HRT and cognition

One of the desired benefits of postmenopausal hormone replacement therapy (HRT) is that of improved cognitive function. Like many aspects of HRT research, results have been mixed. The authors of this study describe a ‘critical window’ hypothesis in which previous studies suggest HRT given to recently menopausal women improves cognitive function, while HRT commenced after 65 years of age has an adverse effect on cognitive function. The Kronos Early Estrogen Prevention Study–Cognitive and Affective Study (KEEPS-Cog), an ancillary study of the Kronos Early Estrogen Prevention Study (KEEPS), is a randomised trial designed to investigate the cognitive and mood effects of up to four years of HRT in recently post-menopausal women. Over 700 women were randomly allocated to receive oral congugated equine oestrogens (CEE), transdermal estradiol or placebo for up to four years. Women were assessed on both mood and cognitive measures both at the beginning and end of the study.

The results of this randomised study did not show an improvement in cognitive function in women receiving HRT in the early menopause, compared to placebo. For mood outcomes, administration of low-dose oral CEE for up to four years was associated with statistically significant improvements in symptoms of anxiety and depression, mood symptoms commonly seen in recently postmenopausal women. Administration of transdermal estradiol did not benefit mood. Women considering HRT for menopausal symptoms may find the results of this study useful when comparing the risks and benefits in their particular case.

Medical treatment of ectopic pregnancy

Ectopic pregnancy complicates one to two per cent of pregnancies. It is a potentially severe complication of early pregnancy and can lead to tubal rupture, haemorrhage and death if untreated. Fortunately, in well-resourced medical settings, ectopic pregnancy is often diagnosed early, owing to improvements in ultrasound and biochemical testing. Once diagnosed, treatment of ectopic pregnancy may be expectant, medical or surgical, with the choice of modality depending on clinical situation, local protocols and patient and clinician preference.

Methotrexate, which inhibits the metabolism of folic acid, is the most commonly used drug for the medical treatment of ectopic pregnancy. Methotrexate may be given in multiple and single-dose protocols but is not invariably successful, with 10–25 per cent of women receiving methotrexate for the treatment of ectopic pregnancy eventually requiring surgical treatment. A recent paper by Capmas and Fernandez reviews the current evidence of using a combination of gefitinib and methotrexate to treat ectopic pregnancy, with the aim of improving the effectiveness of the treatment.1 Gefitinib is an epidermal growth factor receptor (EGFR) inhibitor that is used in the treatment of non-small cell lung cancer and in breast cancer. It can be taken orally, and placental tissues have been found to have the highest expression of EGFR of human non-malignant tissues, making it well suited to the treatment of ectopic pregnancy.

In one small study, 12 women received both a single dose of methotrexate and gefitinib over a one week treatment protocol. Ten out of 12 women’s (83 per cent) ectopic pregnancies resolved with the combination of methotrexate and gefitinib and one out of ten needed a rescue methotrexate injection.² Compared to historical control patients treated with methotrexate alone, the median time to recovery was 11 days shorter in the combination treatment. A second study reported a case series of eight non-tubal ectopic pregnancies (five interstitial, three in caesarean scar) with all cases resolving without the need for surgery.³ The authors of the review article conclude that, while more study is needed, there may be place in the future for the addition to gefitinib to methotrexate in the treatment of ectopic pregnancy.

Reversal of hysteroscopic sterilisation

Selective serotonin reuptake inhibitors (SSRIs) are common anti-depressant medications used by many women in pregnancy. These two studies continue the examination of the evidence of a link between SSRI use in pregnancy and congenital abnormalities. Reefhuis et al report US data on 17 000 pregnancies with birth defects and 9000 pregnancies without birth defects, examining the effect of exposure to citalopram, escitalopram, fluoxetine, paroxetine or sertraline in the month before pregnancy or in the first trimester. High odds ratios excluding zero were observed for five birth defects with paroxetine (anencephaly 3.2, 95 per cent CI 1.6 to 6.2; atrial septal defects 1.8, 1.1 to 3.0; right ventricular outflow tract obstruction defects 2.4, 1.4 to 3.9; gastroschisis 2.5, 1.2 to 4.8; and omphalocele 3.5, 1.3 to 8.0) and for two defects with fluoxetine (right ventricular outflow tract obstruction defects 2.0, 1.4 to 3.1 and craniosynostosis 1.9, 1.1 to 3.0).1 Wemakor et al report European data on over 40 000 pregnancies with infants with congenital abnormalities. SSRI exposure in first trimester pregnancy was associated with congenital heart defects overall (OR adjusted for registry 1.41, 95 per cent CI 1.07–1.86, fluoxetine adjusted OR 1.43 95 per cent CI 0.85–2.40, paroxetine adjusted OR 1.53, 95 per cent CI 0.91–2.58) and with severe CHD (adjusted OR 1.56, 95 per cent CI 1.02–2.39), particularly Tetralogy of Fallot (adjusted OR 3.16, 95 per cent CI 1.52–6.58) and Ebstein’s anomaly (adjusted OR 8.23, 95 per cent CI 2.92–23.16). Significant associations with SSRI exposure were also found for ano-rectal atresia/stenosis (adjusted OR 2.46, 95 per cent CI 1.06–5.68), gastroschisis (adjusted OR 2.42, 95 per cent CI 1.10–5.29), renal dysplasia (adjusted OR 3.01, 95 per cent CI 1.61–5.61) and clubfoot (adjusted OR 2.41, 95 per cent CI 1.59–3.65).²

Both these studies showed paroxetine and fluoxetine were associated with an increased risk of congenital heart defects, while gastroschisis was also increased with SSRI use in pregnancy in both studies. As always, the risk of untreated depression during pregnancy must be weighed for each woman before a decision is made regarding the continuation or cessation of SSRIs in pregnancy. Furthermore, as Wemakor et al state, the individual increased risk of congenital anomaly with SSRIs with these results is in the order of 0.5 per cent per pregnancy. These papers do, however, suggest an increased association with some defects with paroxetine and fluoxetine compared to other SSRIs.