LBW
• Ectopic pregnancies
• Preeclampsia
• Multiple pregnancies - DT & monozygotic twins
• Birth Defects
• Complications following OR
 OHSS Risk Factors
______________________________________________________________________________________________________________________________________________________________

Foll. factors increase the risk independently for developing OHSS:

• Young age (< 30 years)

• Low body weight
• Polycystic ovary syndrome (PCOS)
• Higher doses of exogenous gonadotropins
• High absolute or rapidly rising serum E2 levels (>17,000 pmol/l)
• Previous episodes of OHSS
• Elevated baseline AMH / high AFC
• Large no of oocytes collected (>25)

Whelan JG 3rd , Vlahos NF. Fertil Steril 2000;73:883-96

Navot D, Am J Obstet Gynecol 1998;159:210-5
Haning RV Jr, Fertil Steril 1983;40:31-6
 Clinical Presentation
Mild • Mild abdominal pain
• Abdominal bloating
• Ovarian size usually <8cm
Moderate • Moderate abdominal pain
• Nausea +/- vomiting
• Ultrasound evidence of ascites
• Ovarian size 8-12cm
Severe • Clinical ascites (usually hydrothorax)
• Oliguria
• Haemoconcentration haematocrit >45%
• Hypoproteinaemia
• Ovarian size <12cm
Critical • Tense ascites or large hydrothorax
• Haematocrit >55%
• White cell count >25,000/ml
• Oligo/anuria
• Thromboembolism
• Acute respiratory distress syndrome
Clinical Practice Guideline
Ovarian Hyperstimulation Syndrome (OHSS) Diagnosis and Management
Version 1.0, Guideline No. 9, Date of Publication: April 2012, Revision date: April 2014
Current clinical guidelines and summary of the most recent evidence
for OHSS prevention strategies

OHSS Prevention Strategy Findings based on current evidence Level of evidence

Decreasing exposure to Chronic low dose (OI); limited obvarian stimulation (OI);
Ib, 2a, 2b, 4
gonadotropins mild stimulation protocol (IVF); no FSH on day of hCG.

Decreases risk of severe OHSS, reduces incidence of OHSS

GnRH antagonist hospital admissions, reduces the need for secondary 1a
interventions such as coasting or cycle cancellation.

Reduced dose hCG for Appears to reduce risk of severe OHSS but large RCTs
2a
triggering ovulation needed

Avoiding hCG for LPS Approximately half the risk of OHSS with P for LPS vs. hCG 1a

IVM Promising , but no data on OHSS prevention available. -

Reduces risk of OHSS in women with PCOS undergoing OI

Insulin-sensitizing agents or IVF; may reduce risk of moderate/severe OHSS in normal 1a, 2a
responders.

Humaidan. Prevention strategies for OHSS. Fertil Steril 2010

Current clinical guidelines and summary of the most recent evidence
for OHSS prevention strategies
OHSS Prevention Strategy
Cycle cancellation
Coasting
Alternative agents for
triggering ovulation: GnRHa
Recombinant human LH
Cryopreservation of all
embryos
Antagonist salvage
Findings based on current evidence Level of evidence
Almost eliminates risk of OHSS; in nonsuppressed cycles,
ovulation may still occur and ensuing pregnancy could lead to 4
the development of late OHSS.
Appears to reduce, but not eliminate, the incidence of severe
OHSS in high-risk patients compared with expected values;
1a
no placebo-controlled RCTs; optimal criteria and protocols
remain to be determined.
Very significant reductions in incidence of OHSS in high-risk
1b
patients compared with hCG.
Appears to be effective in reducing the incidence of OHSS,
but associated with poor outcomes and high costs; not 1b
commercially available.
Insufficient evidence available. 1a
Appears to halt the development of severe OHSS; as effective
1b
as coasting.
Humaidan. Prevention strategies for OHSS. Fertil Steril 2010
Current clinical guidelines and summary of the most recent evidence
for OHSS prevention strategies

OHSS Prevention Strategy Findings based on current evidence Level of evidence

Albumin Does not appear to be effective. 1a

Hydroxyethyl starch Appears to reduce the risk of moderate and severe OHSS. 1b

Results are variable and negative drawbacks of this approach

Follicular aspiration 1a
not trivial; cannot recommend.

No literature on the effects of aromatase inhibitors on

Aromatase inhibitors -
incidence or severity of OHSS.

Superior to placebo at reducing incidence of OHSS in high-risk

Dopamine agonists 1b
patients byt does not eliminate the risk.

Conflicting results; may be effective when used at an early

Glucocorticoids 2a
stage of ovarian stimulation.

Humaidan. Prevention strategies for OHSS. Fertil Steril 2010

Oocyte number as predictor for OHSS & live
birth: an analysis of 256,381 IVF cycles
Objective: To investigate the association between oocyte number and the rates of ovarian
hyperstimulation syndrome (OHSS) and live birth (LB) in fresh autologous in vitro
fertilization (IVF) cycles.
Main Rates of OHSS and LB were calculated fir each group. A generalized estimating equation
Outcome (GEE) was used to assess differences in OHSS and LB between groups. Receiver
Measure operating characteristic (ROC) curves were used to evaluate oocyte number as predictor
of OHSS and LB.
Result The LB rate increased up to 15 oocytes, then plateaued (0-5:17%, 6-10:31.7%; 11-
15:39.3%, 16-20:42.7%; 21-25:43.8%; and >25 oocytes: 41.8%). However, the rate of
OHSS became much more clinically significant after 15 oocytes (0-5:0.09%; 6-10:0.37%;
11-15:0.93%; 16-20:1.67%; 21-25:3.03% and >25 oocytes: 6.34%).

Conclusion
Retrieval of >15 oocytes significantly increases OHSS risk
without improving LB rate in fresh autologous IVF cycles.

Ryan G. Steward, MD
Fertil Steril 2014:101:967-73
 What makes them split? Identifying risk factors
that lead to monozygotic twins after IVF
Objective To identify the incidency, risk factors and obstetric/perinatal outcomers associated with
monozygotic twins (MZTs) after IVF.
Design Nested case-control
Result(s): Of 6,223 gestations, 131 MZTs were diagnosed (2.1% incidence, 2% in autologous and 2.7%
in donor IVF cycles), 10 were dichorionic and 121 were monochorionic. Controlling for all
risk factors, young oocyte age, extended culture (noncleavage embryos transferred
on/after day 4) , and year of IVF treatment cycle were significantly associated with MZT.
When assessing factors associated with specific MZT placentation,d day 3 assisted hatching
correlated more with dichrorionic MZT, whereas extended culture and advanced day 5
embryonic stage correlated with monochorionic MZT.
Conclusion After IVF the incidence of MZT is high, with young oocyte age, year of
treatment and extended culture conferring greatest risk. ART procedures may
influence the timing of enbryonic splitting (i.e. may be influenced by ZP
manipulation whereas later splitting may occur during delayed implantation).

Jaime M. Knopman
Fertility and Sterility Vol. 102, No. 1 July 2015
Birth defects in children conceived by IVF & ICSI: a
meta-analysis
Objective: To conduct a meta-analysis of studies assessing the effect of IVF and intracytoplasmic sperm
injection (ICSI) on birth defects.
Patient(s): Patients treated by IVF and/or ICSI.

Result(s): Of 925 studies reviewed of eligibility, 802 were excluded after screening titles and abstracts,
67 were excluded for duplicated data, data un-available, or inappropriate control group, 56
were included in the final analysis. Among the 56 studies, 46 studies had data on birth
defects in children conceived by IVF and/or ICSI (124,468) compared with spontaneously
conceived children. These studies provided a pooled risk estimation of 1.37 (95% confidence
interval [CI]; 1.26-1.48), which is also evident in subgroup analysis. In addition, 24 studies
had data on birth defects in children conceived by IVF (46,890) compared with those by ICSI
(27,754), which provided an overall no risk difference.

Conclusion Children conceived by IVF and/or ICSI are at significantly increased

risk of birth defects, and there is no risk difference between
children conceived by IVF and/or ICSI.

Juan Wen, B.S

Fertility and Sterility Vol 97, No. 6 June 2017
 FIGURE 2

Individual risk ratio estimates and pooled ratio estimates from the studies relating IVF and ICSI children compared with spon taneously conceived
children. Abbreviations as in Fig. 1. *Weight from random effects analysis.
Wen. ART and the risk of birth defects: a meta-analysis. Fertil Steril 2012.
 FIGURE 3

Individual risk ratio estimates and pooled risk ratio estimates from studies relating birth defects in children conceived by IVF compared with ICSI.
Abbreviations as in Fig. 1. *Weight form random effects analysis.
Wen. ART and the risk of birth defects: a meta-analysis. Fertil Steril 2012.
 Congenital Abnormalities
1. Subfertility (Time-to-Pregnancy > 1 Year) – HR1.29 to 1.01
2. Ovulation Induction and IUI – 3.5 vs 2.8 (control) vs 4.2 (ART)
3. Clomiphene Citrate – Neural tube defects & hypospadias
4. ART – 30 to 40% increase risk of malformations
5. IVF Versus ICSI – No difference
6. Blastocyst Culture – increased risk by 33 to 43%
7. FET – No difference.
(a) Slow freezing
(b) Vitrification
Anja Pinborg, M.D.
Fertility and Sterility Vol . 99, No.2 February 2013
Fresh versus frozen transfer
• Ectopic pregnancy

•OHSS – 100 fold increase in VTE

• Dysfunctional placentation
• Decreased IR
• Preterm delivery
• Preeclampsia
Fresh vs. Frozen
• Fresh embryos have higher incidence of LBW & SGA
compared to frozen
Shih W, Hum Reprod 2008
Wang YA, Fertil Steril 2005
Henningsen AK, Fertil Steril 2011
Kaira SK, Obstet Gynecol 2011
Kallen B, Fertil Steril 2005
Nakashima A, Fertil Steril 2012
Maheshwari A, Fertil Steril 2012
Aytoz A, Hum Reprod 1999
Wikland M, Hum Reprod 2010

• Fresh: COH, Anaesthesia, OPU→ Affects endometrial

receptivity, implantation and early pregnancy.
Shih W, Hum Reprod 2008

• Supraphysiological E2 levels with fresh ET

Kalra SK, Obstet Gynecol 2011
 Perinatal morbidity after in vitro fertilization is lower
with frozen embryo transfer
Objective: To study the association of perinatal outcome and IVF transfer type in group of
infertility patients with standardized treatment and similar prognosis.
Result(s): The final sample included 340 pregnancies: 218 fresh and 122 frozen ETs. Singleton
pregnancy was less likely after transfer of fresh embryos (odds ratio [OR} 0.39, 95%
confidence interval [CI] 0.23-0.67), and pregnancies after fresh ET were more likely to
end in first-trimester (OR 1.82, 95% CI 1.05-3.13). Composite adverse outcome after
transfer of fresh (44.0%) versus frozen (32.6%) emrbyos are higher (OR 1.52, 95% CI
0.90-2.56) and was strongly associated with twin gestation (OR 23.82, 95% CI 11.16-
50.82).

Conclusion(s): Perinatal morbidity is higher in IVF pregnancies conceived

after a fresh ET compared with a frozen ET. Although some
differences are related to conception with twin gestations,
these findings suggest that adverse outcomes may be
related to differences in IVF procedures.

Suleena Kansal Kalra, M.D.

Fertility and Sterility Vol . 95, No.2 February 2011
 Ectopic pregnancy after IVF: diff btw fresh and
frozen-thawed cycles
Objective: To evaluate whether the uterine environment is associated with the risk of
ectopic implantation by comparing outcomes of fresh and frozen-thawed
embryo transfer.
Result(s): Among 103,070 cycles that resulted in a clinical pregnancy, 1.38% were
ectopic. The odds of EP were 65% lower in women who had a frozen
compared with a fresh transfer in autologous cycles. Donor-oocyte transfers
had lower odds of EP compared with autologous cycles, with no differences
between fresh and frozen donor transfer. Women who had both a fresh and
a frozen transfer with autologous oocytes had a higher risk of EP in their
fresh cycles compared with their frozen cycles.
Conclusion(s): Embryo transfers in cycles without ovarian hyperstimulation,
such as frozen or donor cycles, were associated with lower
rates of EP compared with fresh autologous cycles,
suggesting that a difference in the tubal-uterine
environment contributes to abnormal implantation after IVF.

Laura Londra. M.D.

Fertility and Sterility Vol. 104, No. 1 July 2015
Low birth weight: is it related to
assisted reproductive technology
or underlying infertility?
Laxmi A. Kondapalli, M.D., M.S.C.E, a and Alfredo Perales-Pucalt, M.D. b
Section of Reproductive Endocrinology and Infertility, University of Colorado Denve, Anschutz Medical Campus, Aurora
Colorado; and Department of Obstetrics and Gynecology, La Fe University Hospital, Valencia, Spain
 Low Birth Weight
• Ovarian Stimulation
- Supraphysiological estradiol levels
- Toxic effect on embryo → Impaired Implantation
- Decrease duration of endometrial receptivity
- Impair uterine gene expression
Ma et al
Proc. Natl Acad Sci USA 2003

- Not replicated in human studies

- PAPPA → Implantation Impairment
- SGA
- IUGR
- LBW
Embryo Culture Media
- Gene expression for maintenance of pregnancy
influenced by culture environment.
Duranthan et al. Reproduction 2008

- Culture media can influence DNA methylation → Decreased IGF2

- 60% reduction in body weight in mice.
- Demonstrated in placentas and cord blood of IVF infants
- Adipocyte development
LBW
- Insulin signalling
Doherty AS. Biol Reprod 2000
Suzuki J Jr, BMC Dev Biol 2009
Shi X, Eur J Obstet Gynecol Reprod Biol 2011
DeChiara TM, Nature 1990
Katari S, Hum Mol Genet 2009
Dumoulin JC, Hum Reprod 2010
Nelissen EC, Hum Reprod 2012
Vergouw CG, Hum Reprod 2012
Multiple mechanisms have been proposed as potential etiologies for low birth weight (LBW) in assisted
reproductive technology (ART). Ovarian stimulation, maternal characteristics, and subfertility may act through an
impairment of the embryo or endometrial quality. The impairment in the endometrial quality may result in
placental associated defects. The culture medium and the stage of embryo development at transfer may act via the
embryo quality. The number of embryos transferred may act through the vanishing twin hypothesis causing
suboptimal implantation. The impairment of the embryo quality can result in either an insult to its implantation
potential or its development potential.