Reproductive stuff Flashcards
Definition of infertility
- primary, secondary
- fecundibility
- fecundity
Failure to achieve a clinical pregnancy after 12 months of regular UPSI
In women >35y, use 6 months
Infertility affects 15% of women of reproductive age
ART = IVF + IUI (not OI)
Primary infertility = no previous pregnancies regardless of outcome
Secondary infertility = previous pregnancy regardless of outcome
Fecundibility = probability that a cycle will result in a pregnancy Fecundity = probability that a cycle will result in a live birth
Normal fertility - chances
Couple of reproductive age has a fecundity of 20-25% per cycle
<36y
- ~85% of couples with conceive within 12 months
- 93% after 24 months
If >36y - only 50% pregnant by 12 months
Male history and exam for infertility
Pregnancies fathered Sexual dysfunction Varicocele PMHx / PSHx - Mumps orchitis, undescended testes, inguinal hernia surgery, testicular injury, STI - Major head or pelvic trauma - Chronic illnesses, infections Meds, allergies FHx Occupational exposures Smoking, spa baths, caffeine intake, anabolic steroids, testosterone
General - HR, BP, BMI
Gynaecomastia, hair distribution
Abdominal exam - masses, scars, exam of inguinal area
Reproductive (if semen analysis abnormal)
- Varicocele, testicular volume and consistency
- Palpation of vas deferens
PR - prostate
Investigations for infertility
Ovarian reserve testing
- Measures to predict likely ovarian response to gonadotrophin stimulation in IVF
- Doesn’t reflect fertility
- AMH
- Antral follicle count
Baseline hormonal profile - Day 2-3 LH, FSH, estradiol - Day 21 progesterone Pelvic USS Assessment of tubal factor - HyCoSy - HSG - If high risk - diagnostic lap + dye studies
Preconception bloods
- serology
- blood group and antibiotic testing
Consider endocrine tests - TFTs, prolactin, PCOS bloods
Causes of infertility
Combined - 40%
Male factors -30%
Ovulatory dysfunction - 25%
Tubal factors - 20%
Other (e.g. cervical factors, peritoneal factors, uterine abnormalities) - 10%
Unexplained -25%
Lifestyle modifications for infertility
Couples should avoid smoking, alcohol consumption, recreational drug use
Smoking:
- Women: likely reduces fertility
- Men: association with reduced semen quality
Target BMI 18.5-25
- Weight loss of 10kg in an anovulatory obese patient can restore ovulation in up to 90%
- Men - BMI >30 are likely to have reduced fertility
Folic acid and iodine
Limit caffeine intake to 1-2 cups of coffee - but no consistent evidence that caffeine is a/w fertility problems
Reduce stress
Ovulation tracking
Coital advice
No. of PID episodes and Incidence of tubal infertility
1 – > 12%
2 –> 23%
3 – > 54%
TV USS for Ix of infertility
- pro and cons
Can include 3D USS
Readily available
Less uncomfortable
Tubes are not seen if normal
Doesn’t assess tubal patency
Operator dependent
Hysterosalpingogram (HSG) for Ix of infertility
- pro and cons
Contrast x-ray study
Non-invasive
Outpatient procedure
No need for GA
Relatively low cost
Oil based dye (Lipiodol) –> tubal flushing, but risk of anaphylaxis
Risk of procedure related PID Pelvic radiation Risk of allergy to contrast Uncomfortable No information on ovaries or peritubal pathology
Hysterosalpingo-contrast-sonography (HyCoSy) for Ix of infertility
- pro and cons
Done under ultrasound guidance
90% concordance rate of tubal patency at laparoscopy USS therefore no risk of radiation Best at imaging uterine cavity Good at imaging fibroids Allows detailed gynaecological scanning Non-invasive
False occlusion rate 10-15% - Can get spasm of tube False patency rate 3-5% Risk of procedure related PID Risk of allergy to contrast Uncomfortable
Tubal dye studies during laparoscopy for Ix of infertility
- pro and cons
Methylene blue dye is instilled through the cervix and uterus, and through the fallopian tubes and visualised laparoscopically
Gold standard
Allows full visualisation of both tubes and concomitant treatment of pathology
Invasive procedure
Surgical and GA risks
Cost
No information of uterine cavity
Impact of Hydrosalpinges in fertility
Several reports have described detrimental effect on IVF
Leakage of fluid into cavity may impede implantation by flushing embryos or disrupting endometrium
Fluid contains microorganisms, debris, toxins, cytokines, prostaglandins
Laparoscopic salpingectomy (uni or bilateral) can improve pregnancy rates from IVF - IVF + bilateral salpingectomy - improves LBR (doubled)
Treatment options for tubal factor infertility
Surgery vs. IVF
LBR with 3-5 cycles is 72% vs. tubal surgery is 24%
Need to balance with risk of OHSS and cost and access to IVF
Surgery - Catheter or guide wire (canulation)
- risks of tubal perforation, infection, ectopic pregnancy
Management of unexplained infertility
25% of couples
Clomiphene or letrozole with IUI is superior to expectant management and natural cycle IUI for outcome of livebirth rate in couples with unexplained infertility
- Multiple gestation rate ranges from 0-12.5%
If >/=38y, then immediate IVF may be associated with higher pregnancy rate and shorter time to pregnancy
If <38y, consider 6 months expectant management or limited course (typically 3-4 cycles) of OS with IUI
- If unsuccessful, IVF is recommended
Semen analysis instructions
One abnormal parameter on its own is not a predictor of infertility
Presence of multiple abnormalities has more clinical relevance
Recommended >2 samples are examined
2-5 day period of abstinence prior to producing sperm sample
Ensure sample collected and stored correctly - cool environment, to lab for processing within 1h
If abnormal, given lifestyle advice and retest in 3 months (Production of sperm takes ~3/12)
Lower reference range limits of sperm parameters
Semen volume - 1.5ml
Total sperm numbers - 39 million spermatozoa per ejaculate
Sperm concentrations - 15 million spermatozoa per ml
Total motility - 40%
Progressive motility - 32%
Sperm morphology - 4% normal forms
Vitality - 58%
Extended investigations if abnormal semen analysis
FSH, LH, testosterone (early morning)
- low test, high FSH+LH –> karyotype
- Hypogonadotropic hypogonadism - do prolactin
- if all normal and azoospermia - evaluate for obstruction
TFT
Genetic tests
- Karyotype (Klinefelter - small firm testes)
- Y chromosome analysis for microdeletions
- CFTR gene mutation - if congenital bilateral absence of vas deferens
Urine sample post ejaculation - to assess for retrograde ejaculation
Ultrasound - scrotal and transrectal
- Presence of testicles and appearance
- Presence of vas deferens
- Additional structures - mass, hydroceles, varicocele
Causes of azoospermia (or oligo)
Pre-testicular (hypogonadotropic)
- Androgen intake
- Pituitary tumours (craniopharyngioma)
- Head trauma, surgery, irradiation
Testicular (~60% of azoospermia cases)
- Undescended testis
- Torsion / Injury / trauma
- Neoplasm / Post-chemotherapy
- Klinefelter syndrome
- Microdeletions of Y chromosome
- Autoimmune- anti-sperm antibodies associated with vasectomy reversal
- Drugs - anabolic steroids, marijuana, alcohol
- Environmental exposures - to heat, radiation, chemicals
Obstruction
- Infective - mumps
- Post-vasectomy
- CBAVD
Disorders of sexual function and / or ejaculation interfering with intromission
- Retrograde ejaculation
- Anejaculation, e.g. spinal injury
- Drugs - anti-depressants, anti-hypertensives
Reversible factors for poor semen analysis:
Smoking Alcohol Heat Solvents (painters, decorators) Lead
Tight clothing / underwear
NICE: Association between elevated scrotal temperature and reduced semen quality, but uncertain if loose-fitting underwear improves fertility
Retrieval of sperm
Testicular sperm extraction (TESE)
- Management of obstruction azoospermia
- Outpatient procedure with LA
- extract seminiferous tubule tissue
Percutaneous epididymal sperm aspiration (PESA)
- Free sperm is aspirated
Clomiphene citrate (Clomid) - Mechanism of action
Selective estrogen receptor modulator
Blocks ER in hypothalamus –> blocks negative feedback effect of circulating estradiol –> increased GnRH pulse frequency –> increased secretion of FSH (and LH)
Clomiphene treatment regime
Can induce withdrawal bleed with progesterone prior if needed
- either spontaneous or induced bleeding
Clomiphene for 5 days from day 2-5
- Typically start day 5, but outcomes comparable
Starting dose 50mg
Ovulation occurs 5-10 days after the last tablet
- Couple advised to have sex every other day
Monitor at least the first cycle with combination of serial USS and serum progesterone levels
Urine pregnancy test 4 weeks post-clomiphene
Subsequent cycles:
- If ovulation occurs, keep dose the same
- if doesn’t, increase to 100mg, then 150mg
6 cycles without pregnancy but ovulation occurs = clomiphene treatment failure
Clomiphene
outcomes and risks
60-85% ovulation rate
30-50% pregnancy rate
- Thought this lower rate due to negative impact that clomid has at endometrium and mucus, Acts primarily as an antiestrogen in the uterus, cervix, vagina
Multiples 5-7%
Risks
- OHSS <1%
- Limit lifetime usage to 12 cycles - risk of borderline ovarian tumours
Side effects
- Hot flushes
- Headaches
- Eye effects
- N/V
Infertility management in PCOS
Clomiphene or letrozole first
If failed or resistant, and anovulatory with no infertility factors, then gonadotrophins or laparoscopic ovarian drilling
If no pregnancy but ovulating –> IVF
Aromatase inhibitors
- mechanism of action
Letrozole
- First line in PCOS
inhibiting the conversion of circulating androgens to oestrogens –> reduced negative feedback –> increased FSH
Shorter half life compared to Clomid
Not teratogenic
Safe and very effective in OI (better than clomiphene)
- No data to suggest cancer risk so far - unlikely given very different mechanism of action to clomiphene
Aromatase inhibitors
- Regime
2.5mg for 5 days on days 2-6
- Increase dose if don’t ovulate to 5mg, then max 7.5mg
Careful instruction and tight monitoring
Generally not more than 6 months
Aromatase inhibitors
- outcomes
Better mono-ovulation rate, less multiple pregnancies
Cochrane 2018 - aromatase inhibitors for ovulation induction in PCOS
- Better live birth rate and pregnancy rates compared with clomiphene (27.5% vs. 19.1%)
- No difference in OHSS rates
Similar effects to laparoscopic ovarian drilling
Metformin
- Mechanism of action
and outcomes
Insulin sensitising agent
Increased insulin mediated uptake by liver and smooth muscle
In PCOS the aim is to reduce hyperinsulinaemia
Used as adjuvant treatment
- Hasn’t been shown useful as OI alone
Cochrane - metformin for OI in women with PCOS 2019
- Metformin may be beneficial over placebo, but more women probably experience GI side effects
With clomiphene citrate
- Inferior to CC
- BMI <30 - added to CC –> increased pregnancy rate and reduced miscarriage rates with no change to live birth rate
Laparoscopic ovarian drilling (LOD)
- mechanism of action
Not clear, but hypothesised that get decreased production of androgens due to stromal damage
- Serum LH and testosterone fall, FSH rises
Make 4 holes in ovary with diathermy, only need to do on one side (from RCT findings)
Outcomes and risks of ovarian drilling
Consider as second line therapy in PCOS, if clomiphene resistant with anovulatory infertility and no other infertility factors
May result in singleton birth in women
No convincing evidence of inferiority over other methods of OI
No increased risk of multiples
No risk of OHSS
ISSUES
Cost
Expertise required for use in ovulation induction
Intra-operative and post-operative risks are higher in women who are overweight and obese
May be a small associated risk of lower ovarian reserve or loss of ovarian function
Peri-adnexal adhesion formation may be an associated risk
Gonadotrophins for OI
- mechanism of action
- outcomes
- issues
Recombinant FSH (rFSH) - FSH only for PCOS LH and FSH for hypogonadotropic hypogonadism Direct stimulation of ovaries
Overcomes negative endometrial impact of clomiphene
RCT - higher pregnancy and LBR compared to clomiphene
Highly successful in inducing ovulation (>95%)
Issues
- Cost
- Requires surveillance - bloods and USS
- More involved
- Expertise required
- Increased multiple pregnancy rate (15%)
- Increased OHSS rate
OI and cancer
Nulliparity doubles the risk of ovarian cancer
Subfertile women who later give birth do not have an increased risk of ovarian malignancy
Available evidence does not suggest a link between OI drugs and ovarian cancer
Possible weak link with borderline ovarian tumours in later life
- Limit CC to 6 months
Complications of ART
Ectopic pregnancy - rate 1-4% with IVF
Acute complications
- Cyst accidents
- Intra-operative injury
- OHSS
- Infection
- Psychological effects
Pregnancy complications
- GDM
- Poly- or Oligohydramnios
- Multiple pregnancy - MC pregnancy rates 0.9-2% vs. 0.4% for spontaneous conceptions
- PTB
- Low birth weight
- Risk of abnormalities of placentation - abruption, praevia, Vasa praevia
- Gestational HTN
- PPH
- VTE
Complications for the child of ART
Congenital defects
- 30-40% increase in risk of major congenital abnormalities compared to normally conceived children
- Risk greater than for ICSI than IVF
Long-term adult disease - diabetes, HTN
Neurodevelopmental outcomes are similar
Prediction of IVF success
Overall LBR per embryo transfer 27.3%
Change of live birth following IVF treatment falls with rising female age
from 4th cycle chance of live birth falls as the number of unsuccessful cycles increases
IVF is more effective in those who have previously been pregnant, particularly those who have had a live birth
BMI ideally 19-30
>1 unit of alcohol/day reduces effectiveness
Maternal or paternal smoking can adversely affect success rates
Ovarian reserve based on AFC or AMH
Hydrosalpinx - associated with poor implantation and low pregnancy rates and early pregnancy loss
Submucosal fibroids - decrease the change of success
Endometrial polyps - uncertain, reasonable to remove prior
Endometriosis - prolonged down-regulation with GnRH agonist 3-6 months prior to IVF improves clinical pregnancy rates
Steps in IVF treatment cycle
- Pre-treatment evaluation
- Controlled ovarian stimulation using gonadotrophins and GnRH analogues (agonists or antagonists)
- Monitoring follicular development using TV-USS +/- serum estradiol levels
- Oocyte maturation using hCG
- Egg collection and sperm production or sperm recovery
- Fertilisation (IVF / ICSI) and subsequent embryo culture
- Fresh embryo transfer into the uterus and cryopreservation of surplus good quality embryos
- Luteal support through progesterone administration
Pros and cons of short over long protocol for IVF
Shorter treatment duration
- Convenient for patients
Avoidance of pituitary down regulation
Lower risk of OHSS with similar rates of fertilisation
On average, one less egg obtained per woman per oocyte collection
Long protocol - 2-3 weeks of down regulation before hand
Brief description of short protocol for IVF
Meds are started at the start of the menstrual cycle in which IVF is performed
Gonadotropins (rFSH) administered in early menstrual phase (cycle day 2)
GnRH antagonists are administered from cycle day 6
- to prevents premature LH surge
Trigger injection is administered to induce final maturation of the oocytes
- Given when 2 or more leading follicles measure 17-19mm
Recombinant hCG GnRH agonist (reduces OHSS by >80%)
Oocyte collection is arranged 36h after trigger
Oocyte retrieval risks
1/1500 overall risk of serious complication:
Pelvic infection
- Increased in patients with endometriosis
- no evidence prophylactic antibiotics reduces this risk
Bleeding
- Usually from the vaginal epithelium
- Rarely from the iliac vessels
Fertilisation of oocyte
IVF
- ~100,000 sperm added to each egg
- Embryo culture from fertilisation to blastocyst stage (usually day 5, sometimes day 6)
- Fertilisation, as determined by the presence of two pro nuclei (2 PN), is assessed at 20 hrs post-insemination
ICSI outcomes
Fertilisation rates for ICSI are 60-70%
IVF gives better fertilisation results than ICSI in couples with non-male subfertility
Pregnancy rates after IVF and ICSI are not significantly different
Steps of IUI
If doing ovulation induction:
- Oral anti-estrogens taken for 5 days
- If gonadotrophins used, sc injections are given for 7-10 days
USS is used to monitor response
- Want 1-3 suitably sized follicles with one dominant follicle
Injection of hCG to trigger ovulation
Insemination of prepared sperm sample 24-36h after hCG trigger injection
- If 2-3 ovulatory follicles present, insemination not undertaken to reduce risk of multiple pregnancy
Embryo cryopreservation
Vitrification = Ultra-rapid cooling
- Survival >90%
- Can be stored indefinitely in liquid nitrogen
Preimplantation genetic testing
In NZ, publicly funded if >25% chance of being affected by serious inherited genetic disorder
Indications
- Advanced oocyte age - Reduces risk of miscarriage or baby born with aneuploidy
- Chromosomal structural rearrangements
- Monogenic disease risk reduction
Incidence of OHSS
Mild OHSS occurs in 33% of ART cycles
Severe requiring hospitalisation in 0.3%
Pathophysiology
of OHSS
Systemic disease resulting from vasoactive products released by hyperstimulated ovaries
production of proinflammatory cytokines
Increased capillary permeability
Leakage of fluid from vascular compartment
Third-space fluid accumulation
Intravascular dehydration
Investigations in OHSS
FBC (haematocrit) Albumin - low LFTs - may be elevated U&Es - hyponatraemia, hyperkalaemia Creatinine CRP Serum osmolality (hypo-osmolality) Coagulation profile HCG USS
OHSS more commonly associated with
Patient factors
- Young age
- PCOS
- Diabetes
- Previous OHSS
- Conception
- Increased in multiple pregnancy
- Increased AFC
- High levels AMH
Treatment factors
- High follicular phase LH
- High-dose gonadotrophin stimulation regimens
- Use of GnRH analogues > antagonists
- Multiple follicular response
- High serum estradiol levels during treatment
- Exposure to hCG (as trigger)
- Number of oocytes retrieved in IVF - Risk increases with increasing number
Strategies to lower the incidence or severity of OHSS
Using low-dose stimulation protocols, or natural-cycle IVF
Follicular monitoring
Utilising GnRH antagonist cycles (short protocol)
Utilising progesterone instead of hCG for luteal support
Abandoning ART cycles prior to hCG administration and oocyte collection if too many follicles
Delaying embryo transfer following collection and elective freezing of all embryos
Metformin for PCOS patients
Routine single embryo transfers
Coasting - hCG trigger is withheld until serum estradiol levels have returned to acceptable levels
Cabergoline (dopamine agonist) may be used to reduce OHSS incidence in high risk women
Classification of severity
Mild OHSS - Ovarian size usually <8cm3
Severe OHSS
- Clinical ascites (+/- hydrothorax)
- Oliguria (<30ml/h)
- Haematocrit >0.45
- Hyponatraemia, Hyperkalaemia (>5 mmol/l)
- Ovarian size usually >12cm3
Critical OHSS
- Tense ascites / large hydrothorax
- Oliguria / anuria
- Thromboembolism
- ARDS
- Haematocrit >0.55
- WCC >25 000/ml
Outpatient Management
of OHSS for mild or moderate OHSS, select severe OHSS
Self-limiting in the majority of women (resolves over a period of 7-10 days)
Give verbal and written info, contact details
Avoid injury to enlarged ovaries (e.g. strenuous physical activity, sex)
Drink to thirst rather than set amount (>1L/day)
To reduce VTE risk, mobilise and avoid strict bed rest
Ideally record fluid input-output
Daily weight
Avoid NSAID
Review every 2-3 days unless signs / symptoms of worsening OHSS
Hospital admission should be considered::
- Are unable to achieve satisfactory pain control with simple analgesics
- Intractable vomiting
- Are unable to maintain adequate fluid intake due to nausea
- Show signs of worsening OHSS despite outpatient intervention
- Are unable to attend for regular outpatient follow up
- Have critical OHSS
- Need IVF, analgesia
- SOB
- hct >0.45, electrolyte disturbance
Inpatient management of OHSS
MDT
Monitoring
- Body weight, abdo girth, fluid balance - daily
- FBC, hct, serum electrolytes, osmolality, LFTs - daily
Fluid management
- Encourage oral fluids
- UO - aim >30-50ml/hr
Analgesia
- Paracetamol, oral opiates
- NSAIDs contraindicated
VTE prophylaxis
Paracentesis of ascitic fluid :
- Severe abdominal distension and pain
- SOB and respiratory compromise
- Oliguria despite adequate volume replacement, secondary to increased abdo pressure –> reduced renal perfusion
Consider IV colloid therapy for women who have large volumes of fluid removed by paracentesis
Pelvic USS if suspect torsion
CPAC Criteria
Exclusion criteria: - Female age >40y - Male age >55y - Either partner current smoker - Female BMI >32 If stored embryos from a previous private IVF cycle, these embryos must be used, before a further publicly funded IVF cycle is initiated CPAC threshold 65 points Up to two packages of care available - 1 package could be 4x IUI or 1x IVF cycle Current wait time ~12-15 months for IVF
