Ovulation induction - rheumatology.org.aurheumatology.org.au/downloads/Ovulationinduction_KateFranklyn2012.pdfOvulation induction (OI) OI is the method used to treat anovulatory infertility

Ovulation induction Kate Franklyn

ARA Vic Torquay 2012

Outline

What are ovulation induction(OI) and Assisted Reproductive techniques(ART)?

What are the indications for ovulation induction?

Why is this relevant to rheumatologists?

Causes of infertility in Autoimmune Diseases

What is the role of hormones in the pathogenesis of autoimmune diseases?

Do fertility treatments aggravate/precipitate autoimmune disease?

Do autoimmune diseases alter outcomes in fertility treatments?

Ovulation induction (OI)

OI is the method used to treat anovulatory infertility.

Ovulatory disorders can be identified in 25-30% of couples who present with infertility(1)

Most present with oligomenorrhoea

OI is targeted at inducing monofollicular development and ovulation. This is different to stimulation of multiple follicles used in assisted conception techniques such as IVF.

All of these terms are described under the umbrella term Assisted Reproductive Techniques (ARTs)

1. Hull et al, Polulation study of causes, treatment and outcome of infertility. BMJ 1985; 291:1693

Infertility

In western societies rates of infertility approaches 10-20%

30/30/30 rule: Male/female/mixed

Causes of infertility:

Ovulatory disorders (25-30%)

Tubal disease (25%)

Rx usually surgery: 30-60% achieve pregnancy within one year.

Infection, prev surgery, congen defects, prev ectopics

Endometriosis (10%).

5% all females affected ; 30-40% of patients with endometriosis are infertile.

Abnormal Uterus (10%)

Ie fibroid, polyps, and adenomyosis may lead to obstruction of the uterus and Fallopian tube.

Unknown 10-20%

Indications OI

Patients eligible for ovulation inductions belong to either world health organisation(WHO) group II or II of anovulation

WHO I: hypogonadotrophic hypogonadism anovulation or ‘ hypothalamic amenorrhora’

5-10%

Causes: Stress, exercise, anorexia nervosa, congenital GnRH deficieny (Kallmann Synd), hypopituitarism

WHO II: normogonadotrophic normoestrogenic anovulation

~70%

most have PCOS

Treat with LOW first as this tends to restore spontaneous ovulation

Indications OI - cont

WHO III: hypergonadotrophic hypoestrogenic anovulation

10-30%

Primary ovarian insufficiency ie absence of ovarian follicles due to early menopause

Typically these patients do not respond to ovarian stimulation.

Hyperprolactinaemic Anovulation

5-10%

Prolactin inhibits gonadotrophic and therefore oestrogen secretion

Causes: anti-psychotics, primary hypothyroidism, pituitary tumours.

What sort of ARTs are available?

Ovulation Induction

Anti-Oestrogens

Gonadotrophic Therapy

Pulsatile GnRH therapy

Dopamine Agonists

Laparoscopic Ovarian Diathermy

IVF +/- donor oocytes

Future treatments:

Insulin sensitisers in PCOS

Aromatase inhibitors

Anti-Oestrogens

Mechanism unclear:

Thought to occupy oestrogen receptors in the hypothalamus and pituitary, thereby blocking negative feedback action of oestradiol.

The body thinks it is oestrogen deficient prompting a rise in FSH/LH.

stimulation of follicle growth and

follicular oestradiol production.

Plasma estradiol levels reach 6-10x the average concentration in nonpregnant women.

Messinis et al, Ovulation Induction a mini review. Human Reproduction 2005; 2688-2697

Anti-Oestrogens

Clomiphene Citrate

First Line for: normogonadotrophic anovulatory women (PCOS).

Tamoxifene

Possible less efficacious and more SE’s.

Monitoring is required as dose titrated to produce ovulation.

Outcomes:

60-85% of anovulatory women ovulate in response to clomifene.

Of the ovulators 30-40% conceive

SE’s :

twins 8% (gen popln 2%),

birth defects / ectopics : no change

Some studies indicate risk ovarian cancer increased after 12 cycles of clomiphene therapy

Most likely just an association, but underlying infertility causeal.

Risk Ovarian HyperStimulation Syndrome <1%


Ovarian HyperStimulation Syndrome (OHSS)

Life threatening complication of ovulation induction

Massive ovarian enlargement with multiple cysts and third space accumulation of fluid.

Haemoconcentration

ARF, hypovolaemic shock, VTE, ARDS, & Death.

Gonodadotrophin Therapy

Indications:

First line: Class I (stress) with hypopituitarism

Second line: Class II (PCOS) (failed anti-oestrogen)

Step 1: Recombinant Follicle Stimulating Hormone(rFSH)

To promote ovulation, a transient increase in serum FSH occurs at the beginning of the cycle. The concentration is then decrease to prevent more than one follicle maturing. This varies from person to person and so dosing is not uniform and monitoring must be carefully undertaken.

Step 2: Human chorionic gonadotrophin (hCG) is then given to trigger ovulation when the ovarian follicle is mature.


Gonodadotrophin Therapy

Outcomes:

Live birth rate 50-60%.

Using classic clomifene + Gonadotrophic therapy over 24mths live birth rate ~71%

Multiple pregnancies 30%

OHSS ~1%

Ovarian Ca – similar association to clomiphene

Pulsatile GnRH therapy Pulsatile administration of GnRH using an infusion pump

stimulates the production of endogenous FSH and LH more closely able to mimic endogenous production and therefor reduce the risk of SE’s.

minimising risk OHSS

Indication

hypogonadotrophic hypogonadal anovulation (Class I) who have normal pituitary function.

Iv or sc with a pulse every 60-90mins.

Outcomes: ovulation rate 90%, pregnancy 96% after 6 cycles.

Multiple pregnancies: 2-17% quoted


Dopamine Agonists

Dopamine agonists enhance the tonic suppression of prolactin synthesis and release from the pituitary, substituting for or supplementing endogenous dopamine.

Bromocriptine & cabergoline.

Indication: Hyperprolactinaemic anovulation.

Bromocriptine appears least teratogenic, but should be stopped immediately once pregnancy established.

Outcome: 80% ovulate, 70% pregnancy rate

Assisted reproductive techniques (ARTs)

Laparoscopic Ovarian Diathermy PCOS

IVF for patients failing the above.

For IVF (9), oocytes are surgically retrieved after an OI protocol, by ultrasound-guided transvaginal puncture. The extracted oocytes (which may number 20 or more) are fertilized in vitro by any one of several techniques and then reimplanted in the patient or her surrogate. Exogenous progesterone is usually administered to support the resulting pregnancy.

OI protocols in this scenario used considerably higher dosese as they aim to produce multiple follicles.

IVF with donor oocytes for Class III (primary ovarian failure)

Summary slide, Class & Rx

WHO I: hypogonadotrophic hypogonadism anovulation

‘ hypothalamic amenorrhora’

Ie SLE flares.

Clomiphene as first line – however, most will not respond

Pulsatile GnRH as second line (or first line if accessible)

Gonadotrophin therapy as third line

WHO II: normogonadotrophic normoestrogenic anovulation

Clomiphene first line +/- metformin in PCOS

Gonadotrophin therapy as second line

WHO III: hypergonadotrophic hypoestrogenic anovulation ‘ early menopause’

Ie cyclophosphamide.

IVF with donor oocytes

Hyperprolactinaemic Anovulation

Ie SLE flares

Dopamine agonists

Where are we up to?





Do autoimmune diseases/treatments cause infertility?

Causes of infertility in Rheumatology

Disease related

Most extensive data available on SLE

Anovulation occurs during disease flares SLE / chronic renal failure

Increased incidence of endometriosis in autoimmune disease theory that pro-oxidant apoptotic endometrial cells trigger auto-antibody production

Endometriosis SLE 0.8% vs 0.04%; RA 1.8% vs 1.2% (1)

Secondary Anti Phospholipid Syndrome

Treatment related

Cyclophosphamide premature ovarian failure

NSAID’s Unruptured follicle syndrome

? PNL and MTX

(1)Sinaii N, Cleary SD, Ballweg ML, Nieman LK, Stratton P. High rates of autoimmune

Infertility SLE

General consensus that patients with SLE have normal fertility rate, however….

1. 10% of couples worldwide suffer infertility; one study found SLE contributes to 1% of infertile patients(1)

SLE affects ~1 in 2000 adult women (0.002%)

Small sample size, one patient with SLE had male infertility issues too.

2. There is a known drop in the pregnancy rate once SLE is diagnosed (2)

Multifactorial – may just be an association

3. There are numerous causes of infertility secondary to SLE and its treatment.

1.J Rheum 2011 Causes and management of infertility in systemic lupus erythematosus Hickman 2. Fraga A, Mintz G, Orozco H. Fertility rates, fetal wastage and maternal morbidity in SLE. J Rheumatol 1974;1: 2938.

Nephritis and infertility

Lupus nephritis affects between 30 and 75% of patients with SLE depending on the nature of the cohort studied (1).

Chronic renal failure infertillity

hypothalamic/pituitary dysfunction.

raised prolactin reduced GnRH

Men: erectile dysfunction with reduced spermatogenesis,

Women: menstrual irregularity with anovulatory cycles manifest

1. Davidson A, Aranow C. Pathogenesis and treatment of systemic lupus erythematosus nephritis. Curr Opin Rheumatol 2006;18:46875.

APLS and infertility

Secondary APS occurs in ~30% of SLE patients and for many years, APS has been considered a risk factor for foetal loss, rather than a condition that can affect the ability to become pregnant.

Evidence against APLS being associated with infertility:

Two recent studies have not detected a higher prevalence of these autoantibodies in infertile women, or a correlation with the type of female infertility diagnosed(2,3).

. 2.Cervera R, Balasch J. Bidirectional effects on autoimmunity and reproduction. Hum Reprod Update 2008;14:359–66. 3. Bellver J, Soares SR, Alvarez J, Mu~noz E, Ramırez A, Rubio C, et al. The role of thrombophilia and thyroid autoimmunity in unexplained infertility, implantation failure and recurrent spontaneous abortion. Hum Reprod 2008;23:278–84.

APLS and infertility

Evidence affirming APLS being associated with infertility :

There may be an earlier influence of APS on fertilization, implantation and even reproductive function as a whole.[1]

APS can lead to thrombosis of main vessels draining the reproductive organs, thereby threatening fertility [2].

Some retrospective reports have suggested a relationship between antiphospholipid antibodies and infertility and poor ART outcome [3].

Furthermore, APLS affecting the trophoblast could impair implantation of the blastocyst and so while not affecting conception itself [52, 53] would make the patient appear infertile.

Validity of much of the above is limited and has yet to be established. It should not impact on treatment and Mx.

1. Carp HJ, Shoenfeld Y. Antiphospholipid antibodies and infertility. Clin Rev Allergy Immunol 2007;32: 159–61 2. Udoff LC, Management of patients with antiphospholipid antibodies undergoing IVF. J Autoimmun 2000;15:209–11 3. Kim HC, Kemmann F, Shelden RM, Saidi P. Response of blood coagulation parameters to elevated endogenous 17b estradiol evels induced by menopausal gonadotropins. Am J Obstet Gynecol 1981;140:807–10. 4. Jungers P, et al. Influence of oral contraceptive therapy on activity of SLE. Arthritis Rheum 1982;25:618–23.

Other AI and ‘infertility’

Sjogrens Syndrome:

Journal of Rheumatology, 2007, Sarwen et al, Nest case control N = 196

Conclusions: Pregnancy occurs later in life in pSS women. Mothers with pSS give birth to offspring with lower birthweight and less commonly have normal partus.

Scleroderma and RA:

Arthritis and Rheumatism 1999 Steen et al , N = 492

‘There were no significant differences in the overall fertility, rates of miscarriage, or neonatal deaths between the 3 groups. Women with SSc and RA were more likely than those without SSc to have adverse outcomes of pregnancy, particularly premature births and small full-term infants.

Vasculitis:

No trials re: fertility or ovulation induction

No of cases published re: outomes in pregnancy active disease = complications.

Rx: Cyclophosphamide

CYC damages ovarian follicles +/- depletes primordial

follicles.

Leads to temporary amenorrhoea when maturing follicles are destroyed; or permanent amenorrhoea/premature ovarian failure when all primordial follicles are destroyed.

Dose and age dependent

Pts may still menstruate but have exhausted ovarian function.

There may be a role for GnRH agonists may protect fertility

gnRH agnonist blocks the receptor decreased gonadotrophin conc lower oestrogen reduced ovarian perfusion.

Poor quality data in pts with neoplasia.

GnRH agonists worsened SLE in a murine model [1].

1. Jacobson et al. Modulation of the expression of murine lupus by gonadotropin-releasing hormone analogs. Endocrinology 1994;134:2516

NSAIDs infertility

The use of NSAIDs in women with lupus has the capacity to increase the risk of infertility by inducing luteinized unruptured follicle syndrome [1,2]

This is defined as the failure of a follicle to rupture between Days 10 and 20 of the menstrual cycle as visualized by US [3].

However, the risk associated with NSAIDs is contentious.

Some authors recommend that women having problems conceiving should be advised to stop NSAIDs, but not all women on NSAIDs who wish to become pregnant have to stop them on the basis of present evidence.

1 Katz E. The luteinized unruptured follicle and other ovulatory dysfunctions. Fertil Steril 1988;50:83950. 2 Akil Infertility may sometimes be associated with NSAID consumption. Br J Rheumatol1996;35:768. 3. Ostensen et al. Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res Ther 2006;8:209.

Methotrexate

Systematic review on the safety of methotrexate in RA regarding fertility, pregnancy and breastfeeding concluded:

CONCLUSIONS:

MTX and pregnancy: there is not sufficient evidence to support whether it is MTX or the disease what underlies miscarriage in these patients.

Pooling the data from the studies included, the rates of miscarriages are similar to the rates observed in healthy population.

MTX and lactation and fertility: there is absence of confirming evidence.

There is indirect evidence of reversible infertility from case reports.

Infertility in AI summary slide

Therefore, fertility is likely to be normal in women with SLE, except for three situations:

amenorrhea accompanying severe flares,

renal insufficiency-related hypofertility, and

ovarian failure secondary to CTX therapy .

In AI

Overall slightly increased level infertility related to:

Medicatios used ie NSAIDS, cyclophosphamide

Disease flares causing amenorrhoea

Associated endometirosis, APLS

27. Bertsias G,. EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for international clinical studies including therapeutics. Ann Rheum Dis 2008;67:195–205

Progress update…..







What role do sex hormones play in Rheumatological conditions if we

plan use OI?.....SLE

SLE exhibits a female bias, disease activity may be sex-determined or hormonally regulated. Exogenous estrogens are generally not prescribed for women with SLE because of the widely held view that these medications can activate disease. Concern appears based on:

1. The 10-fold greater incidence of SLE in women than men (1),

However: SLE occurs in men; SLE can occur after menopause. SLE activity does not cease after menopause .

2. Disease onset after menarche and before menopause, skewing of estrone metabolism toward more feminizing 16-hydroxylated metabolites (2, 3),

3. Exacerbation of murine lupus by estrogens (4),

4. Cases of disease flares during exogenous hormone therapy (5–13),

5. A retrospective study in patients with preexisting renal disease (14), and

6. The ability of estrogens to augment murine B-cell survival and autoreactivity (15).

7. Scientific data: Phyto-oestrogens induced up to a threefold increase in anti-Ro levels in human keratinocytes. (16)

See last page of slide show for references

Hormones and RA

Because the majority of individuals who develop RA are women, estrogens have long been thought to influence the risk of developing disease. However…..

The OCP may have a protective effect in the development of RA; [1–3].

A recent study demonstrated lower prevalence of rheumatoid factor positivity in women on OCPs compared with those who were not in patients without rheumatoid arthritis.

Possibly a protective effect of OCPs with regards to the development of rheumatoid factor, but not necessarily for RA.

1. Brennan P, Bankhead C, Silman A, Symmons D. Oral contraceptives and rheumatoid arthritis: results from a primary care-based incident case-control study. Semin Arthritis Rheum 1997;26:817–823. 2. Doran MF, Crowson CS, O'Fallon WM, Gabriel SE. The effect of oral contraceptives and estrogen replacement therapy on the risk of rheumatoid arthritis: a population based study. J Rheumatol 2004;31:207–213. 3. Hazes JM, van Zeben D. Oral contraception and its possible protection against rheumatoid arthritis. Ann Rheum Dis 1991;50:72–74. 4. Bhatia et al. Rheumatoid factor seropositivity is inversely assocaiated with oral contraceptive use in women without rheuamtoid arthritis. Ann Rheumatic Dise 2007

SLE and pregnancy

If we are concerned oestrogen exacerbates SLE then surely pregnancy is the perfect example:

At the end of pregnancy, oestrogen levels are up to 100 times that of a non-pregnant female.

IVF levels reach 6-fold higher than non pregnancy

HRT only one-fifth peak menstrual cycle levels

OCP only slightly above normal hormone levels.

SLE and pregnancy

There are three main implications of SLE on pregnancy:

1. Increased risk, by 2–6 times, of complications related to placental insufficiency, including

Miscarriage/ intrauterine death,

hypertension,

preeclampsia,

low birth weight, and preterm delivery.

2. In women with positive anti-Ro or anti-La antibodies, fetal heart block and cutaneous neonatal lupus appears in 1%–3% and 16% of fetuses, respectively

3. Pulmonary hypertension, reported in up to 14% patients with lupus, is associated with a high risk of maternal death.

Fertility and Sterility 2009 Ovarian stimulation for ovulation induction and in vitro fertilization in patients with systemic upus erythematosus and antiphospholipid syndrome Jose Bellver,

OCP in AI: Trial 1

The ’ Safety of Estrogens in Lupus Erythematosus National Assessment ‘(SELENA) group. 2005

Randomised, double blind, placebo controlled clinical trial

Severe lupus flare: 7.7% OCP vs 7.6% placebo

OCP in AI: Trial 2

Single blinded trial N = 162

Randomised 1 COCP :1 POP:1 IUD

2 thromboses each COCP & POP

No increase in flare rate.

OCP and risk of developing AI: Trial 1

Population-based nested case–control study using the UK’s General Practice Research Database N = 7800

COCPs was associated with an increased risk of SLE.

Particularly in recent COCP commencers and increased strength of pill. (RR from 1.1 – 2.9)

OCP in developing AI: Trial 2

Prospective cohort study of 121,645 women: The Nurses’ Health Study.

Using the most stringent case definition (ACR criteria plus a diagnosis of SLE by an ACR member) (n = 58), the relative risk for past users compared with never users was 1.9.

OCP : Summary

Current decision to avoid appears based on animal data and theoretic risk, individual cases and small poor quality trials. Maybe the pill isn’t as bad as first thought?

Would appear not to flare SLE in patients with stable inactive or mild disease.

Not generalisable to patients with severe disease, unstable disease, APLS or PHx nephritis.

Increased flare rate in patients on COCP with PHx SLE nephritis

Benefit of progestin only pill unclear.

In appropriately screened and informed patients the OCP could be very useful.

Possible risk developing SLE

Recent RCT 12/12 no incident cases of SLE, similar to other Case-control studies.

Not powered to Ax this

HRT disease activity SLE

2005 RDBPCT by the ’ Safety of Estrogens in Lupus Erythematosus National Assessment ‘(SELENA) group. (n=351)

Mild to moderate flares were significantly increased in the HRT group: RR 1.34; P 0.01.

HRT & RA trial 2

RPCDBT

168 (91 Rx, 77 placebo)

1987 ACR diagnostic criteria RA

N = 132

This study did not show an overall effect of HRT on disease activity when used as an adjunct therapy in postmenopausal patients.

HRT on AI : Trial 3

There were no significant differences between the groups in maximum disease activity, incidence or probability of flares, or medication use.

Thromboses occurred in 3 patients who received menopause hormonal therapy and in 1 patient who received placebo.

HRT and AI

Although a few prospective and one small RCT found no increased incidence of flare related to SLE, the most robust large RCT demonstrated a moderate risk of mild-mod flare in SLE patients on SLE.

As expected a significant safety signal for thrombosis was seen.

HRT does not appear to alter RA disease activity

The difference between OCP and HRT in SLE could be the proportionate difference in basal levels of hormone in pre and post-menopausal women….

Progress report...







Do fertility treatments aggravate/precipitate autoimmune disease?

Do autoimmune diseases alter outcomes in fertility treatments?

Ovulation Induction in Autoimmune disease….the evidence.

1. Guballa et al, Retrospective case series, NYC 2000

2. Huong et al, Retrospective Study, Paris 2002

OI in SLE: Series 1

Series 1: Outline

Methods. Nineteen women who underwent 68 cycles of OI/IVF were studied by interview and retrospective chart review.

10 patients with APLS, 7 with SLE, 2 with APLa only.

Patient Selection: ‘polling’ of ‘selected’ physicians at two tertiary centres in NYC to identify patients with SLE or APLS(ACR criteria).

Flares: defnined on physician assessment – no validated tool used.

Series 1: Results

Results.

5 of 7 SLE patients had live births. Live births resulted from 31% IVF cycles

Surrogates used in three of the five patients who became ‘pregnant’ due to significant complications from natural pregnancies prior.

5 of 10 ALPS patients had live births .

Live births resulted from 10% IVF cycles.

.

Series 1: results continued.

Complications:

25% of IVF cycles in SLE patients resulted in increased lupus activity

13%(n = 2) suffered OHSS (Usually 1% of women on IVF).

One patient with primary APS who was given heparin during multiple cycles developed osteopenia. No thrombosis occurred.

Seven of 14 living children (50%) were premature,

3 had neonatal lupus (no information re maternal serology):

Usually 3% overall risk in SLE

Postpartum complications:

Lupus nephritis flare wk 1 post-partum on bx

1x Suicidal depression.

Series 1: Conclusions

Author Conclusion. Although OI/IVF can be successful in SLE and primary APS patients, rates of foetal and maternal complications are high.

Issues:

Primarily it is a retrospective case series…….

Paper has a significant lack of information

re: SLE treatment, duration of stability of SLE prior to pregnancy, patient age/demographics and serology.

Internal and external validity questionable and therefore generalisability poor.

Series 2:

Seminars in Arthritis & Rheumatism 2002

Series 2:

Methods: A Retrospective study of 21 consecutive women with SLE or APLS, followed by a single tertiary centre in Paris over 114 cycles of OI, with or without IVF.

Patients:

SLE n=6, 1oAPLS n=3, SLE + 2oAPLS n=3, Discoid SLE n=1

SLE stable 12/12 on <0.5mg/kg PNL and HCQ

Excluded: Hx Nephritis/PAH/HTN

However, 5 of these women intentionally concealed their Dx from their physician.

No known disease in 8 patients at initiation of OI.

3 Dx with SLE & 5 with 1oAPLS after Cx during OI.

Series 2: Results

18 pregnancies of 114 OI cycles, resulting in 9 live births

Success rate: 7% (general success rate IVF ~25% )

By ARTs modality:

GnRHa (25% cycles)

Clomiphene (4% cycles)

When O&G not aware of disease 75% of pregnancies from OI+IVF resulted in embryonic/foetal loss.

2 live births from 70 cycles

85% of pregnancies fro OI + IVF when physician aware of disease resulted in live births (p < 0.001)

7 live births from 44 cycles.

Series 2: Results

SLE flare rate:

Overall 50% pts with known SLE flared.

Higher on Gonadotrophin or GnRHa(27% cycles) than on clomiphene (6% cycles)

Higher when O&G not aware of underlying Dx

Outcome per ART modality similar

17 cycles clomiphene in SLE– only 1 mild flare;

5 cycles gonadotrophins in SLE – no flare; 2 preg but fetal death and 1 HELLP.

IVF using GnRHa or gonadotrophins had higher flare rate (27% per cycle) compared to those using clomiphene(6% per cycle) – not statistically significant.

No cases OHSS

Series 2: Conclusions

Authors Conclusions: [‘ The OI may precipitate SLE or APS. A careful review of the patients history and appropriate laboratory tests should be undertaken before OI .][When gonadotrophins are prescribed, preventative anti-inflammatory therapy should be considered in women with SLE’]

Issues:

Again retrospective uncontrolled, non-randomised study, but at least consecutive!

Most patients with OI unmasked SLE had a clue in their history ie ‘arthritis’, thrombocytopaenia, +ve ANA.

More transparent case series, but information on SLE pre-OI limited.

Outcomes ART in SLE

Some conclusions can be obtained from these two studies:

Although one might expect an increase in lupus flares during ovarian stimulation for ART, two studies on lupus flares in ART patients argue that this does not occur.

The mild flare frequency per 9-month period in nonpregnant women is 40%–80%.

When the disease is known, a planned ovarian stimulation with co-administration of prophylactic therapy is frequently successful.

Presumably better outcomes in known SLE was due to aggressive (corticosteroid) Mx in SLE patients.

Do we need to consider prophylactic treatment prior to OI?

Outcomes in ART

Exogenous oestrogens can also increase the risk of thrombosis in patients with positive antiphospholipid antibodies and should be avoided in this sub group

Excessive ovarian response and lupus flares are more common in patients treated with gonadotropins than in clomiphene-treated subjects.

A trend towards a worse prognosis in cases of SLE patients undergoing ART both for pregnancy rate and live-birth rate can be seen.

Friendly ovarian stimulation, single embryo transfer, avoidance of OHSS, administration of coadjuvant therapy, and use of natural E2 or P through a nonoral route may constitute the safest approach. If not the use of clomiphene or lowest effective dose of gonadotrophin is appropriate.

Careful selection of patients for OI/ IVF appears prudent. We need a multi-centre prospective study – RDBPCT preferable!

VTE Cx related to SLE

Chan and Dixon (41) recently performed a systematic review of

thromboembolic complications (TEC) related to ART, from

1966–2006. They included 58 articles, case reports, or series, with information

relating to 71 episodes of TEC in association with ovarian

stimulation or ART in 70 women. Not one case related to SLE or APS

In women affected by SLE or APS, ovarian stimulation seems to be safe and successful when the disease is in clinical remission and appropriate prophylactic anticoagulant or anti-inflammatory therapy is administered (6, 27, 46, 58, 64). Hence, the most dangerous period is not ovarian stimulation but pregnancy, in which the rates of fetal and maternal complications are high (6).

(6)Askanase AD. Estrogen therapy in systemic lupus erythematosus. Treat Endocrinol 2004;3:19–26.


VEGF VTE

Recent observations from animal studies suggest that the VEGF plays a pivotal role in increasing vascular permeability in hyperstimulated subjects [32]. In autoimmune diseases, the VEGF level correlates with disease activity and falls during pharmacological treatment. Not surprisingly, some cardinal features of the OHSS can also be considered as lupus flares: pleural or pericardial effusion, oliguria, anuria, respiratory distress, low creatinine clearance and thrombo-embolism [prevalence of venous thrombo-embolism (VTE) is 1/128 in severe OHSS].

A 1997 literature review reported 54 cases of thrombo-embolic disease associated with ovarian stimulation and IVF, 75% venous and 25% arterial. Seventy-two percent of patients obtained pregnancy. Sixty-six percent of thrombo-emboli were associated with OHSS, 60% were located in the upper part of the body and 4–12% were associated with pulmonary emboli. Overall, VTE frequency is very low in IVF cycles (1.6/100 000 cycles), but OHSS increases the risk [33].

IS LUPUS assocaited with increased risk OHSS??? Jrheum2008 treating infertiliyt

Are fertility Rx effective?

Success

2 series

Guballa

Le thi huong

No prospective randomised data – information about pat treatments, stability pre-treatment is lacking.

Trend towards a worse prognosis in cases of SLE patients undergoing ART both fr pregnancy rate and live-birth rate

ANA series……

11. Geva E, Amit A, Lerner-Geva L, Azem F, Yovel I, Lessing JB. Autoimmune disorders: another possible cause for in-vitro fertilization and embryo transfer failure. Hum Reprod 1995;10:2560–3.

12. Birkenfeld A, Mukaida T, Minichiello L, Jackson M, Kase NG, Yemini M. Incidence of autoimmune antibodies in failed embryo transfer cycles. Am J Reprod Immunol 1994;31:65–8.

13. Casoli P, Tumiati B, La Sala G. Fatal exacerbation of systemic lupus erythematosus after induction of ovulation. J Rheumatol 1997;24:1639–40.


References SLE hormone slide

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