The ideal contraceptive for a woman with HIV will help prevent pregnancy as well as the transmission of HIV and STIs. Dual contraception using condoms plus an additional contraceptive is the best strategy. Preexposure (PrEP) and postexposure (PEP) prophylaxis should be available to partners regardless of contraceptive method used.
There does not appear to be an association between the use of non-injectable hormonal contraception and risk of HIV acquisition. Studies regarding the risk of HIV acquisition with the use of progestin-only DMPA injectable are conflicting, and the CDC continues to recommend it.
SUMMARY:
Combined hormonal contraception (pill, patch and ring) and progestin-only pills
Considered MEC cat. 1 for patient who are not on antiretrovirals or are not clinically well
For patients who are taking antiretrovirals, can decrease hormone levels but are still considered safe (either cat. 1 or 2 depending on which antiretroviral is being used)
Protease inhibitors, pharmacologic boosters, and efavirenz can cause decreased effectiveness of hormonal contraception
Fostemsavir: can cause increased levels of ethinyl estradiol and raise risk of thromboembolic events | Dosing of ethinyl estradiol should not be higher than 30 mcg daily
Contraceptive implants are highly effective and benefits outweigh risks in women with HIV (MEC cat. 1)
Injectable depot medroxyprogesterone acetate (DMPA) is safe and effective (MEC cat. 1) and does not appear to have interactions with antiretrovirals
Studies regarding increased risk of HIV transmission and acquisition are conflicting.
Intrauterine devices, both copper containing and levonorgestrel-releasing
MEC cat. 1 for women with HIV who are clinically well and on antiretrovirals, with no known drug interactions with antiretrovirals
For women with HIV who are not clinically well or not on antiretrovirals, initiation of IUD is considered MEC cat. 2, but continuation for an already placed IUD is cat. 1
Limited data suggest a low risk of pelvic inflammatory disease and no changes in genital shedding of HIV RNA
Condoms reduce transmission of HIV between discordant partners but are not represent optimal contraception, with an annual pregnancy rate of over 15% per year. Should be used concurrently with another contraceptive method
Spermicides: not recommended due to potential of causing genital lesions
Nonoxynol-9, the active ingredient in most formulations, can cause genital lesions and may increase the likelihood of HIV transmission to a partner
KEY POINTS:
HIV infection does not pose a barrier to sterilization, which remains an appropriate contraceptive option
Emergency contraception including hormone-based (progestin-only pills, ulipristal acetate, combined oral contraceptives), and the copper IUD should be offered to women with HIV whenever appropriate
Emergency contraception interventions are intended to prevent an unplanned pregnancy after unprotected or inadequately protected intercourse. Contraceptive failure or failure to use contraception are common indications for use.
CLINICAL ACTIONS:
Offer emergency contraception (EC) to all women who have had unprotected or inadequately protected intercourse and who do not desire pregnancy
There are no exclusionary health conditions –women who have contraindications to oral contraceptives can be given EC
Offer EC to all reproductive-aged women who have sustained sexual assault
No clinical examination or pregnancy testing is necessary
Treatment should be initiated as soon as possible, and should be made available up to 5 days after unprotected or inadequately protected intercourse
If menses are delayed by a week or more, a woman who has received EC should have a pregnancy test and clinical evaluation
EC may be used more than once even in the same menstrual cycle
Regular contraception should be started immediately after EC and women should abstain or use barrier contraception for 14 days or until onset of next menses
Those receiving uripristal acetate should delay starting hormonal contraception until 5 days after use
SYNOPSIS:
All of the methods below are effective only before a pregnancy is established. Hormonal EC does not pose a risk to an established pregnancy and is not associated with embryonal developmental abnormalities. Adverse effects for all of the oral methods include nausea and headache as well as irregular bleeding. Adverse effects for the copper IUD include perforation, changes in menses or dysmenorrhea. Pregnancy rates after EC range from 0% to 2.2% and may be impacted by body weight.
KEY POINTS:
Uripristal acetate, a selective progesterone receptor modulator, is given as a single 30 mg dose
Requires a prescription
Efficacy may be reduced in women with BMI ≥30
Effective up to 5 days after unprotected intercourse
FDA approved for EC
Progestin only EC, either 1 tablet Levonorgestrel in a single dose (1.5 mg) or as a split dose (1 dose of 0.75 mg of levonorgestrel followed by a second dose of 0.75 mg of levonorgestrel 12 hours later)
May be less effective in women with BMI ≥25
1 tablet formulation available over the counter without age restriction
2 tablet formulation available over the counter to women ≥17 years with photo ID
Effective for up to 3 days after unprotected intercourse
FDA approved for EC
Copper IUD insertion
Requires office visit and insertion by a clinician
Efficacy not impacted by body weight
Effective up to 5 days after unprotected intercourse
Safe and effective but not FDA labeled for use as EC
LNG-IUDs “are currently being investigated” (ACOG PB) | Recent RCT suggests LNG-IUD is not inferior to copper IUD (see ‘Related ObG Topics’)
Combined progestin-estrogen pills
Can use a variety of formulations (see ‘Learn More – Primary Sources’ WHO entry below for a list of appropriate formulations)
Two doses every 12 hours
All aim for 100 to 120 micrograms of ethinyl estradiol and 0.5 to 0.6 milligrams of levonorgestrel per dose
Requires a prescription
Effective up to 5 days after unprotected intercourse
Safe and effective but not FDA labeled for use as EC
Shen et al. (Cochrane Review, 2017) sought to determine which emergency contraceptive method is the most effective, safe and convenient to prevent pregnancy
METHODS:
Systematic review and meta-analysis
Pooled data from different databases and literature
Primary outcome was observed number of pregnancies
Secondary review outcomes were side effects and changes in menses
RESULTS:
115 trials with 60,479 women were included
Pharmacologic emergency contraceptives were ranked as follows (from most to least effective)
Mifepristone
Mid-dose mifepristone (25 mg to 50 mg) associated with fewer pregnancies than low-dose (less than 25 mg)
Ulipristal acetate (a selective progesterone receptor modulator)
Levonorgestrel
Inconclusive whether single-dose levonorgestrel (1.5 mg) or two-dose regimen (0.75 mg 12 hours apart) is superior
No statistical difference identified between Cu-IUD and mifepristone
Nausea and vomiting
Yuzpe > Mifepristone
Yuzpe > Levonorgestrel
Menstrual irregularities
Ulipristal acetate users are more likely than levonorgestrel to have delayed menstruation
Menstrual delay was more common with mifepristone than with any other intervention and appeared to be dose-related
Obesity: The authors cite results from Jatlaoui and Curtis (Contraception, 2016) systematic review
Levonorgestrel
4-fold increase risk of pregnancy in obese women (BMI ≥ 30 kg/m2) compared to BMI ≤ 25 kg/m2
At weight of 80 kg, pregnancy rate > 6% which is the same as probability without contraception
At weight < 75 kg, rate of pregnancy < 2%
Ulipristal acetate
2-fold increase risk of pregnancy in obese women (BMI ≥ 30 kg/m2) compared to BMI <30 kg/m2 but CIs wide and did not reach statistical significance
However, other analyses did not demonstrate consistent association when adjusting for other covariates
CONCLUSION:
Levonorgestrel and mid-dose mifepristone were more effective than Yuzpe with fewer side effects
Cu-IUD is the most effective emergency contraceptive along with mifepristone and the only method that will provide ongoing contraception and not weight sensitive
With respect to obesity, data is considered limited and poor to fair quality but suggests reduced effectiveness, especially with levonorgestrel
Heavy menstrual bleeding accounts for 1/3 of gyn visits in the US
Multiple treatment options exist when conservative medical therapy (e.g. oral contraceptives) are not sufficient for good control
Spencer et al. (AJOG, 2017) evaluated the relative cost effectiveness of 4 possible treatments
METHODS:
Researchers constructed a hypothetical cohort of 100,000 premenopausal women
Researchers developed a decision tree which weighed a private payer cost with quality-adjusted life years (QALYs) over 5-years for women with heavy menstrual bleeding
4 treatment options
Hysterectomy
Resectoscopic endometrial ablation (REA),
Non-resectoscopic endometrial ablation (NREA)
Levonorgestrel-releasing intrauterine system (LNG-IUS)
Each treatment option’s probabilities of minor complications, major complications, and treatment failure was derived from literature review
Treatments were compared in terms of total average cost, total quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio
RESULTS:
Compared to hysterectomy:
LNG-IUS had superior quality of life outcomes with lower costs
After analysis, LNG-IUS was more cost-effective in 90% of scenarios
Both REA and NREA had reduced costs, but lower average quality of life
Hysterectomy is associated with superior quality of life and fewer complications but more expensive than other treatments
CONCLUSION:
Strong evidence that LNG-IUS is a cost-saving alternative to hysterectomy for heavy bleeding with comparable quality of life outcomes but reduced costs
If LNG-IUS is not an option (patient choice or clinical reasons), decision is not as clear
Hysterectomy results in better quality of life and fewer complications than either type of ablation but at higher cost
Cost, potential complications and patient choice may drive decision
Do Hormonal Contraceptives Protect Against BV and Potential HIV Infection?
BACKGROUND AND PURPOSE:
Studies have shown that the composition of the vaginal microbiome may also impact predisposition to STDs and BV
There is an association between BV and HIV susceptibility
Research also indicates that hormonal contraception may impact STDs and BV
Use of estrogen-containing contraceptives appears to decreases BV
Effect of progesterone inconclusive
This study by Brooks et al. (Contraception, 2017) aimed to explore the effects of hormonal contraceptives on the vaginal microbiome
Researchers also sought ascertained amount of H2O2-producing Lactobacillus abundance as a decrease in Lactobacillus and replacement by bacteria can result in BV
METHODS:
Retrospective Study
16s rRNA genes from vaginal bacteria were sequenced and identified
Gene survey data was taken from the Human Vaginal Microbiome Project
682 women who used a single form of birth control were included
Types of birth control were: condoms, combined oral contraceptives (COCs), depot medroxyprogesterone acetate (DMPA), or IUD, specifically the levonorgestrel-releasing intrauterine system (LNG-IUS)
RESULTS:
Compared to women using condoms,
COC (adjusted odds ratio 0.29, 95% CI 0.13-0.64) and DMPA (adjusted odds ratio 0.34, 95% CI 0.13-0.89) are both less likely to have BV-associated bacteria
Women who used COCs (adjusted odds ratio 1.94, 95% CI 1.25-3.02) had increased Lactobacillus species
Neither LNG-IUS nor DMPA was associated with Lactobacillus abundance
CONCLUSION:
Use of COCs significantly increased the odds of vaginal colonization by healthy lactobacilli
This study provides supporting data that COCs increase healthy, protective vaginal flora
IUDs and Implants: How to Manage Potential LARC Complications
Use of long-acting reversible contraceptive (LARC) methods, both intrauterine devices and subdermal contraceptive implants, has increased dramatically in the past ten years. Although the risk of complications is low, as use increases the absolute number of complications will increase.
CLINICAL ACTIONS:
Intrauterine device:
Pain
Lidocaine paracervical block reduces pain scores on insertion
Misoprostol does not improve pain scores and may be associated with nausea and vomiting
Strings not visualized
Rule out pregnancy and expulsion
Recommend backup contraception until IUD position can be verified
Ultrasound and X-ray of abdomen and pelvis can be used for localization
Possible expulsion
IUDs seen in the cervix are partially expelled and should be removed
Replacement or use of another method are both acceptable options
Low-lying IUDs (lower uterine segment) can be expectantly managed
Risk factors for expulsion include
Young age
Heavy menstrual bleeding and dysmenorrhea
Placement postpartum or post second trimester abortion
Presence of anatomic distortion of the uterine cavity
Uterine perforation
Is rare and generally asymptomatic
Usually occurs at the time of insertion
Do not use misoprostol routinely prior to insertion in nulliparous women but may be considered with difficult insertions
Rule out pregnancy and remove surgically unless the surgical risks of removal outweigh the benefits
PID
Can be treated with the IUD left in situ
Consider removal if no clinical improvement after 48-72 hours of antibiotics
Pregnancy with an IUD in place
Remove the IUD if the strings are visible or IUD within the cervix
IUD can be removed at time of procedure if patient elects termination
Evaluate for ectopic pregnancy
Implant:
Infection prevention
Use antiseptic technique and cover the insertion/removal site
Skin flora are the most common cause of infection
Remove implant if infection does not resolve
Bruising
Is common
Ice and anti-inflammatory medication can help
Nonpalpable implant
Locate with high frequency (>/= 10 MHz) ultrasound probe, two dimensional X-ray, or CT scan/fluoroscopy
Obtain a serum etonogestrel level if all studies are negative/equivocal
Refer to a surgeon with knowledge of the anatomy of the arm if implant is within muscle or neurovascular bundle
Pregnancy
Is rare
Remove the implant if the pregnancy is to be continued
Rule out ectopic pregnancy
SYNOPSIS:
LARCs are highly effective contraceptives with a low risk of complications. Those mentioned above should be discussed with patients as part of informed consent.
KEY POINTS:
Recognition and prompt diagnosis/treatment of the untoward outcomes described above are important aspects of care
Overall, complication rates are low and LARCs remain a very effective mode of birth control
Prolactinoma: Early Detection, Evaluation and Management
CLINICAL ACTIONS:
Prolactinomas are generally benign prolactin-secreting tumors and account for 40-66% of all pituitary adenomas. The vast majority are microadenomas (diameter < 1cm) and suppress the hypothalamic-pituitary gonadal hormonal axis, while 10% are macroadenomas (≥ 1cm) and may cause additional mass effects due to size. Ageprevalence varies widely, but they are commonly found in women during childbearing years, in part due to development of menstrual irregularities. Despite their benign nature, if diagnosis is delayed bone loss and vertebral fractures can occur, and the loss of bone density can be permanent.
Clinical signs and symptoms:
Oligo or amenorrhea
Galactorrheaand gynecomastia
Loss of libido and erectile dysfunction
Infertility
Decreased bone density
Mass effect:
Headache
Visual field abnormalities
Evaluation:
Endocrine Society practice guideline
“To establish the diagnosis of hyperprolactinemia, we recommend a single measurement of serum prolactin; a level above the upper limit of normal confirms the diagnosis as long as the serum sample was obtained without excessive venipuncture stress”
History should be obtained to rule out obvious causes of elevated prolactin such as medications
MRI pituitary with and without contrast to assess size and type of tumor
Prolactin levels
Prolactin levels above 200 µg/L is usually a prolactinoma
Prolactin levels above 500 µg/L likely indicates a macroprolactinoma
Prolactin macroadenomas can present with a falsely normal prolactin level due to the “hook effect” (false negative levels if excessive amount of analyte is present)
When prolactin values are lower than expected in a patient, consider discussion with endocrinologist or clinical pathologist for further guidance
Non-prolactin secreting pituitary adenomas can cause pituitary stalk or hypothalamus compression and consequent prolactinemia
TSH, free thyroxine (FT4), and creatinine levels to exclude secondary causes
Treatment:
Minimal symptoms (mild galactorrhea and normal menses): observation and monitor q6-12 months may be acceptable
Oligo or amenorrhea (pregnancy not desired): oral contraceptives or other estrogen/progesterone combinations
Most patients placed on dopamine agonists
Cabergoline > bromocriptine in reducing prolactin levels
Nearly 80% of patients treated with dopamine agonists will normalize prolactin level and reduce the size of their adenoma
Transsphenoidal surgery
Can result in normal prolactin levels in majority of microadenomas and up to 40% in macroadenomas
Recommended: When dopamine agonists not tolerated/desired | Acute tumor complications |Visual deficits not corrected with medical therapy
Recurrence is possible (20% over 10 years)
Radiotherapy
Rarely used for those cases that do not respond to the above
Chemotherapy
Temozolamide rarely used with limited success
Follow Up
Once prolactin levels have improved monitoring is recommended with repeat prolactin levels every 3 to 6 months for the first year and then every 6 to 12 months thereafter
MRI should be repeated in 1 year for microadenomas or 3 months for macroadenomas after medical therapy is initiated
Therapy may be tapered after 2 years of treatment for patients with normal prolactin levels and no visible tumor on MRI
Recurrence rates after stopping dopamine agonists is between 26 to 69% and most likely to occur in the first year, and should be monitored with serial prolactin measurements every 3 months for the first year and annually thereafter
SYNOPSIS:
The prevalence of prolactinomas is reported to be between 35 to 50 per 100,000. They are most commonly seen in women (10:1 ratio female/male) and the usual age range is between 20 to 50 years of age. Dopamine originating in hypothalamic neurons is a principal inhibitory regulator of prolactin release by pituitary lactotrophs and this pathway is the basis of medical treatments. Fortunately, only a minority of microadenomas will continue to grow (< 10%) but early detection, monitoring and a management plan, which may be multidisciplinary, is required for good outcomes. Consider accessing expertise in endocrinology and radiology to ensure correct differential between prolactinoma and non-secreting pituitary adenoma as treatment for the latter is usually surgical, not medical.
KEY POINTS:
Severe adverse effects of dopamine inhibitors are unusual but cabergoline may include compulsive behavior (e.g. excessive gambling) as well as cardiac valvular abnormalities at high doses
Expert Opinion: Over-the-Counter Contraceptives for Adolescents
PURPOSE
This article by Upadhya et al. (JAH, 2017) aimed to review the regulatory and scientific issues with changing oral contraceptives (OCs) to over-the-counter status for adolescents under 18 years of age.
METHODS
Expert Opinion
RESULTS
This review delves into information about: 1) how the process of switching a drug to over-the-counter status works, 2) risk of pregnancy and the safety of OC use in adolescents, 3) adolescents’ ability to properly use OCs, 4) access to over-the-counter OCs, 5) effects on sexual risk behaviors, 6) potential in reduction of occasions for doctors to inform adolescents about reproductive health care. There is strong rationale for allowing adolescents access to over-the-counter OCs if there occurs any regulatory change. OCs are effective and safe for adolescents, and easy access to OCs, condoms, and emergency contraception increases their use while not increasing sexual risk behaviors.
Is there a Link Between Oral Contraception Use and Cancer Risk?
PURPOSE:
This study by Iversen et al. (AJOG, 2017) sought to explore the relationship between oral contraceptive use and cancer risk.
METHODS:
Prospective Cohort Study
RESULTS:
46,022 women were recruited for this study between 1968-1969 and were followed up for 44 years. Long term users of combined oral contraceptives were compared to women who had never used. 4,661 of the 884,895 (0.005%) ever users had at least one cancer, compared to 2,341 of the 388,505 (.006%) never users. Ever use of oral contraceptives was associated with lower incidences of colorectal, endometrial, ovarian, and lymphatic and hematopoietic cancers. Increased risk of breast and cervical cancer was seen in current and recent users, but appeared to be lost within five years of stopping oral contraception, with no further increased risk in either of these cancers over time. This long-term study found that the majority of women taking oral contraceptives do not have an increased risk for cancer, and many benefit from reductions in risk of certain cancers.
Does Use of Oral Contraceptives Impact Risk of MS Relapse?
PURPOSE:
This study by Bove et al. (Multiple Sclerosis, 2017) evaluated the relationship between oral contraceptives (OCs) and risk of relapse for women with multiple sclerosis (MS).
METHODS:
Longitudinal observational cohort study
RESULTS:
162 women with MS or clinically isolated syndrome (CIS) taking OCs who had begun injectable disease-modifying therapy within two years of diagnoses were studied. The study examined women who currently take OCs, had taken OCs in the past, and those who had never taken OCs. Women who had previously taken OCs had lower rates of relapse than those who had never take OCs. Annualized relapse rate was not significantly different across the three groups of women. Important conclusion based on the data – OC use does not increase risk of MS relapse.
PCOS: Targeting Treatments to Improve Reproductive Outcomes and Reduce CVD
Polycystic ovary syndrome (PCOS) is poorly understood and is characterized by varying degrees of hyperandrogenism, ovarian dysfunction and polycystic ovaries. Due to insulin resistance, women with PCOS are at increased risk for metabolic syndrome and consequent diabetes and cardiovascular events. Unopposed estrogen may result in endometrial cancer. Once identified, women need to be counseled and treated appropriately to reduce their risk of these health problems.
CLINICAL ACTIONS:
Treatment for Menstrual Disorders
Women with PCOS who are not attempting to conceive:
Combined oral contraceptives suppress luteinizing hormone secretion, ovarian androgen secretion and increase circulating sex hormone binding globulin (SHBG)
Recommended for primary treatment of menstrual disorders
May also be used to treat hirsutism
Progestin-only contraceptives or progestin containing IUDs protect the endometrium but lead to abnormal bleeding patterns in over 50% of patients
Insulin sensitizing agents, including biguanides (metformin) and thiazolidinediones (pioglitazone, rosiglitazone)
The use of insulin sensitizers are associated with decrease in androgen levels, improved ovulation, improved glucose tolerance
Important to discuss contraception
The insulin sensitizing agents are not currently approved by the FDA for the treatment of PCOS
Metformin, according to ACOG has the “safest risk-benefit ratio”
The International Guideline recommends metformin for those women with metabolic features of glucose intolerance/ insulin resistance
Treatment for Hirsutism
Women with PCOS can be treated with the following:
Treatment to Reduce Cardiovascular and Diabetes Risks
Women with PCOS who are not attempting to conceive:
Lifestyle modification (e.g. regular exercise and weight loss)
Weight loss is the primary therapy in PCOS: As little as 5% reduction in weight can restore regular menses and improve response to fertility medications
No advantage in any particular diet – caloric restriction is the key factor
Insulin sensitizing agents such as metformin can delay development of diabetes in those at risk
Data currently insufficient to recommend insulin-sensitizing agents prophylactically for women at higher risk of diabetes due to PCOS
Statins lower testosterone, total and LDL cholesterol levels but do not improve menses, hirsutism or acne
No evidence that combined hormonal contraceptives or progestins will increase the risk of diabetes or CVD in women with PCOS
Treatment for Women with PCOS Planning to Conceive
First-Line Interventions
Letrozole
Letrozole (aromatase inhibitor) is considered a first-line treatment due to data demonstrating increased ovulation rates, clinical pregnancy rates and live-birth rate vs clomiphene citrate
Counsel patients that letrozole is not approved by the FDA for ovulation induction
Letrozole starting dose is 2.5 mg/day for 5 days starting day 3, 4 or 5 of cycle and increase to 5 mg/day for 5 days with a maximum dosage of 7.5 mg/day if ovulation does not occur at lower, initial dose
Clomiphene Citrate
‘Traditional’ first-line treatment with improved performance compared to metformin alone or placebo
Over 50% of those who conceive do so on 50 mg/day dose and 20% on 100 mg/day dose
Most pregnancies occur within 6 months
Both clomiphene citrate and letrozole are associated with increase in multiple births, preterm birth, and hypertensive disorders
Second-Line Interventions
If clomiphene citrate or letrozole fails
Gonadotropins
Laparoscopy with ovarian drilling
Third-Line Intervention
The International Guideline considers IVF to be a third line intervention for PCOS
Diabetes Assessment
Screening for Diabetes
Assess glycemic status at baseline in all women at time of PCOS diagnosis and repeat every 1 to 3 years depending on other risk factors
To assess glycemic status, use one of the following tests
Oral glucose tolerance test (OGTT)
Fasting plasma glucose
HbA1c
OGTT is recommended in women with PCOS and risk factors
BMI > 25 kg/m2
Asians > 23 kg/m2
History of impaired fasting glucose
Impaired glucose tolerance or gestational diabetes
Family history of diabetes mellitus type 2
Hypertension
High-risk ethnicity
Women considering fertility treatment or preconception planning
Prior to fertility treatment and/or preconception planning
Offer all women a 75-g OGTT
In pregnancy
If not performed preconception, offer OGTT<20 weeks
Offer all pregnant women with PCOS an OGTT at 24-28 weeks gestation
SYNOPSIS:
Once diagnosed, treatment of PCOS should be tailored to patient’s risk factors and desires. Lifestyle modifications including weight reduction and regular exercise have been shown to decrease the metabolic and hormonal effects of PCOS. Treatment regimens are based on protecting the endometrium from the effects of unopposed estrogen, reestablishing a regular menstrual cycle, preventing the metabolic syndrome and cardiovascular sequelae of PCOS, and providing support for ovulatory dysfunction in those anticipating pregnancy.
KEY POINTS:
ACOG Practice Bulletin updated based on recent data that letrozole outperforms clomiphene citrate for ovulation induction
Higher live-birth rate: 27.5% vs 10.1% (P=0.007) with odds ratio of 1.64 (95% CI, 1.32-2.04)
Higher ovulation rate: 61.7% vs 48.3% (P<0.001)
Higher clinical pregnancy rate: Odds ratio of 1.40 (95% CI, 1.18-1.65)
Before starting medical/surgical ovulation induction therapies, counsel about lifestyle modification including
Stop smoking
Reduce weight and increase exercise especially in setting of overweight/obesity
Reduce alcohol consumption
Both letrozole and clomiphene citrate are contraindicated in pregnancy
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