Risks and Complications of Infertility

8/19/2019 Risks and Complications of Infertility

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TMC FERTILITY CENTRE

Risks and Complications of Infertility TreatmentDr Surinder Singh

Consultant Obstetrician & Gynaecologist

Infertility & Reproductive Medicine Specialist


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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.


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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


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AEs Unique to ART

• OHSS

• Multiple pregnancy

• Placentation Disorders

•preeclampsia


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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


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Complications ____________________________________________________________________

• OHSS

• Perinatal morbidity – PE, SGA, IUGR, LBW

• Ectopic pregnancies

• Preeclampsia

• Multiple pregnancies - DT & monozygotic twins

• Birth Defects

• Complications following OR


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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


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Clinical Presentation

Mild • Mild abdominal pain

• Abdominal bloating• Ovarian size usually 45%

• Hypoproteinaemia• Ovarian size 55%• White cell count >25,000/ml

• Oligo/anuria• Thromboembolism• Acute respiratory distress syndrome

Clinical Practice Guideline

Ovarian Hyperstimulation Syndrome (OHS S) Diagnosis and Management

Version 1.0, Guideline No. 9, Date of Publication: April 2012, Revision date: April 2014


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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

gonadotropins

Chronic low dose (OI); limited obvarian stimulation (OI);

mild stimulation protocol (IVF); no FSH on day of hCG.Ib, 2a, 2b, 4

GnRH antagonist

Decreases risk of severe OHSS, reduces incidence of OHSS

hospital admissions, reduces the need for secondaryinterventions such as coasting or cycle cancellation.

1a

Reduced dose hCG for

triggering ovulation

Appears to reduce risk of severe OHSS but large RCTs

needed2a

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. -

Insulin-sensitizing agents

Reduces risk of OHSS in women with PCOS undergoing OI

or IVF; may reduce risk of moderate/severe OHSS in normal

responders.

1a, 2a

Humaidan . Prevention strategies for OHSS. Fertil Steril 2010


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Cycle cancellation

Almost eliminates risk of OHSS; in nonsuppressed cycles,

ovulation may still occur and ensuing pregnancy could lead to

the development of late OHSS.

4

Coasting

Appears to reduce, but not eliminate, the incidence of severe

OHSS in high-risk patients compared with expected values;

no placebo-controlled RCTs; optimal criteria and protocolsremain to be determined.

1a

Alternative agents for

triggering ovulation: GnRHa

Very significant reductions in incidence of OHSS in high-risk

patients compared with hCG.1b

Recombinant human LH

Appears to be effective in reducing the incidence of OHSS,

but associated with poor outcomes and high costs; not

commercially available.

1b

Cryopreservation of all

embryosInsufficient evidence available. 1a

Antagonist salvageAppears to halt the development of severe OHSS; as effective

as coasting.1b





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Albumin Does not appear to be effective. 1a

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

Follicular aspirationResults are variable and negative drawbacks of this approach

not trivial; cannot recommend. 1a

Aromatase inhibitorsNo literature on the effects of aromatase inhibitors on

incidence or severity of OHSS.-

Dopamine agonistsSuperior to placebo at reducing incidence of OHSS in high-risk

patients byt does not eliminate the risk.1b

GlucocorticoidsConflicting results; may be effective when used at an early

stage of ovarian stimulation.2a





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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

Outcome

Measure

Rates of OHSS and LB were calculated fir each group. A generalized estimating equation

(GEE) was used to assess differences in OHSS and LB between groups. Receiver

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%).

Ryan G. Steward, MD

Fertil Steril 2014:101:967-73

Conclusion Retrieval of >15 oocytes significantly increases OHSS riskwithout improving LB rate in fresh autologous IVF cycles.


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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.

Jaime M. KnopmanFertility and Sterility Vol. 102, No. 1 July 2015

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 ZPmanipulation whereas later splitting may occur during delayed implantation).


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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 spontaneouslyconceived 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.

Juan Wen, B.S

Fertility and Sterility Vol 97, No. 6 June 2017

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

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


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FIGURE 2

Indivi dual risk ratio estimates and pooled ratio estimates from the s tudies relating IVF and I CSI chi ldren compared with spon taneously conceived

chil dren. Abbreviations as i n Fig. 1. *Weight from random effects anal ysis.

Wen. ART and the risk of birth defects: a meta-analysis. Fertil Steril 2012.


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FIGURE 3

Indi vidual risk ratio estimates and pooled risk ratio estimates from studies relating bir th defects in chi ldren conceived by I VF compared with ICSI.

Abbreviations a s in Fig. 1. *Weight form random effects anal ysis.

Wen. ART and the risk of birth defects: a meta-analysis. Fertil Steril 2012.


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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


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Fresh versus frozen transfer

• Ectopic pregnancy

•OHSS – 100 fold increase in VTE

• Dysfunctional placentation• Decreased IR

• Preterm delivery

• Preeclampsia


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Fresh vs. Frozen

• Fresh embryos have higher incidence of LBW & SGAcompared to frozenShih W, Hum Reprod 2008

Wang YA, Fertil Steril 2005

Henningsen AK, Ferti l Steril 2011

Kaira SK, Obstet Gynecol 2011

Kallen B, Fertil Steril 2005

Nakashima A, Fertil Steri l 2012

Maheshwari A, Fertil Steri l 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 ETKalra SK, Obstet Gynecol 2011


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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 berelated to differences in IVF procedures.

Suleena Kansal Kalra, M.D.Fertility and Sterility Vol . 95, No.2 February 2011


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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 transfershad 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 lowerrates 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


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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 Inferti lity, University of Colorado Denve, Anschutz Medical Campus, Aurora

Colorado; and Department of Obstetrics and Gynecology, La Fe University Hospital, Valencia, Spain


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Low Birth Weight• Ovarian Stimulation

- Supraphysiological estradiol levels- Toxic effect on embryo → Impaired Implantation

- Decrease duration of endometrial receptivity

- Impair uterine gene expressionMa et alProc. Natl Acad Sci USA 2003

- Not replicated in human studies

- PAPPA → Implantation Impairment

- SGA

- IUGR- LBW


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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

- Insulin signallingLBW

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


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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 animpairment 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 i ts development potential.

Risks and Complications of Infertility

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