Safety

The most common adverse events reported in studies of oral NMP in obstetric indications were drowsiness/somnolence and dizziness.16,27,31 In the largest placebo-controlled trial of oral NMP, somnolence occurred in 41.6% of oral NMP recipients versus 19.7% of placebo recipients (p = 0.002), and dizziness in 29.1% versus 9.8% (p = 0.002).31 Studies of oral NMP-SR have reported considerably lower rates of adverse events: 4.3%38 and 6.7%12 for drowsiness, and 3.2% for dizziness.38
The low incidence of adverse events associated with NMP-SR is further supported by a prescription-event monitoring study conducted in India.39 The study evaluated 153 patients with a poor obstetric history (50%), unexplained fertility (43.8%) or secondary amenorrhea (5.9%) who received oral NMP-SR 300 or 400 mg once daily after natural or stimulated ART cycles. Oral NMP-SR was well tolerated. Incidences of adverse effects were low (hyperemesis: 1.3%; drowsiness: 0.6%; giddiness: 0.6%), and events were generally mild and transient.
Only a few direct comparisons of oral NMP with other agents have been published. Oral NMP was associated with more drowsiness and giddiness but less nausea compared with dydrogesterone,27 and with more drowsiness/somnolence but less vaginal irritation compared with vaginal progesterone.16,17,19
In a retrospective analysis, NMP-SR and dydrogesterone were both well tolerated in women who underwent stimulated IUI for unexplained fertility.12 Among 45 women treated with NMP-SR and 33 women treated with dydrogesterone, three drowsiness events and one nausea event were reported with NMP-SR, compared with four nausea events and one drowsiness event with dydrogesterone.
Recently a positive association was described between dydrogesterone exposure during the first trimester of pregnancy and congenital heart disease in the newborns,40 although other authors have argued that weaknesses in the study design preclude ascribing a causal relationship.41 Natural progesterone may have metabolic advantages compared with synthetic progestogens. Oral NMP in 200, 600 and 1200 mg single doses had no effect on mood/performance compared with placebo.42 In contrast to levonorgestrel and medroxyprogesterone acetate which significantly decreased high-density lipoprotein cholesterol subfractions, oral NMP had no apparent effect.43 Oral NMP administered at doses of 50, 100, or 200 mg daily with oral micronised 17β-oestradiol for 4 months in postmenopausal women had no effect on liver enzymes or on circulating levels of lipoprotein A, an independent risk factor for cardiovascular disease in women.44