Clinical Opinion

This woman represents not only women’s trend of having a baby in late 30s1 but also the obesity epidemic2

Age, anovulation, tubal, pelvic, uterine pathology and male factors affect fecundity.

In infertility it is important to assess: Age, duration, previous evaluations/therapy, menstrual, medical, surgical, gynaecological, obstetrical, sexual; personal and life-style history. Physical assessment includes BMI; thyroid gland; galactorrhea; hirsutism, acne, male-pattern baldness and pelvic examination3.

Immediate evaluation should be offered to women older than 35yrs4,5. Women’s fertility is 95% lower at 40-45yrs compared to 20- 24yrs6. Follicular depletion accelerates after 37-38yrs7, 8. Oocytes aneuploidy is 10% at 35yrs; 30% at 40yrs and 50% at 43yrs9. Spindle formation and function deteriorate with age10. In women aged 40-45 abnormalities of spindle or chromosome alignment during meiosis-II are 4-5 folds those aged 20-2511.

Standard infertility tests may not detect abnormal folliculogenesis causing older women infertility4.

Many older infertile women have an impaired response to ART ovarian stimulationbecause of occult ovarian failure associated with elevated Day-3-FSH12. FSH increase and inhibin-B decrease are due to decreasing number of follicles in each cohort of active follicles13.

Ovarian reserve (OR) describes reproductive potential i.e. number and quality of oocytes. Female age is the basicfactor that is related to both quantity and quality. OR-tests were designed to determine oocyte numberand quality and to be able to predictthe outcome of IVF in terms of oocyte yield and pregnancy.

OR-test should identify women of relatively young age with diminished reserve and those around 40-41yrs with adequate OR. Women may be advised against IVF or advised to start IVF earlier before OR is depleted or have their stimulation dose adjusted. Quantity in an ORis more measurable. Quality however; is best expressed in IVF setting14.

FSH-Day-3 prediction ofpoor response is adequate only at very highthreshold levels with false positive rate of 5%. The test is not suitableas a diagnostic test to exclude patients, but only as screeningtest for counselling purposes and further diagnostic steps,in which a first IVF attempt may be the step of choice15.

FSH-Day-3, AMH, Inhibin-B, Estradiol, AFC, Ovarian Volume, Ovarian vascular flow, CCCT, Exogenous-FSH ORT, GAST and Multivariate models have been used to assess OR. False positivetest may eliminate couples from the IVF trial even ifthey do have adequate prospects. OR-Tsshould be considered as screening tests. An abnormal screen test necessitates confirmation by another test such as ovarian response to first IVF cycle. Combinationsof independent predictive tests could improve the diagnostic performance of the singletest15.

Age and OR-tests are independent predictors of IVF outcome16.

The probability of achieving a live birth without treatment decreases with increasing age and duration of infertility17,18,19,20,21,22.

IVF success decline significantly at 35 years23,24,25

Live-birth per transfer for ART cycles using fresh non-donor oocytes or embryos were 41.1% for women <35 yrs, 25.4% for women 38-40 yrs, 14.5% for 41-42 and 6.7% for women >42yrs26.

In repeated poor responders pregnancy probability never surpassed10%27.

Obesity

Normal BMI is (18.5-24.9Kg/M2) and overweight is (25 to 29.9 Kg/M2). Obesity is defined commonly as BMI (30kg/M2)28. Obesity classes are: Class-I (30.0–34.9); Class-II (35.0–39.9) and Class-(III≥40)29,30. Our patient BMI could range from 36.1 at 1.8M and 53.3 at 1.5Mt.

This woman’s insulin resistance can be associated with non-IDDM, obesity, hypertension, lipid abnormalities, and atherosclerotic cardiovascular disease31. Hyperinsulinemia appears to be present in a significant number of PCOS patients, independent of obesity32, while others associate hyperinsulinemia in PCOS only with obese patients33.

With obesity and insulin resistance; we should assess her for metabolic syndrome if she has three or more of the following; hypertension≥130/85mmHg, triglyceride level≥1.7mmol/L, HDL-cholesterol<1.3 mmol/L, abdominal obesity>90cm or fasting glucose≥6mmol/L. Hypertension develops later in life34.

If her waist-circumference>90cm she has cardiovascular risk35.

She may qualify for PCOS diagnosis with at least 2 of the following; US-PCO, oligo- or anovulation, symptoms and tests of androgen excess after excluding other causes of androgen excess36,37.

Use of metformin in PCOS should be restricted to those patients with obesity and insulin resistance38,39.

Obesity is associated with anovulation40, menstrual disorders, hirsutism, infertility, miscarriage and obstetric complications. It impairs human reproduction through insulin resistance, hyperandrogenism and elevated leptin levels41.

Obesity is an independent risk factor for early pregnancy loss42, late pregnancy loss43, pre-eclampsia and gestational diabetes44,45, thrombo-embolism and postpartum haemorrhage, maternal and foetal deaths45.

Obesity causes response failure to CC46, gonadotrophins47,48,49 and laparoscopic ovarian diathermy-LOS50.

In obese infertile women undergoing ART the ovary plays a leading role in the fertility prognosis. The endocrine and metabolic environment may affect oocyte quality, embryo development, implantation and pregnancy outcome41.

Endometrium plays a negative role in ART based on ovum donation model41,51,52,53.

Obesity impairs the outcome of ART48,41, 52,51,54,53. The lower probability of a healthy live birth in obese women seems to be the result of a combination of lower implantation and pregnancy rates, higher preclinical and clinical miscarriage rates and increased complications during pregnancy for both mother and fetus41.

In infertile obese patients undergoing IVF/ICSI; class-II has lower pregnancy rates when compared to class-I55.

Compared to normal weight women; Class-III obese women are 35% less likely to become pregnant; Class-II has 28% less chance; 9% for Class-I; and 3% for overweight women. Stillbirth in obese women was more than doubled and premature birth paralleled increasing obesity: from 16% for overweight to 34% for Class-III obesity56.

British Fertility Society recommends ART treatment should be deferred until the BMI is<(35 kg/M2) 57. However it is recommended that clinicians adopt a flexible approach where possible and look at cases on an individual basis.”

A recent Scottish study suggested overweight and obese women have as much chance of having a baby through fertility treatment as normal weight women. No significant difference was found between groups: overweight, obese class-I and class-II in the proportion of women having a positive pregnancy test, ongoing pregnancy, and live-birth. But a higher proportion of women in the overweight or obese groups had a miscarriage. They needed higher doses of drugs to stimulate the ovaries. The study showed patients should not be discriminated against because of their size58.

However they agreed with British Fertility Society57 that women with a BMI over 35 should not be offered IVF until they had lost weight because of the particularly high risk of complications unless their age is against them.

While obesity has a powerful effect on fertility, you can overcome it with fertility drugs58.

Progesterone a week before the expected menses>9.54nmol/L provides objective evidence of ovulation prior to COH59. Anovulatory women (particularly PCOS) pose a greater risk for hyperstimulation.

Ovarian Reserve Test; SHBG, FAI, Total Testosterone, DHEA; TSH; Prolactin; GTT, lipid profile and HIV, Hep B and Hep C are ordered to assess ovarian reserve, hormonal, metabolic and infection state.

Semen analysis is requested.

Abnormal tests that have an established correlation with impairedfecundability are semen analysis, tubal patency by HSG or laparoscopy, and laboratory assessment of ovulation.Since tubal patency maynot be the only cause of infertility, laparoscopy may also helpto detect other factors, e.g. endometriosis, adhesions60.

For infertile women of advanced reproductive age; however, there is decreased emphasis on diagnosis ‘possiblelack of usefulness’ and rapid movement toward ART61,62,63.Progress in ART led to its use after a limited and non-invasive infertility work-up in all infertility patients4.

HSG and CAT screening have proven their clinical value and cost-effectiveness for the diagnosis of tubal infertility64. Early laparoscopy to assess tubal status is indicated in high CAT in infertile women65. HSG has reasonable specificity (83%) but low sensitivity (65%) to document tubal patency66. It’s value prior to laparoscopy was questioned67.

Hysterosalpingo-contrastsonography (HyCoSy) demonstrates normal anatomy and tubal patency with high reliability and permits advance selection of patients in whom more invasive diagnostic procedures may be required68. HyCoSy is first line outpatient investigationof tubal patency, uterine and ovarian abnormalities69. Compared to HSG,and laparoscopy; HyCoSyis reliable for evaluatingtubal patency as an outpatient procedure prior to more invasive procedures70. HyCoSy is an attractive alternative to HSG without exposure to X-rays or iodinated contrast media with concordance rates and accuracy similar to that of HSG71. Imaging techniques allows scheduling for definitive surgery if abnormality is seen.

Uterine cavity should be carefully evaluated before IVF cycle as submucus myomas or endometrial polyps can interfere with implantation or have adverse effect on pregnancy outcome. A normal US or HSG performed earlier may suffice. If uterine cavity abnormality is suspected sonohysterography (SHG) or office hysteroscopy is indicated. Routine hysteroscopy before IVF has been indicated72,73,74,75.

SHG is easier to perform with sensitivity and specificity compare favourably with diagnostic hysteroscopy for detection of abnormalities within the uterine cavity76,77,78. SHG can detect hydrosalpinges or ovarian endometriomas that may require attention before IVF begins.

There is high incidence of pathological findings on hysteroscopy in patients with repeated failures of IVF-embryo transfer despite transfer of good-quality embryos. Relevant therapeutic interventions before the third cycle; significantly improves clinical pregnancy and implantation rates in comparison with a control group79.

The value of diagnostic laparoscopy in case of abnormal HSG findings has been highlighted67,80. Diagnostic laparoscopy to evaluate all cases of anovulatory infertility cannot be advocated due to lack of good-quality studies, but laparoscopy can offer the opportunity to assess and treat endometriosis and adhesions that may limit conception81. Laparoscopic ovarian diathermy as an alternative to gonadotropin in CC-resistant PCOS patient is an option but counselling should be offered with regard to the unknown long-term effects of this procedure on the ovarian function81, particularly inwomen in late 30. 

Laparoscopy has a recognised role in diagnosis and assessment of mullerian duct abnormality in conjunction with HSG and ultrasound and MRI.

Laparoscopy is considered the gold standard in the diagnosis of tuboperitoneal infertility. It’s routine use in the work-up of infertility has been challenged82.

IVF clinics are omitting diagnostic laparoscopy to reduce cost, anaesthetic and surgical complications.  Diagnostic laparoscopy complications are 0.6/100083. In morbid obesity complications could be higher. With thorough preoperative evaluation, laparoscopy can be performed in obese patient safely84.

Laparoscopy advantages become obvious with flexibility to treat at the same time and also perform diagnostic or operative hysteroscopy.

Implantation and pregnancy rates in IVF cycles increase after salpingectomy for ultrasonically visible hydrosalpinges with best results in bilateral hydrosalpinx85,86,87.  Salpingectomy must be performed very close tothe tube in order to avoid disrupting the normal blood flowto the ovary88.

Diagnosis of endometriosis is still unduly delayed in many patients with infertility89. In the absence of endoscopy there is no reliable technique to diagnose the presence and extent of endometriotic adhesions or the presence of ovarian endometriomas when the diameter is not >2cm.

Diagnosis and treatment of minor endometriosis in an early stage of subfertility is beneficial90,91. Patients with endometriosis of any stage should be referred for early aggressive infertility treatment, including IVF, to increase chances of conception92.

Removal of asymptomatic small endometriotic cysts<3cm prior to IVF did not improve fertility outcome93. However, laparoscopic cystectomy of larger symptomatic endometriotic cysts>4cm improved fertility94,95,96. Radical treatment of all endometriotic lesions by experienced laparoscopist, after several failed IVF cycles, produced spontaneous pregnancies and success with repeated IVF cycles97.

Management

This woman age is against her. A concerted plan to lose weight and maintain weight loss should be provided through psychological support, dietary advice, exercise, weight reducing agents or even bariatric surgery. Relevant investigations and procedures for large endometrioma, hydrosalpinges and submucus fibroids, should be completed during this time. 

Fertility treatment should start in 3-4 months or sooner if her BMI become ≤35 kg/M2. If this woman is 180cm tall losing 5-6Kg would get her BMI to 35; however if she is 150cm, she needs to lose 40 Kg to reach BMI 36 which is unlikely.

Treatment should not be deferred until the BMI is ≤ 35 kg/M2. If treated at high BMI she must understand all the risks involved with consent and documentations. 

Weight loss is first-line therapy. Losing 5% of body-weight can produce pregnancy98. Low-calorie diet reduces weight by 12% in 6/12 and improves reproductive outcome99. Weight loss prior to conception improves live-birth rate in obese women with or without PCOS100. Weight loss and exercise lead to a reduction of central fat and improved insulinsensitivity, which restores ovulation in overweight infertilewomen with PCOS101,102. Smokers and those with BMI≥40Kg/M2 after ‘diet and exercise’ did not do as well103.

Regular exercise helps long-term weight loss104 but has orthopaedic and cardiovascular limitations in obese women100. Bariatric surgery can help reduce weight in class II-III obesity105. Appetite suppressant Sibutraminereduces androgens and insulin resistance independent of weight-loss106 and intestinal fat absorption-blocker Orlistat reduce androgens and insulin resistance independent of weight-loss107.

Metformin is used to treat diabetes, it reduces gluconeogenesis, increases sensitivity to insulin; consequently reduces hyperinsulinaemia, LH levels, total testosterone, FAI and PAI-1 in overweight women with PCO. It reduces acne and hirsutism. Metformin raises SHBG levels108. Metformin reduces androgens, improves insulin resistance, type-II diabetes, dyslipidemia, and cardiovascular alterations in PCOS patients109. In PCOS, metformin does not cause significant changes in BMI or waist-to-hip ratio108. Metformin main side effect is diarrhoea; which improves when taken with meal or dose is reduced108.

Metformin in ART reduces incidence of ovarian OHSS110,111. Metformin in IVF/ICSI improves viable pregnancy rates110, others do not agree111.

If FSH is normal and she is anovulatory without indications for IVF/ICSI; CC is a good choice to induce ovulation. CC is economical, oral, safe and requires little monitoring112.

Weight, age, increased insulin resistance and excess-androgen predicts treatment success113. Pregnancy rates when BMI>30 are significantly less compared with BMI<30114. CC produces ovulation in 75%–80% of PCOS-patients112,115, but pregnancy is 22% per-ovulation and differences are due to CC antiestrogenic effects112,115. Multiple pregnancy is <10% and hyperstimulation is rare116.

Adding hCG mid-cycle does not improve pregnancy rates117. Treatment is usually six ovulatory-cycles116,112, with 50–60% cumulative live-birth rates in six cycles26. In this woman because of age 3-4 months would suffice118.

Combined CC and metformin as primary therapy to induce ovulation has no beneficial effect119,114. There is; however apparent advantage to adding metformin to CC in women with BMI>35kg/m2 and in those with CC resistance114. Metformin use for OI in obese or normal weight women with PCOS does not increase live-birth rates when compared to CC alone119,114,120. Adding metformin did not reduce miscarriage, which was higher in metformin group114.

Metformin treatment during pregnancy may protect against complications121; currently it should be used only in research122. PCOS-women with insulin resistance and taking metformin should stop it if pregnancy occurs114.

Aromatase inhibitor letrozole does not improve ovulation or pregnancy123.

Exogenous gonadotrophins are second possible line of therapy in CC- resistance38. Gonadotrophins drawbacks are ovarian hyperstimulation and multiple pregnancies which can be reduced with US monitoring and oestradiol measurements124

Ovulation induction by LOS-diathermy is an option in CC-resistant or excess LH or if laparoscopic assessment of pelvis is required or if she lives too far for monitoring required during gonadotrophin therapy125. Because of inherent risks of surgery and lack of long-term evidence from RCTs, LOS cannot be recommended126. LOS in morbidly obese may carry higher risks and further reduce ovarian reserve in 39 years old. Adjuvant therapy CC or FSH will be required in 50% of LOS-treated women127.

RCTs comparing LOS with gonadotrophins for CC-resistant PCOS showed similar ongoing pregnancy rate and live birth rate128,129,127; but multiple pregnancy rates were significantly higher in gonadotrophin compared with LOS. Treating CC-resistant PCOS by LOS resulted in reduced costs130,131.

In addition to laparoscopic complications; ovarian adhesions as late complication are common132.

The most clinically useful predictors of gonadotrophin ovulation induction outcome in normogonadotrophic women are obesity and insulin resistance47.

In principle, anovulation is not an indication for IVF. IVF is used when weight reduction, CC, gonadotrophins, LOD and metformin have failed38.

In our patient Age however; has to be considered and ART should start after 3-4-months CC treatment

After failure of weight reduction, anti-oestrogen or LOS, it may be argued that gonadotrophin should be omitted and replaced by ovarian stimulation and IVF133.

Tubal damage, severe endometriosis, PGD and male infertility indicate IVF134. Women with PCOS undergoing IVF had more cycle cancellation56.

In this woman, because of her age, ART would be her best option after a short trial of CC ovulation induction.

Effectiveness of immediate IVF (up to 4 cycles) was compared with six-month delayed IVF in couples with all causes of infertility. Control group patients were permitted to have any form of fertility treatment other than IVF. Pregnancy rates and live birth were more than doubled in IVF group135.

The stimulation regimen is based on age, ovarian reserve and the presence of PCOS.

In ART; GnRH-agonist long protocol, is the gold standard; based on clinical pregnancy rate per cycle started, it is superior to GnRH-agonist short and ultrashort protocols136.

The efficacy of GnRH-antagonist and standard long GnRH-agonist protocols in patients undergoing COH for ART was evaluated137. Using GnRH-antagonist; clinical/ongoing pregnancy and live-birth rates were significantly lower; however incidence of severe OHSS, coasting and cycle cancellation were more frequent in the GnRH-agonist group.

GnRH-antagonists other advantages138 in IVF include the possibility of triggering ovulation with native GnRH agonists, possible avoidance of luteal supplement resulting from the short half-life of the GnRH-antagonist and rapid recovery after its cessation.

GnRH-antagonist protocols are short and simple with good clinical outcome. There is a significant reduction in the incidence of severe OHSS and amount of gonadotropins. However, the lower pregnancy rate compared to the GnRH-agonist long protocol necessitates counselling subfertile couples before recommending change from GnRH-agonist to GnRH-antagonist. ICSI can improve efficacy.

In PCOS patients the GnRH-antagonist protocol is associated with comparable pregnancy outcome but a lower risk for OHSS when compared with GnRH-agonist long protocol139.

In GnRH-antagonist cycles a worse reproductive outcome is expected in PCOS patients with BMI>29kg/m2 in whom stimulation is initiated with 200 IU of rFSH as compared with PCOS patients with BMI≤29kg/m2 in whom stimulation is initiated with 100 IU of rFSH140.

Exaggerated follicular response with massive ovarian enlargement and serum E2 > 11000pmol/L; OHSS risk is substantially increased141,142,143. Cancelling the cycle and starting a new cycle with lower dose may maximise success chances145. Dual suppression with OCP and GnRH-agonist with subsequent low dose rFSH can attenuate the response146. Coasting reduces the risk of OHSS with a reasonable chance of success147,148,149. Completing the cycle and freezing all embryos can salvage the cycle but avoid the greater risks of serious OHSS observed in conception cycle149,150. Delaying transfer (for 5 days post-retrieval) until after symptoms abate and freezing all embryos when symptoms persist is another option151.

Poor response presents greater challenge. More aggressive or alternative stimulation regimen is warranted. The long protocol with higher doses of FSH may generate better follicular response. Doses higher than 450IU do not improve the outcome152,153,154.  Discontinuing or decreasing GnRH-agonist dose may improve response quality155,156,157,158,159. A short follicular phase GnRH-agonist standard or flare protocol may improve response160,161,162. Using GnRH-antagonist in the stimulation regimen instead of GnRH-agonist eliminate suppressive effect of the agonist163. Sequential treatment with CC and FSH may yield an improved response164. The efficacy of flare protocols and CC may reflect a greater sensitivity to endogenous forms of FSH in some individuals.

Dose of rFSH may be increased for her Age. If she has PCOS or has any of the following in addition to insulin resistance: (PCOS-defined (in this instance) as any two of the following): clinical stigmata of PCOS; LH day3>10IU/L; LH:FSH Ratio>2.5 or PCO on U/S the dose may be reduced to avoid OHSS.

Women with PCO and PCOS should commence stimulation monitoring on 6th day of rFSH.

I should counsel the couple regarding the need for appropriate stimulation to achieve pregnancy whilst having an acceptable level of risk of complications. Fully informed couples will be better able to tolerate the cancellation of a COH cycle when the risks are unacceptable.

Serious maternal complications with full-blown OHSS include thrombosis, stroke, hepato-renal failure, cardiopulmonary compromise and even death165,166,167,168.

Infertile couples often desire multiple gestations more than a singleton pregnancy. Multiple pregnancies should be minimised as they increase complications for the mother and increase preterm delivery rate with its complications. Twin pregnancy is associated with doubling of perinatal mortality rates and a 5X increase in the incidence of cerebral palsy. Higher multiples are at even greater risk.

Risk of multiple pregnancies is markedly reduced in IVF with single-ET169,170.

The standard practice in Australia now is to transfer only one embryo except in older patients or repeated failed cycles associated with poor embryo quality. The rate of twins after a single embryo transfer is less than 1% compared with 20% after the transfer of 2 embryos.

ICSI  is indicated in: severe deficits in semen quality as judged by strict criteria WHO-III-standard oligo171, astheno 171 and teratospermia 171,172; obstructive173 or nonobstructive174 azoospermia; treatment plan includes ‘PGD’ and Previous IVF cycle resulted in failed or very poor fertilisation.

ICSI between 1993 and 1994 showed that the fertilisation rates achieved with ejaculated, epididymal and testicular spermatozoa were 64%, 62.5% and 52%, respectively175.

13.7% of men with azoospermia and 4.6% of men with oligozoospermia had an abnormal karyotype176. In severe deficit of sperm quality or nonobstructive azoospermia, the male partner’s karyotype should be established. Microdeletions in the Yq part of the chromosome among men with otherwise unexplained oligo- or azoospermia are common.177,178. They cause the azoospermic or oligozoospermic phenotype and are likely to be passed on to the sons of these infertile men if ICSI is carried out179,180. Screening would enable couples to make informed decisions about the genetic repercussions of ICSI before treatment.

PGD with IVF is indicated in couples who carry autosomal-recessive or sex-linked genetic disorder or a balanced chromosomal translocation to avoid the risk of delivering an affected child. It can identify and exclude aneuploid embryos in women of advanced reproductive-age and could be used in repeated unexplained IVF failure despite transfers of morphologically normal embryos.

Donor semen is effective in obstructive or nonobstructive azoospermia, male partner HIV, severe deficits in semen quality in couples who do not wish to undergo ICSI or ICSI failed and in certain cases with high risk of transmitting a genetic disorder to the offspring. ICSI is preferred to donor insemination in severe male factor infertility because the resulting child is genetically related to both parents.

IVF with Oocyte donation from younger woman is the most successful technique for producing pregnancy in perimenopausal women181 or women with diminished ovarian reserve182. Low chances of conception using their own gametes, even with ART should be discussed. Adoption is another option.

Donor oocyte/IVF success rates are similar in women with or without primary ovarian failure, despite recognisable differences in recipient age and degree of male factor infertility183.

Other indications include gonadal dysgenesis “Turner syndrome” bilateral oophorectomy, ovarian failure following chemotherapy or radiotherapy, severe pelvic adhesive disease, inaccessible ovaries, IVF/ICSI failure, poor quality embryos and in certain cases where there is a high risk of transmitting a genetic disorder to the offspring not amenable to PGD or PGD is rejected.

Egg sharing enables two or more infertile couples to benefit from a single IVF cycle.

Gestational surrogacy offers the woman opportunity to have genetic offspring if she has no uterus (congenital or hysterectomy), an irreparably damaged uterus (congenital malformation, multiple myomas, severe intrauterine adhesions), or medical condition for which pregnancy poses a life threatening risk. It involves transfer of embryos to the uterus of a woman who is willing to carry a pregnancy on behalf of the infertile couple. The legal, ethical and psychological issues involved are complex.

Cryopreservation of a semen specimen in advance of the planned IVF cycle is prudent when there is a reason to anticipate difficulty with obtaining a fresh specimen on VPU-OC.

Mock embryo transfer helps to achieve a successful and atraumatic ET184.

Folic acid and vitamin supplements should be taken around the time of conception.

Parental alcohol consumption185, parental smoking 186,187,188,189and male smoking 190 are associated with a significant decrease in ART success.

Caffeine consumption is a risk factor for not achieving a live birth in women undergoing ART191.

ART may be declined due to cultural, personal, religious or financial factors. Other factors include health problem diabetes, cardiac disease, severe hypertension etc.

This lady should be offered concerted efforts to lose weight while simultaneously investigating and treating conditions which reduce oocyte quality, implantation or cause miscarriage. If she does not have indications for ART and she is anovulatory; she could benefit from short course of Clomid. If no success, her best option would be ART.

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