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26th March 2024
Rheumatic diseases can have a wide-ranging impact on men’s and women’s reproductive health, with effects comparable to other immune-mediated conditions, a Finnish study finds.
It was known that immune-mediated diseases (IMDs) could impair reproductive success and pregnancy outcomes, but systematic evaluations across diseases were lacking, Finnish, US and UK researchers wrote in the journal Rheumatology.
Using Finnish registry data comprising 5,339,804 citizens, individuals born from 1964 to 1984 and diagnosed with any one of 19 IMDs before age 30 (women) and 35 (men) were matched with 20 controls by birth year, sex and education.
Researchers then analysed the impact of rheumatic diseases compared with other IMDs on reproductive health measures, such as reproductive success and, for women, adverse maternal and perinatal outcomes.
‘Overall, we observed a high variability in the prevalence of childlessness and the number of children between diseases, as well as high variability in the impact of individual diseases,’ the researchers reported.
On average, women with IMDs experienced a higher prevalence of childlessness than controls (mean difference 3.6%), with women with Addison’s disease experiencing 23.9% more childlessness, those with juvenile idiopathic arthritis (JIA) 9.3% more childlessness, and those with vitamin B12 deficiency anaemia experiencing 8.6% more childlessness.
Men with an IMD also had a higher prevalence of childlessness than controls (mean difference 4.7%).
In men, most diseases made no difference to childlessness rates, but the three conditions found to have the most impact were myasthenia gravis (20.1% more childlessness), Addison’s disease (16.4% more childlessness), and vitamin B12 deficiency anaemia (13.7% more childlessness).
Several of the rheumatic diseases, particularly systemic lupus erythematosus (SLE), JIA, and seropositive rheumatoid arthritis, were associated with higher rates of childlessness and fewer children in both men and women.
‘IMDs such as psoriatic disease, asthma, alopecia areata, coeliac disease, and [immune thrombocytopenia] ITP, were not associated with an increased prevalence of childlessness or reduced number of children in either sex, although some had higher use of assisted reproductive technology,’ the researchers noted.
“Inflammatory bowel disease (IBD) was not, in contrast to the findings of previous studies, associated with an increased risk of childlessness, suggesting that treatment improvements may have positively impacted the reproductive health of these patients.’
In other findings, the risks for pre-eclampsia, newborns being small for gestational age, preterm delivery, non-elective Caesarean sections, and need of neonatal intensive care were increased in many IMDs.
‘Particularly, SLE, [Sjogren’s syndrome] SS, type 1 diabetes, and Addison’s disease showed >2-fold risks for some of these outcomes,’ the researchers reported.
‘Of the rheumatic diseases, SLE and SS conferred the largest risk increases on perinatal adverse event outcomes.’
In most rheumatic diseases, moderate (1.1–1.5-fold) risk increases were observed for diverse adverse pregnancy outcomes, with similar effects in IBD, coeliac disease, asthma, ITP and psoriasis.
Lead author Dr Anne Kerola, resident in rheumatology at the Helsinki University Hospital in Finland, said despite seeing an elevated risk for diverse childbearing problems in rheumatic and other IMDs, many of the complications were still fairly rare.
‘Family planning should actively be discussed between patients, both men and women, with rheumatic diseases and their healthcare providers,’ she said.
‘Pregnancies in women with rheumatic diseases are carefully followed up to tailor medications appropriately, which helps reduce risks.’
IMDs have also been linked to other adverse outcomes including an increased risk of atrial fibrillation (AF). In a prospective study published last year, Dutch researchers found there were elevated risks of AF for those with several autoimmune diseases including Crohn’s disease (HR = 1.23), ulcerative colitis (HR = 1.17), rheumatoid arthritis (HR = 1.39), SLE (HR = 1.82) and systemic sclerosis (HR = 2.32).
7th December 2023
New regulatory measures tightening the rules around valproate prescribing are set to come into force from January 2024, and the Medicines and Healthcare products Regulatory Agency (MHRA) is urging healthcare organisations to adequately prepare.
From the new year, the first phase of the new measures will curb the use of valproate in new male or female patients under 55 years of age unless two specialists independently find there is no other effective or tolerated treatment, or that there are ‘compelling reasons that the reproductive risks do not apply’.
The measures aim to reduce the significant risk of serious harm to babies if sodium valproate, valproic acid or valproate semisodium are taken during pregnancy, as well as the risk of impaired fertility in males associated with the drug’s use.
These regulatory changes have been recommended by the Commission on Human Medicines to increase scrutiny of valproate prescribing and ensure that valproate is only used when the benefits outweigh the risk.
In addition to limiting new valproate prescribing, the measures include using a revised valproate Annual Risk Acknowledgement Form at the next annual specialist review of all women who could become pregnant and girls who are currently taking valproate.
This review will include the need for a second opinion’s signature if the patient is to continue with valproate.
A similar system will be introduced later in 2024 for male patients currently taking valproate.
The MHRA is urging healthcare organisations to adequately prepare for the changes, including designating a new or existing group to co-ordinate their implementation.
It is also encouraging patients to attend any offered appointments to discuss their treatment plan and to talk to a healthcare professional if they are concerned.
Dr Alison Cave, MHRA chief safety officer, said: ‘To better protect patients from [harm], we are taking robust regulatory action to ensure greater scrutiny of valproate prescribing. Valproate should only be used when no other treatment is effective.’
She added: ‘No one should stop taking valproate without advice from their specialist.’
Dr Henrietta Hughes, the Government’s independent patient safety commissioner for England, said: ‘We must dramatically reduce the number of babies exposed to teratogens which can cause physical and learning disabilities in children. To do this, all organisations must ensure they bring in new measures from January 2024.’
Professor Munir Pirmohamed, chair of the Commission on Human Medicines, added: ‘I am pleased to see the recommendations of the independent Commission on Human Medicines being prepared to be put into practice.
‘Valproate is a highly teratogenic medicine that also carries known risks to male fertility – it is therefore vital valproate is only used when there is no other effective or tolerated treatment option.
‘We have consulted with patients and healthcare professionals with experience of valproate to inform our recommendations and to ensure that they are introduced in a way that does not disrupt ongoing patient care.’
According to the MHRA, it is estimated that one in nine babies exposed to valproate during pregnancy will be born with major birth defects and as many as four in 10 born with a neurological disorder, ranging from poor educational attainment to autism spectrum disorder.
In spring 2018, the MHRA banned the use of valproate for epilepsy during pregnancy without a pregnancy prevention programme.
In May 2023, NHS England launched a valproate decision support tool to help maintain patient safety and curb inappropriate prescribing of valproate during pregnancy.
And in September, new measures recommending the avoidance of all medicines containing topiramate during pregnancy were published by the European Medicines Agency‘s Pharmacovigilance Risk Assessment Committee.
22nd June 2023
The use of biologics in women with psoriasis who are either pregnant or planning to conceive is not associated with an increased risk of miscarriage, abortion or congenital malformations, according to the findings of a recent study.
The available literature suggests that psoriasis improves during pregnancy although there is a slight risk of a disease flare following delivery. Although biologics are used for patients with moderate to severe psoriasis, the continued use of biologic therapy in pregnancy is a difficult decision to make because of the lack of safety data. Moreover, these decisions are further hampered by the fact that pregnant women are invariably excluded from clinical trials using biologics.
With uncertainty over the safety of biologics in pregnancy, in the current study, published in Journal of the European Academy of Dermatology and Venereology, Spanish researchers conducted a systematic review and meta-analysis to examine examine pregnancy outcomes in women with psoriasis exposed to biologics within three months before or during pregnancy. The team also included studies where women were planning to conceive and who were exposed to biologics.
A total of 51 observational studies in women with a mean age of 30.3 years and with 739 pregnancies exposed to approved biologics were included in the analysis. In most cases (70.4%) the biologics were administered during the first trimester, with the most common agent being ustekinumab (36.0%), followed by etanercept (19.3%). However, there were no studies with newer agents such as brodalumab, risankizumab or bimekizumab.
The estimated prevalence of miscarriage was 15.3% (95% CI 12.7 – 18.0) and elective abortions, 10.8% (95% CI 7.7 – 14.3). Congenital malformations occurred in about 3.0% (95% CI 1.6 – 4.8) of live births. These estimates were similar to those reported in the general population.
The researchers concluded that biologics used in psoriasis are safe and pose an acceptable risk to foetuses and neonates.
26th May 2023
Decision support tools to help clinicians and patients decide whether or not valproate is the right option for them have been launched by NHS England.
In efforts to maintain patient safety and curb inappropriate prescribing of valproate during pregnancy, the tools are aimed at women, girls and anyone who could become pregnant, aged between 12 and 55, who are considering or taking valproate for epilepsy or bipolar disorder.
Developed in accordance with the NICE standards framework for shared decision-making support tools, the aim is to help patients understand the benefits and harms of taking valproate, and come to a decision based on what matters most to them.
NICE guidance states that the medication ‘must not be used in women and girls of childbearing potential (including young girls who are likely to need treatment into their childbearing years), unless other options are unsuitable and the pregnancy prevention programme is in place.’
Sodium valproate is prescribed as a treatment for epilepsy and bipolar disorder and can cause birth defects in around one in 10 babies born to those taking it while pregnant, as well as causing developmental problems in 30-40% of children whose mothers took the medicine while pregnant.
The new tools come after the independent Commission on Human Medicines (CHM) advised in December that two specialists must independently consider that valproate is the only effective or tolerated treatment before a patient under the age of 55 can be initiated on the medication.
The Commission also advised that men under the age of 55 should also be offered the opportunity to have their treatment reviewed. The UK’s Medicines and Healthcare Regulatory Agency is set to release information about additional versions of the tools for men imminently.
According to NHS Digital, between April 2018 and September 2020, 180 females in England were prescribed valproate while pregnant. Some 47,532 females aged 0-54 were given one or more prescriptions for the drug over the reporting period, and 238 females stopped receiving prescriptions of valproate prior to their pregnancy.
A version of this story was originally published by our sister publication The Pharmacist.
17th March 2023
Prenatal leukotriene receptor antagonist use does not increase the risk of neuropsychiatric events among their offspring despite previous concerns over this class of drugs according to the findings of a study by Taiwanese researchers.
The leukotriene-receptor antagonists have demonstrated favourable anti-asthmatic activity over a wide spectrum of disease severity either alone or in combination with inhaled corticosteroids but also as an effective treatment for allergic rhinitis. Despite this, in the US, the FDA issued warnings about the risk of neuropsychiatric side effects (NSE)-related to the use of one leukotriene antagonist, montelukast and which often occurred within the first 10 days of use and were most common in 4 – 6 year old children. Moreover, other evidence also hints at such an association with a 2022 study of patients initiated on montelukast observing an increased odds of adverse neuropsychiatric outcomes among those starting the drug. Nevertheless, whether prenatal leukotriene receptor antagonist use might also increase the subsequent risk of NSE in children remains unclear.
In the current study researchers identified a group of women and their offspring, where the mother had been dispensed any prescription for a leukotriene receptor antagonist during her pregnancy. They set the outcome as a primary diagnosis of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD) or Tourette syndrome (TS) in the offspring of these mothers and propensity matched these mothers with non-exposed control children.
Prenatal leukotriene receptor antagonist use and neuropsychiatric outcomes
After propensity score matching, a total of 1,988 leukotriene receptor antagonist exposed children and 19,863 non-exposed children with included in the analysis.
Among the offspring, there was no significant association observed between prenatal leukotriene receptor antagonist exposure and ADHD (adjusted hazard ratio, aHR = 1.03, 95% CI 0.79 – 1.35, p = 0.82), ASD (aHR = 1.01, 95% CI 0.65 – 1.59, p = 0.96) and TS (aHR = 0.63, 95% CI 0.29 – 1.36, p = 0.24). This association remained non-significant when the prenatal leukotriene receptor antagonist use was categorised as either 1 – 4 weeks or > 4 weeks and where the cumulative dose ranged from 1 – 170 mg or > 170 mg, for each of the three outcomes.
The authors concluded that there was no significant risk of neuropsychiatric events in children following prenatal leukotriene receptor antagonist use, although they called for further work to confirm these findings.
Citation
Tsai HJ et al. Use of Leukotriene-Receptor Antagonists During Pregnancy and Risk of Neuropsychiatric Events in Offspring. JAMA Netw Open 2023
12th December 2022
The combination of nirmatrelvir and ritonavir appear to be safe and well tolerated when used in pregnancy among mothers infected with COVID-19.
The nirmatrelvir and ritonavir (Paxlovid) can be used safely in pregnant women infected with COVID-19 according to a case series study by researchers from Johns Hopkins University School of Medicine, Baltimore, US.
COVID-19 leads to a consistent and substantial increase in severe maternal morbidity and mortality and neonatal complications in pregnant women.
In fact, available data suggests that severe acute respiratory syndrome caused by COVID-19 during pregnancy leads to placental inflammation and a reduced antiviral antibody response, which could impact upon the efficacy of treatment in pregnancy.
The combination of nirmatrelvir and ritonavir has been authorised by the European Medicine’s Agency for the treatment of COVID-19 in adults who do not require supplemental oxygen and who are at increased risk for progression to severe COVID-19.
However, the summary of product characteristics states that ‘there are no data from the use of paxlovid in pregnant women’ and that ‘paxlovid is not recommended during pregnancy.’
Despite the lack of human data, animal studies of nirmatrelvir and ritonavir reported no clinically relevant risks associated with administration during pregnancy or in males and females of reproductive age.
In the present study, the US researchers reported on a case series that included pregnant patients who were diagnosed with COVID-19 and who received nirmatrelvir and ritonavir. The team recorded the clinical characteristics and pregnancy outcomes through a manual review of medical records.
A total of 47 women with a median age of 34 years were included and who received the drugs during pregnancy, 57.4% during the third trimester and 34% during the second trimester.
In addition, 85.1% of women had received some level of COVID-19 vaccination, with 44.7% having received the initial series and one booster. Co-morbidities included a mental health disorder (44.7%), obesity (25.5%) and diabetes (10.6%).
A total of 53.2% of mothers delivered after treatment with nirmatrelvir and ritonavir and of whom, 12 (48%) underwent a caesarean delivery, although three quarters of these were scheduled. Only two patients discontinued the drugs due to adverse effects.
Based on these findings, the authors concluded that pregnant patients treated with nirmatrelvir and ritonavir tolerated the treatment although there was an unexpectedly high rate of caesarean deliveries.
They added that the lack of serious adverse effects affecting pregnant patients or offspring suggests that the drug combination is suitable for the treatment of infected, pregnant women.
Citation
Garneau WM et al. Analysis of Clinical Outcomes of Pregnant Patients Treated With Nirmatrelvir and Ritonavir for Acute SARS-CoV-2 Infection. JAMA Netw Open 2022.
14th October 2022
Could prenatal high-dose folic acid use among pregnant women prescribed anti-epileptic medication increase the risk of childhood cancer was the subject addressed in a recent observational study by a team of Norwegian researchers.
In a report from the International League Against Epilepsy Task Force on Women and Pregnancy, it was recommended that women of childbearing potential taking anti-epileptic drugs should be on at least 0.4 mg/day of folate.
Nevertheless, concerns have been expressed that the use of folic acid, particularly in association with vitamin B12 is associated with increased cancer outcomes and all-cause mortality in patients with ischaemic heart disease. Despite these findings, there is also evidence that maternal use of folate supplementation in pregnancy reduces the risk of common acute lymphoblastic leukaemia in the child.
As prenatal folate use is a recommendation in women prescribed anti-epileptic medication during pregnancy, it is uncertain whether the drug, especially prenatal high dose folic acid (i.e., > 1 mg daily) impacts on the incidence of childhood cancer.
For the present study, the Norwegian researchers undertook an observational study in the Nordic countries between 1997 and 2107 and looked at pregnant women who were prescribed a range of anti-epileptic medicines and who also used folic acid. They turned to data collected as part of the Nordic Register-Based Study of Anti-epileptic Drugs in Pregnancy (SCAN-AED) collaboration project. For the purposes of the study, prenatal high-dose folic acid use was defined as at least 1 filled prescription of either 1 mg or 5 mg folic supplementation between 90 days before the first day of the last menstrual period and birth. To identify cases of childhood cancer, they used data held in a national cancer registry and in their analysis, they also adjusted for covariates known to be risk factors for childhood cancer.
Prenatal high-dose folic acid and childhood cancers
A total of 3,379,171 children were included in the analysis with 27784 were born to mother with epilepsy. These children were followed for a median of 7.3 years.
Overall, 21.4% of children had been exposed to prenatal high-dose folic acid. The incidence of cancer in children whose mothers had taken high-dose folic acid was 42.5 per 100,000 person-years compared to 18.4 per 100,000 person-years in mothers who did not take prenatal high-dose folic acid. This translated into a higher risk of cancer compared to the children of mothers with epilepsy not exposed to high-dose folic acid (adjusted hazard ratio, aHR = 2.7, 95% CI 1.2 – 6.3).
In a separate analysis, among epileptic mothers who continued with anti-epileptic medication and prenatal high-dose folic acid, the risk of childhood cancer was three-times higher than those who did not use high-dose folic acid (aHR = 3.0, 95% CI 1.1 – 7.9). Moreover, there was no association between childhood cancer risk among epileptic mothers prenatally exposed to anti-epileptic medicines but not folic acid (absolute risk = 0.6%, 95% CI 0.20 – 1.3%).
The authors concluded that there was an association between an increased childhood cancer risk and epileptic maternal use of high-dose folic acid.
Citation
Vegrim HM et al. Cancer Risk in Children of Mothers With Epilepsy and High-Dose Folic Acid Use During Pregnancy JAMA Neurol 2022
24th August 2021
A refractive error represents a common eye disorder that prevents the eye from being able to focus images properly leading to blurred vision. There are several types of high refractive errors (HRE) including myopia (near-sightedness), hyperopia (far-sightedness), astigmatism (distorted vision) and presbyopia (difficulty in reading at arm’s length). The World Health Organisation has estimated that 153 million people worldwide have a visual impairment due to HRE. In children, the most common error is astigmatism, with one study finding a global prevalence of 14.9%. The cause of HRE remains uncertain although refractive changes are known to be associated changes in blood glucose levels and hence can be present in those with diabetes. In fact, there is some evidence that gestational diabetes can result in a three-fold increased probability of refractive errors compared to mothers without diabetes. In contrast, another study of refractive errors among diabetic and non-diabetic mothers found no significant differences in astigmatism between the two groups.
With some uncertainty over the relationship between HRE errors and diabetes, a team led by researchers from the Department of Clinical Epidemiology, Aarhus University, Denmark, undertook a population-based cohort study using Danish national registers. Mothers were considered to have diabetes if they were diagnosed either before or during their pregnancy. Their primary outcome of interest was high refractive errors in offspring and secondary outcomes were the specific types of refractive errors that developed over a 25-year follow-up period. The team used regression analysis to model the association between prenatal diabetes exposure and high refractive errors, adjusting for several factors including maternal age, smoking status, calendar period of delivery.
Findings
During the 25-year follow-up, there were 553 children of mothers with diabetes and 19,695 children of mothers without diabetes, diagnosed with a HRE. The children exposed to maternal had a 39% increased risk of having a HRE compared to those without diabetes (adjusted hazard ratio, aHR = 1.39, 95% CI 1.28 – 1.51, p < 0.001). This risk was significantly increased, compared to mothers without diabetes, for all forms of pre-gestational diabetes e.g., type 1 (aHR = 1.32), type 2 (aHR = 1.68) and gestational diabetes (aHR = 1.37). The risks for each type of HRE were also increased, e.g., hypermetropia (HR = 1.37), myopia (HR = 1.34) and astigmatism (HR = 1.58). In addition, the risks of HRE were higher in children of mothers who had at least one diabetic complications (aHR = 1.76) and higher still, in the presence of two or more complications (aHR = 2.24).
In trying to account for these elevated risks, the authors suggested the among diabetic mothers, it was possible that increased plasma glucose levels could result in foetal hyperglycaemia or that an increased oxidative stress and inflammatory response from the ensuing hyperglycaemia could have damaged the optical nerves. They concluded that given these finding, early ophthalmological screening should be undertaken in the children of mothers with diabetes.
Citation
Du J et al. Association of maternal diabetes during pregnancy with high refractive error in offspring: a nationwide population-based cohort study. Diabetologia 2021
16th August 2021
Pregnant women have been deemed to be at a higher risk of severe illness from COVID-19. Moreover, in a systematic review in May 2020, it was concluded that mothers infected with COVID-19 were at an increased risk of pre-term birth although the authors urged caution, as their data were derived from a small number of cases and also included the SARS and MERS viruses. In order to provide as much information as possible on the pregnancy outcomes associated with COVID-19 infection, a team from the Department of Obstetrics and Gynaecology, St George’s University Hospitals NHS Foundation Trust, London, UK, undertook a systematic review of all available literature on COVID-19 and pregnancy in order to provide comprehensive data and to direct the course of ongoing research and studies. They searched all major databases and included a wide range of studies e.g., case reports, case series, and randomised trials, provided that studies reported on women with a PCR-confirmed diagnosis of COVID-19. Extracted information on maternal outcomes including clinical symptoms, laboratory findings, any obstetric complications and perinatal outcomes including death and vertical transmission were also collected.
Findings
A total of 86 studies were identified which included 2567 pregnancies. Nearly a third of mothers (30.6%) were older than 35 years and half of the cohort (50.8%) were of Black, Asian or other ethnic minority groups. Overall, antiviral therapy was given to a fifth (21.1%) of women though a much higher proportion (51.15%) received anticoagulation and 18.2% required nasal or non-invasive oxygen support.
COVID-19 symptoms were predominately cough (71.4%), fever (63.3%), dyspnoea (34.4%) and loss of taste or smell (22.9%). The most common laboratory abnormality was a raised D-dimer (84.6%), followed by a raised C-reactive protein or procalcitonin (54%). Fortunately, only 7% of women needed admission to an intensive care unit. Pre-term birth which was primarily iatrogenic was found to be common (21.8%) though this was medically indicated in 18.4% of all cases. The incidence of neonatal COVID-19 infection was low at 1.2%.
Commenting on their findings, the authors noted that generally, pregnancy outcomes were good. The incidence of admission to maternal intensive care was low and likely to be similar to the rates for other non-infected women. Furthermore, there was a very low incidence of maternal mortality. The authors did note how their analysis had several limitations including the retrospective nature of most studies and a lack of standardisation of care, given that studies came from several different countries. While the incidence of vertical transmission appeared to be low, the authors felt that more evidence was needed to confirm whether this represents a significant problem. However, there was a higher-than-average increase in pre-term births which was consistent with findings from other studies.
Citation
Khalil A et al. SARS-CoV-2 infection in pregnancy: A systematic review and meta- analysis of clinical features and pregnancy outcomes. EClinicalMedicine 2021
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