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