What are the potential side effects of Clomid (clomiphene citrate) in women of childbearing age with ovulation disorders?

Side Effects of Clomid (Clomiphene Citrate)

Clomid carries significant risks including visual disturbances that may be irreversible, ovarian hyperstimulation syndrome (OHSS) that can be life-threatening, and increased rates of multiple pregnancy—all of which require careful monitoring and patient counseling before initiating therapy. 1

Visual Symptoms and Ophthalmologic Effects

Visual disturbances are among the most concerning side effects and may be permanent:

• Blurring, spots, flashes (scintillating scotomata), and phosphenes occur with increasing frequency at higher doses and longer treatment duration 1
• These symptoms are usually reversible but cases of prolonged and irreversible visual disturbances have been documented, particularly with increased dosage or extended therapy 1
• Visual symptoms result from intensification and prolongation of after-images, often first appearing or worsening with exposure to bright lighting 1
• Ophthalmologically definable scotomata and retinal cell function changes (electroretinographic abnormalities) have been reported 1
• Patients must discontinue treatment immediately and undergo complete ophthalmological evaluation if any visual symptoms occur 1
• Visual symptoms may render activities like driving hazardous, particularly under variable lighting conditions 1

Ovarian Hyperstimulation Syndrome (OHSS)

OHSS is a potentially life-threatening complication that can progress rapidly:

• OHSS may develop within 24 hours to several days and represents a medical emergency distinct from simple ovarian enlargement 1
• Severe cases manifest with gross ovarian enlargement, gastrointestinal symptoms, ascites, dyspnea, oliguria, and pleural effusion 1
• Additional serious manifestations include pericardial effusion, anasarca, hydrothorax, acute abdomen, hypotension, renal failure, pulmonary edema, intraperitoneal and ovarian hemorrhage, deep venous thrombosis, ovarian torsion, and acute respiratory distress 1
• Death has occurred due to hypovolemic shock, hemoconcentration, or thromboembolism 1
• Early warning signs include abdominal pain and distention, nausea, vomiting, diarrhea, and weight gain 1
• Laboratory abnormalities include elevated urinary steroid levels, electrolyte imbalance, hypovolemia, hemoconcentration, and hypoproteinemia 1
• Transient liver function test abnormalities suggestive of hepatic dysfunction, sometimes with morphologic changes on liver biopsy, have been reported with OHSS 1
• Women with polycystic ovary syndrome are particularly sensitive and may have exaggerated responses even to usual doses 1
• The American Society for Reproductive Medicine confirms OHSS as a potential side effect, especially with multifollicular development 2

Multiple Pregnancy Risk

Multiple pregnancy represents a major adverse outcome with significant morbidity:

• Multiple pregnancy rates are substantially increased, including bilateral tubal pregnancy and coexisting tubal and intrauterine pregnancy 1
• Higher-order multiple pregnancies carry increased risks of prematurity, low birthweight, and neonatal complications 3
• Twin pregnancies from ovarian stimulation with IUI show higher rates of neonatal mortality, assisted ventilation, and respiratory distress syndrome compared to naturally conceived twins 4
• Clomiphene-stimulated pregnancies are associated with higher risk of small for gestational age infants compared to natural cycle conception 4
• The European Society of Human Reproduction and Embryology recommends lower doses to minimize multiple follicular development and reduce multiple pregnancy risk 2

Metabolic and Cardiovascular Effects

Metabolic disturbances and rare cardiovascular events have been documented:

• Hypertriglyceridemia has been reported, particularly with preexisting or family history of hyperlipidemia and with higher doses or longer treatment duration 1
• Periodic monitoring of plasma triglycerides is recommended in at-risk patients, with pretreatment screening advised 1
• The American Academy of Family Physicians notes that clomiphene can alter serum lipid profiles 2
• Acute myocardial infarction has been reported in a young woman without cardiac risk factors taking clomiphene, with total LAD occlusion and heavy thrombus burden 5
• Pancreatitis cases have been documented 1

Ovarian Enlargement and Cyst Formation

Ovarian enlargement is common and requires careful management:

• Ovarian enlargement and cyst formation usually regress spontaneously within days to weeks after discontinuing treatment 1
• Maximal enlargement may not occur until several days after stopping therapy 1
• Due to fragility of enlarged ovaries in severe cases, abdominal and pelvic examination must be performed very cautiously 1
• If ovarian enlargement occurs, additional therapy should not be given until ovaries return to pretreatment size, and subsequent dosage or duration should be reduced 1
• Unless surgical indication exists, cystic enlargement should always be managed conservatively 1

Endometrial Effects

Clomiphene has anti-estrogenic effects on the endometrium:

• Women treated with clomiphene have significantly thinner endometrial thickness compared to those treated with gonadotropins (mean difference: −0.33 mm) 4
• Clomiphene may impair fertility through effects on cervical mucus and various endometrial dysfunctions 6
• However, endometrial thickness has not been shown to correlate with pregnancy rates in IUI treatment 4

Pregnancy Outcomes and Congenital Anomalies

Available data suggest no increased risk of congenital anomalies, but spontaneous abortion rates warrant discussion:

• The spontaneous abortion rate is 20.4% and stillbirth rate is 1.0% based on clinical trial data 1
• Available data suggest no increase in rates of spontaneous abortion or congenital anomalies with maternal clomiphene use compared to the general population 1
• Neural tube defects have been reported at higher proportions among individual case reports, but this has not been supported by population-based studies 1
• Perinatal outcomes after clomiphene pregnancies represent intermediate risk between IVF/ICSI and naturally conceived pregnancies 4

Contraindications and Special Populations

Specific patient populations require avoidance or extreme caution:

• Clomiphene is contraindicated in patients with liver disease, especially decompensated cirrhosis 2, 1
• The drug should not be used in patients with ovarian cysts (except polycystic ovary syndrome), pregnancy, or abnormal vaginal bleeding 1
• In functional hypothalamic amenorrhea, clomiphene should only be used when sufficient endogenous estrogen levels are present 4, 2
• The Endocrine Society recommends BMI ≥18.5 kg/m² before offering ovulation induction to women with functional hypothalamic amenorrhea 4
• Caution is advised with uterine fibroids due to potential for further enlargement 1

Other Reported Adverse Effects

Additional side effects documented in males and through postmarketing surveillance:

• Testicular tumors and gynecomastia have been reported in males using clomiphene, though cause-and-effect relationship is not established 1
• Clomiphene is not recommended for treatment of male infertility 1

Clinical Monitoring Recommendations

To minimize risks, specific monitoring protocols should be followed:

• Pelvic examination is mandatory prior to first treatment and before each subsequent course 1
• Patients must be instructed to report any abdominal or pelvic pain, weight gain, discomfort, or distention 1
• The lowest dose consistent with expected clinical results should be used to minimize ovarian enlargement 1
• Women with PCOS should be started on the lowest recommended dose and shortest treatment duration for the first course 1
• Treatment should probably be limited to a maximum of 12 cycles due to potential association with ovarian tumors 7