Abstract
It is understood that drugs administered to sufferers of bipolar disorder during pregnancy might increase the probability of complications during gestation or birth. Research has now been published in the BMJ suggesting that expectant mothers with the disorder are more likely to experience premature labor or give birth to infants with growth abnormalities, even if the women remain untreated.
Scientists from Uppsala University (Sweden) and the Karolinska Institutet (Solna, Sweden) undertook an analysis of data from three national databases. Two of the registers covered drug prescriptions and births in Sweden between 2005 and 2009, while the third included patient information from 1997 to 2009. Using the patients' identification numbers given on each register, the researchers were able to collate and compare the information.
From this data, they were able to find records of 320 mothers who had received treatment for bipolar disorder during pregnancy, and 554 mothers who remained untreated. The researchers compared the results of these pregnancies to the 331,263 unaffected mothers who gave birth during that time period, adjusting for factors such as weight, maternal age and substance abuse.
The results of the data analysis highlight a significant statistical difference between the outcome of births from women with or without bipolar disorder, whether or not they were treated with mood-stabilizing drugs during pregnancy. According to the data set, women with bipolar disorder are approximately 50% more likely to have experienced preterm birth, induced birth or a cesarean delivery compared with women without bipolar disorder. Induced and cesarean deliveries occurred in 37.5, 30.9 and 20.7% of births for treated women with bipolar disorder, untreated women with bipolar disorder and women without bipolar disorder, respectively. Preterm births occurred in 8.1, 7.6 and 4.8% of cases, respectively.
Furthermore, untreated women were shown to be statistically more likely to give birth to children with growth abnormalities. It was found that 3.9% of the untreated women gave birth to a microcephalic infant, while 2.3% of the infants of women without bipolar disorder were affected. Similarly, 4.3% of infants born to women with untreated bipolar disorder demonstrated neonatal hypoglycemia (periodic low blood sugar levels), compared with 2.5% among infants of mothers without bipolar disorder. Intriguingly, the researchers did not find a statistically significant difference between women who were treated and untreated for their disorder during pregnancy, suggesting that the disorder itself might be having an effect on the outcome of pregnancy and birth rather than just the medication.
Growth-related outcomes of babies from women with bipolar disorder who were either treated with mood-stabilizing drugs or untreated throughout pregnancy.
In an Editorial published alongside the research, Salvatore Gentile (Centro di Salute Mentale, Cava de' Tirreni, Italy) discussed the implications of the findings for the provision of medication to pregnant patients with bipolar disorder. He concluded that “drug treatment is only one part of the overall management of pregnant women diagnosed with severe and persistent psychiatric disorders.” Instead, Gentile suggested that an “integrated tailored approach to management must be provided for these vulnerable mothers,” where the provision of medication will be considered beside other case-specific factors.
This is a point of view shared by Robert Bodén (Uppsala University), one of the lead researchers of the study. He explained that “many pregnant women with bipolar disorder can become severely ill if not treated with prophylactic mood-stabilizing drugs, but due to fear of harming the fetus they might stop their medication.” He hopes that clinicians will incorporate the findings “in their risk–benefit analyses when guiding these women through their pregnancies, providing them with a more balanced view of drug treatment of their mood disorder.”
Speaking to Women's Health about plans for research following this study, Bodén said that one goal is to “analyze lithium exposure alone” in pregnant bipolar women, and perhaps through international collaboration they could have access to “a larger cohort to be able to study the risk of malformations and also to explore dose–response and timing effects of medication.” He commented that “another important area for future research is placental passage of these medications and to see if there are long-term effects on cognition and other developmental outcomes in the infants.”
– Written by Michael Mansbridge
Sources: Bodén R, Lundgren M, Brandt L, Reutfors J, Andersen M, Kieler H. Risks of adverse pregnancy and birth outcomes in women treated or not treated with mood stabilisers for bipolar disorder: population based cohort study. BMJ doi:10.1136/bmj.e7085 (2012) (Epub ahead of print); Gentile S. Bipolar disorder in pregnancy: to treat or not to treat? BMJ doi:10.1136/bmj.e7367 (2012) (Epub ahead of print).
Women with treated cervical intraepithelial neoplasia remain at higher risk of developing cervical cancer, study indicates
Research published recently in the BMJ by scientists from Erasmus Medical Center (Rotterdam, Netherlands) suggests that women treated for cervical intraepithelial neoplasia (CIN) might be up to four-times more likely to develop cervical cancer than untreated women. Significantly, the probability of developing cancer appears to remain higher for women affected by CIN long after the condition has been treated.
“Women treated for cervical intraepithelial neoplasia might be up to four-times more likely to develop cervical cancer than untreated women.”
The investigators analyzed the data found on the Dutch national databases between 1991 and 2007, which cover 99% of all incidents of histopathology and cytopathology in The Netherlands. Collating and comparing the information given on different registers, the researchers were able to statistically analyze the proportion of women previously affected and unaffected by CIN who had later developed cervical cancer.
The results showed that of the women previously diagnosed and treated for CIN, 20 incidences of cervical cancer were reported within the 56,956 woman-years following the completion of treatment. By contrast, 1613 incidences of cervical cancer were reported within the combined 25,020,697 woman-years when CIN was not detected in the initial smear test. Equating to an average of 35.1 and 6.4 incidents of cervical cancer per 100,000 woman-years, respectively, this represents a fourfold increase in the likelihood of women diagnosed with CIN developing cervical cancer.
Although the link between cervical cancer and CIN has already been suggested, the policy at present is often to return women to routine cytological screening regularity as soon as CIN has been shown to be fully treated. The new evidence suggests that even after three clear cytological tests, women previously diagnosed with CIN are still significantly more likely to develop cervical cancer than unaffected women.
“Even after three clear cytological tests, women previously diagnosed with cervical intraepithelial neoplasia are still significantly more likely to develop cervical cancer than unaffected women.”
The researchers, however, warn that their study alone cannot “give a straightforward answer as to what should be recommended in the longer term”. They advise that “several factors should be taken into account when deciding on the optimal length of post-treatment follow-up” and suggest that although the risk of contracting cervical cancer is significantly higher in women who have previously been diagnosed with CIN, the likelihood is “still low”.
On the other hand, a recent study independently published within the same journal does provide recommendations for the future of cervical cancer screening. A team of researchers analyzed the relative cost–effectiveness of cytological and human papillomavirus (HPV) screening in women following diagnosis of CIN.
Lead researcher Rosa Legood (London School of Hygiene and Tropical Medicine, UK) described the implications of the results to Women's Health. “When women have been treated for precancer cervical lesions, until recently, the recommendation was to have annual repeated cytology testing for 10 years. Our modeling results suggest that it would be more effective to change the screening method to also test them for HPV.” She states that if given the HPV test, women can be safely returned “to routine screening, reducing the need for follow-up.”
Legood believes this results in a “benefit for women from reduced follow-up and also cost savings” for health institutions. As a result, in the UK, “recommendations from the National Health Service cancer screening program have now been changed to recommend HPV testing in post-treatment management of precancer lesions.”
– Written by Michael Mansbridge
Sources: Rebolj M, Helmerhorst T, Habbema D et al. Risk of cervical cancer after completed post-treatment follow-up of cervical intraepithelial neoplasia: population based cohort study. BMJ 345, e6855 (2012); Legood R, Smith M, Lew J et al. Cost effectiveness of human papillomavirus test of cure after treatment for cervical intraepithelial neoplasia in England: economic analysis from NHS Sentinel Sites Study. BMJ 345, e7086 (2012).
Molecular flags identified in women with breast cancer that could predict their response to tamoxifen
Researchers at the University of Manchester's Paterson Institute for Cancer Research (UK) have recently discovered a molecular flag in women with breast cancer that can be used by doctors to help predict how a patient will respond to treatment with the drug tamoxifen.
Tamoxifen is used in complementary (adjuvant) hormone therapy, with radiotherapy and chemotherapy, to treat types of breast cancer where the hormone estrogen is essential for tumor growth. In these patients, who have estrogen receptor-positive breast cancer, tamoxifen is used to block the hormone and has been shown to increase breast cancer survival rates by up to one third. Estrogen receptor-positive breast cancer is the most common form of the disease, accounting for 70% of all breast cancers. However, not all patients respond positively to hormone therapy. Approximately one third do not, or develop resistance to tamoxifen.
Lead author Göran Landberg, University of Manchester, explained: “The identification of molecular flags to classify subgroups of breast cancer and so determine the best treatment for each patient is of increasing importance in cancer therapy. Tamoxifen has been shown to be highly effective in some breast cancer patients when used alongside traditional cancer therapies but, in a third of cases, the result has not been what we would hope. If we can predict which patients will respond to tamoxifen and those who won't, then this is clearly advantageous as it means the correct treatment is provided instantly, which will improve disease outcomes.”
The study, recently published in the journal PLoS ONE, investigated the tumor growth signals sent by connective tissue surrounding the tumor. The team analyzed tissue microarrays of two breast cancer cohorts. This included samples from 564 women with invasive breast cancer. Some of the women were treated with tamoxifen and some were not. They discovered that connective tissue cells (fibroblasts) differed between patients and could indicate how a patient might respond to treatment with tamoxifen.
Study author, Susan Busch, University of Manchester, discussed the findings: “We discovered that women who had low levels of a protein known as pERK in their cancer-associated fibroblasts did not respond to tamoxifen. Testing patients for the pERK flag could help doctors determine whether tamoxifen is an appropriate treatment for their patient or whether alternative therapies should be explored, so saving time and money”
The researchers intend to continue studying molecular flags in cancer-associated fibroblasts in the hope of understanding how these cells encourage the tumor to grow. Understanding this could lead to new therapies developed to block these signals and conquer drug resistance.
– Written by Madeleine Nowak
Sources: University of Manchester press
release: www.manchester.ac.uk/aboutus/news/display/?id=8967; Busch S, Rydén L, Stål O, Jirström K, Landberg G. Low ERK phosphorylation in cancer-associated fibroblasts is associated with tamoxifen resistance in pre-menopausal breast cancer. PLoS ONE 7(9), e45669 (2012).
Early menopause in mothers might predict fertility problems in their daughters
In a recent study at the Copenhagen University Hospital (Denmark), the number of eggs remaining in a woman's ovaries has been found to correlate with their mother's age at menopause.
Researchers compared the maternal age at menopause with measurements of the levels of anti-Müllerian hormone (AMH) and antral follicle count (AFC), both indicators of ovarian reserve, in their daughters. They found that AMH and AFC decline at a faster rate in women whose mothers had an early menopause compared with those whose mothers had a later menopause. The ovarian reserve is an indication of the ability of a woman to conceive naturally.
Lead investigator Janne Bentzen, Copenhagen University Hospital, commented: “This is the first study to suggest that the age-related decline of AMH and AFC may differ between those whose mothers entered menopause before the age of 45 years and those whose mothers entered menopause after the age of 55 years. Our findings support the idea that the ovarian reserve is influenced by hereditary factors.”
The number and quality of eggs in a woman's ovaries start to decline as she gets older, and previous research has suggested that the onset of menopause occurs about 20 years after a woman's fertility starts to decline. Therefore, a woman entering menopause at 45 is expected to have experienced declining fertility from the age of 25. Bentzen said: “In line with the suggested 20-year interval between the first decline in fertility and the menopause, we hypothesised that maternal factors may also have an impact on a woman's fertility potential in terms of ovarian reserve.”
The researchers divided 527 women aged between 20–40 years into three categories early menopause (younger than 45 years); normal maternal age at menopause (46–54 years); and late maternal age at menopause (older than 55 years). The AFC was performed using transvaginal sonography and the AMH levels were measured from blood samples.
The results, adjusted to take into account factors known to affect AMH and AFC measurements (i.e., smoking, contraceptive use, age and BMI) showed that in the groups of women with mothers who had early, normal or late menopause, the average AMH levels declined by 8.6, 6.8 and 4.2% a year, respectively. The AFC results also followed a similar pattern, with annual declines of 5.8, 4.7 and 3.2% in the same groups, respectively.
However, Bentzen urged caution when applying this research to individual cases: “Conclusive evidence can only be obtained when we have longitudinal studies that follow women who have AMH measurements over time until menopause. Therefore, interpretations of our data are limited and the findings we have described may not occur in any given individual.”
– Written by Sophie Breeze
Sources: Press release: European Society of Human Reproduction and Embryology press release. www.eshre.eu/ESHRE/English/Press-Room/Press-Releases/Press-releases-2012/Maternal-menopause/page.aspx/1764; Bentzen JG, Forman JL, Larsen EC et al. Maternal menopause as a predictor of anti-Müllerian hormone level and antral follicle count in daughters during reproductive age. Human Reprod. doi:10.1093/humrep/des356 (2012) (Epub ahead of print).