Dr Anju Agarwal

Procedures involved in ART; long and short term complications

Infertility: (n)

A medical condition which diminished self-esteem, your social life, as well as checking and savings account. Causes sudden urges to pee on sticks, cry, scream, and

a fear of pregnancy announcements.

Treated by a medical specialist who you pay to knock you up- this does not always work.

Affects 1 in 10 couples

July 25 1978

•Louise Brown born

•First IVF baby

•Born to Lesley

Brown, bilateral

tubal blockage

•Natural cycle,

single egg

fertilization

Since 1978 after Louise brown, over over five million "test-tube" babies have been born globally!

Advances in IVF

Stimulation drugs

TVS

ICSI

Culture Medium

Freezing Methods

Expansion of Indications

PGS

Efficacy Cost

Safety

Decision – Making Paradigm

2018-19 VARTA report:

Reported complications in 2018-19 VARTA report:

Pre-treatment: Poor selection(Pre-existing risks) Treatment: Stimulation Procedural: Oocyte retrieval – Laboratory phase – Embryo transfer – Luteal phase Post-treatment: Pregnancy (Mother/baby ) Long-term: Woman /child

Ovarian hyperstimulation ( OHSS)

A medical condition characterized by ovarian enlargement. Fluid accumulates within peritoneal, pleural and (rarely) pericardial cavities following treatment with ovarian stimulating drugs, most typically FSH containing preparations.

The action of LH or hCG is required to develop the syndrome.

Aetiology

Usually Iatrogenic- ovarian stimulation

2 types Early onset: related to hCG trigger Late onset: related to ensuing pregnancy

spontaneous FSH receptor mutations

Risk Factors

Polycystic Ovarian Syndrome (PCOS) -- strongest RF OHSS in a previous cycle Low BMI Young age < 30 years E2 > 9000 pmol/L Gonadotropins, high dose Gestation esp. multiples Significant follicular No. > 20

Clinical features of OHSS • Lower abdominal pain and bloating

•Nausea, vomiting and diarrhoea

• Shortness of breath, decreased exercise tolerance

•Vulval and peripheral oedema, ascites and pleural effusions.

•Cerebral Oedema (Confusion)

Complications of OHSS • Deep venous thrombosis (DVT)

• Pulmonary embolism (PE)

• Arterial thrombosis

• Internal jugular vein thrombosis and stroke -dizziness, neck pain, loss of vision

• Renal failure

• Adult respiratory distress syndrome (ARDS)/ Respiratory failure

• Cerebral Oedema

• Ovarian torsion

• Ileus

• Ascites

• Pericardial effusions (rarely)

1/30,000 = mortality •Thromboembolic complications - stroke, PTE •Complications of treatment such as heparin induced thrombocytopenia •Ovarian bleeding

• Cabergoline around the time of hCG administration or oocyte pickup in ART cycles ( moderate -quality evidence). • Intravenous fluids (plasma expanders) around the time of hCG administration or oocyte pickup in ART cycles (very low-quality evidence). • Progesterone for luteal phase support in ART cycles (low-quality evidence). • Coasting (withholding gonadotropins) - a promising intervention that needs to be researched further for reduction of OHSS. (very low-quality evidence

Metformin treatment before and during an ART

cycle for women with PCOS (moderate-quality

evidence).

(GnRH) antagonist protocol in ART cycles

(moderate-quality evidence).

GnRH agonist (GnRHa) trigger in donor oocyte

or 'freeze-all' programs (moderate-quality

evidence).

Results: GnRHa triggering reduces OHSS incidence without compromising oocyte retrieval and

fertilization rates in donor and autologous cycles. However, GnRH-agonist triggering causes a

luteal phase deficiency in autologous cycles, deleteriously compromising pregnancy rates.

Elective embryo cryopreservation overcomes this deficiency, reducing the risk of OHSS and

may improve neonatal and obstetric outcomes.

Conclusions: GnRHa triggering should be considered in all donor cycles. It should also be

selectively considered in autologous cycles in combination with elective cryopreservation of all

viable embryos.

Ovarian torsion

• 0.1% of all IVF pts

• If OHSS 7.5 %

• 2.3 % in nonpregnant women

• 16 % in pregnant women

• High level of suspicion

• R/ Untwisting

T/V EPU or T/V OPU

Standard of care

Ultrasound guidance aspiration of follicles

T/V EPU complications

• Infection – 1/5000, reduced by half with antibiotic • Particularly with endometriomas , hydrosalpinges

• ?Increased with PID

• Injury to other structures • Blood vessel

• Bowel

Complications of TxBx.

• Bleeding

(scrotal hematoma)

• Infection

• Pain

• Unprecedented successful

development of ART which has

revolutionized the

management of severe male

infertility

• The procedure involves the

direct injection of a single

sperm into the egg cytoplasm.

Intracytoplasmic Sperm Injection- ICSI

ICSI

Short term consequences

•Oocyte damage

•Infection

Long term consequences

•Risk of congenital malformations

•long term risks to the fetus

• Imprinting disorders

• Trans-generational passage of male factor infertility? - Y‐chromosome deletion

The ICSI procedure from past to future: a systematic review of the more controversial aspects Patrizia Rubino, Paola Viganò, Alice Luddi, Paola Piomboni Human Reproduction Update 2016, 22 (2): 194-227

Perinatal outcomes Perinatal outcomes of ICSI-conceived singletons are similar to singletons born after conventional IVF. No difference based on sperm source

Congenital malformations

•No increase in major or minor malformations in ICSI newborns. Some small studies have indicated slightly higher rates of major birth defects

• Increased trend towards de novo and abnormal sex chromosomes in ICSI newborns ( some studies)

•No difference based on sperm source

Developmental outcomes

•No differences in physical, psychological and cognitive outcomes between ICSI and NC children until adolescence.

•Studies reporting lower intelligence scores, child behaviour problems or motor development issues are often confounded by the educational level and socioeconomic status of parents, as well as cultural and selection biases

•No difference based on sperm source

Medical health •Medical health of ICSI children - similar to general

population. •Pubertal ICSI girls may be more prone to central, peripheral

and total adiposity ? •Associations between ART and imprinting disorders,

particularly Beckwith–Wiedmann syndrome. • Slightly increased incidence of autism in ICSI children ?

Reproductive health

•Pubertal development is similar between ICSI and NC children. Thelarche maybe lesser in ICSI-conceived girls

•ICSI-conceived men may have lower sperm concentration, total sperm count and total motile sperm count.

•Ovarian reserve parameters are similar. Reproduction (2017) 154 F61–F70

Embryo Transfer

Embryo transfer

Ultrasound control Avoid fundal contact Aim for upper to middle third of uterus

Infection Bleeding Uterine cramps Ectopic pregnancy

Infection Bleeding Uterine cramps Ectopic pregnancy

Ectopic pregnancy

General population (19 per 1000 pregnancies)

Risk of Ectopic Pregnancy

Ectopic pregnancy rate - 1.9–2.1 % for fresh cycles

( similar to NC pregnancies)

The EP rate for FET’s may be even lower.

Decline in the ectopic pregnancy rate :

• a lower number of embryos transferred.

• reduced frequency of tubal corrective surgery.

Risk of Ectopic Pregnancy

GnRHa trigger : independent risk factor for EP - 20%.

Consideration should be given to refraining from fresh transfer altogether and cryopreserving all embryos if triggered with GnRHa.

• Trends in ectopic pregnancy rates following assisted reproductive technologies in the UK: a 12-year nationwide analysis including 160 000 pregnancies. Samuel Santos-Ribeiro, Herman Tournaye, Nikolaos P Polyzos. Human Reproduction 2016, 31 (2): 393-402

• Sahin S, Ozay A, Ergin E, Turkgeldi L, Kürüm E, Ozornek H. The risk of ectopic pregnancy following GnRH agonist triggering compared with hCG triggering in GnRH antagonist ivf cycles. Arch Gynecol Obstet. 2014.

• Weiss A, Beck-Fruchter R, Golan J, Lavee M, Geslevich Y, Shalev E. Ectopic pregnancy risk factors for ART patients undergoing the GnRH antagonist protocol: a retrospective study. Reprod Biol Endocrinol. 2016;14:12.

Multiple pregnancy

•Known complication of ART

. Higher order multiples are clearly associated with adverse neonatal outcomes

FACT : Risks of Multiple Pregnancy Risk Twins Triplets

Average Duration of Pregnancy (Term = 40 weeks) 37 weeks 34 weeks

Proportion of premature low birth weight infants 50% 90%

Neonatal death (1st week of life) 5 x higher 9 x higher

Postnatal cerebral palsy 4 x higher 18 x higher

Maternal pre-eclampsia 3 x higher 9 x higher

Maternal diabetes 2-3 x higher 2-3 x higher

Maternal coronary heart disease 2 x higher 2 x higher

Maternal death from cardiovascular causes 7-11 x higher 7-11 x higher

Maternal death (overall) 2 x higher 2 x higher

Dutch National Registry based study 6,694 after ART Vs 3,276 after NC Overall, maternal and perinatal risks other than those due to multiplicity are similar for twin pregnancies conceived after MAR and after NC

GDM, 1.4 [1.01-2.0] IUGR, 2.7 [1.7-4.3] VLBW, , 6.9 [4.7-10.2] Low Apgar scores 1.9 [1.1-3.3] Perinatal mortality 2.4 [1.2-4.5]

(adjusted odds ratios with their respective 95% confidence intervals) Evron E, Sheiner E, Friger M, Sergienko R, Harlev A. Vanishing twin syndrome: is it associated with adverse perinatal

outcome? Fertil Steril. 2015;103:1209–14.

Vanishing Twin Syndrome

• IVF pregnancies that progress to at least 24 weeks , vanishing twin and singleton pregnancies had similar perinatal and peripartum outcomes. Both were significantly better than twin pregnancies.

• When compared with twins, those with a vanishing twin

had lower odds of preterm delivery and small-for-gestational-age birth weight.

Multiple PR 8% (ANZARD) Vs 20% (HEFA)

SET ; 70% of IVF cycles in Australia VS 31% in UK

Total of 425 360 and 422 003

Preterm birth - singleton

• Increased risk after

ART from 1/14 to 1/7

RR 2 present for

singleton gestation

• ? Iatrogenic

• ?underlying pathologies

e.g. fibroids

(Helmerhorst et al, BMJ 2004;328:261)

Other pregnancy related-

Poorer perinatal outcome: higher rates of caesarean sections, fetal malpresentation. Maternal GDM in pregnancy.

Oocyte donated pregnancy - an independent risk factor for - hypertensive disorders in pregnancy.

Children born after ART had similar cognitive, motor, and language development as children born after natural conception at 2 years of age.

Drugs used for ovulation induction during IVF increase the levels of gonadal hormones- ?? concerns - risk of cancer - breast, ovary, endometrium, and other target organs

Long term Cancer risk

.

JAMA. 2016;316(3):300-312.

This meta-analysis points to a non-deleterious effect of fertility drugs towards the development of uterine cancer.

• 255,786 women who underwent ART in England, Wales, and Scotland between 1991-2010, 386 ovarian cancers were recorded .

• This is a 1/3 greater (15 in 10,000 Vs. 11 in 10.000 ) likelihood of developing ovarian cancer compared to the general population of women.

Sutcliffe A et al. Ovarian Tumour risk in women after assisted reproductive therapy (ART); 2.2

million person years of observation in Great Britain. 71st Annual Meeting of the ASRM O-93.

The study also found that the cancer risk was higher in the first three years after treatment.

• The study also showed that women who underwent ART for non-female infertility did not have an increased risk of ovarian cancer

• This is reassuring, because it suggests that ovarian cancer is not caused by ART per se; however the question of whether the risk of ovarian cancer is associated with the underlying infertility diagnosis and its potential causes yet to be answered.

The study found no increased risk of breast or uterine cancer in the former IVF patients.

Sutcliffe A et al. Ovarian Tumour risk in women after assisted reproductive therapy (ART); 2.2 million person years of observation in Great Britain. 71st Annual Meeting of the ASRM O-93.

Results – • Women who have gone through ART have a higher

risk of ovarian cancer and BOT. • Part of that risk seems to be due to the underlying

infertility and not the treatment per se • As ART treatments are becoming more common

and ovarian cancer usually occur in women of advanced age, larger studies/ longer follow up is needed

17 th June 2019

• Overall, based on 37 studies, which included a total of 4,684,724 women, they did not find enough strong evidence suggesting a potentially higher risk of ovarian cancer in women treated with fertility drugs.

• What are the conclusions?

Infertility has been found to be an important risk factor for ovarian cancer. However, the association between infertility drugs and ovarian cancer needs to be addressed with consideration of other factors such as age, BMI, parity, genetic factors (i.e. family history for ovarian cancer), and aetiology of the infertility, along with longer follow-up times.

Summary

• More than 90% of children born following

ART are healthy and normal

• ART is increasingly used allowing couples

to achieve pregnancies not otherwise

achievable.

• Long term data on the health of ART

children are lacking.

• Long term cancer risk is not established.

Thank you for listening!