Maternal perinatal mental illnesses and adverse pregnancy outcomes: population-based studies using data from United Kingdom primary care

Background: Perinatal mental illness, especially depression, is a leading cause of maternal morbidity and mortality in high-income countries. In the United Kingdom (UK), mental illness commonly presents to and is treated at primary care level; however there are no up-to-date estimates of the burden of different mental illnesses in women in and around pregnancy. The potential impact of mental illness with or without psychotropic medication on the risk of non-live pregnancy outcomes is unclear. In this context, the safety of psychotropic drugs, especially antidepressants, remains controversial. Aim and objectives: To estimate the clinical burden of depression, anxiety and serious mental illness (defined as bipolar disorder, schizophrenia and other related psychotic disorders) presenting to and/or being treated in UK primary care, and to investigate the effects on pregnancy outcomes while trying to differentiate the effects of psychotropic medication from mental illness itself. Methods: Women aged 15-45 years from 1990 to 2009 were identified from The Health Improvement Network, a UK primary care database. Coding of mental illness diagnoses and psychotropic drug prescriptions were examined by separately assessing the proportions of women with recordings of diagnoses, symptoms, and drug prescriptions over the study period. Three separate studies were then carried out. A cross-sectional study was firstly conducted to estimate the prevalence and diagnostic overlap of mental illnesses before, during and after pregnancy and the variation by maternal age, socioeconomic status and other maternal factors. The second study examined the risks of non-live pregnancy outcomes (defined as perinatal death, miscarriage, and termination) in women with no history of depression and anxiety, a diagnosis of such illness prior to pregnancy, illness during pregnancy or illness during pregnancy with use of medication (stratified by medication type). Multinomial logistic regression models were used to compare risks of non-live outcomes across these groups, adjusting for important socio-demographic and lifestyle characteristics. The third study examined the risks of major and system-specific congenital anomalies in children born to women with depression or anxiety that was untreated or treated with psychotropic medication. Logistic regression with a generalised estimating equation was used to compare risks of major congenital anomalies in children exposed and unexposed to psychotropic medication during the first trimester of pregnancy, adjusting for important socio-demographic, lifestyle and chronic comorbidity in the mother. Results: There were 344,042 women who had one or more singleton pregnancies identified between age 15 and 45 from 1990 to 2009. Recording of mental illness and prescriptions of psychotropic drugs increased considerably over the study period. There was high prevalence and overlap of different maternal mental illnesses, especially depression and anxiety, during and after pregnancy, and the prevalence was generally highest in younger, socioeconomically deprived women who had smoked before childbirth, were outside the normal range of BMI and had other chronic medical conditions, such as diabetes. Socioeconomic deprivation was associated with increased risk of all mental illnesses, although the impact of deprivation was more marked in older women. Those aged 35-45 in the most deprived group had 2.63 times the odds of antenatal depression (95% confidence interval [CI] 2.22-3.13) compared with the least deprived; in women aged 15-25 the increased odds associated with deprivation was more modest (odds ratio [OR]=1.35, 95%CI 1.07-1.70). Similar patterns were found for anxiety and serious mental illness. Women with antenatal exposure to antidepressant or anti-anxiety drugs showed the greatest increased risks for non-live pregnancy outcomes, relative to those with no history of depression or anxiety, although women with prior (but currently un-medicated) illness also showed modest increased risks. Compared with un-medicated antenatal morbidity, there was weak evidence of an excess risk in women taking tricyclic antidepressants (TCAs), and stronger evidence for other medications. The absolute risks of major and system-specific congenital anomalies were small in the general population (269 per 10,000 children for major congenital anomalies). Compared with un-medicated antenatal depression or anxiety (278 per 10,000 children for major congenital anomalies), the use of antidepressants during early pregnancy was associated with excess risks, especially for selective serotonin reuptake inhibitors (SSRIs) (290 per 10,000 children for major congenital anomalies). Compared with children born to women with no depression or anxiety, there was an increased risk of heart anomalies in children with antenatal exposure to SSRIs (adjusted OR=1.25, 95% 95%CI 1.02-1.53), particularly in those exposed to paroxetine (adjusted OR=1.89, 95%CI 1.24-2.88). Children exposed to sertraline and escitalopram also had similar increased risks, although fewer women were exposed to these drugs. No increased risks of major congenital anomalies were found in children exposed to TCAs or benzodiazepines; however, the risks of right ventricular outflow tract anomalies were notably higher for all drug classes. Conclusion: Strong socioeconomic inequalities in perinatal mental illnesses occur and persist with increasing maternal age. Women with depression or anxiety have higher risks of miscarriage, perinatal death and therapeutic terminations than women without these diagnoses and the risks are even higher if prescribed psychotropic medication during early pregnancy than if not. There is also an increased risk of congenital heart anomalies in children exposed to paroxetine and other SSRIs during the first trimester compared with those who are unexposed, although the absolute risk is small. There could be other associated factors also related to depression, anxiety or use of medications, which yet unlikely fully explain the observed excess risks. Whilst medicated depression or anxiety could be a marker of more severe illness than un-medicated ones, my findings indicate there may be some specific drug effects Targeting detection and effective interventions to women at risk of mental illness during pregnancy may reduce inequity and avoid substantial psychiatric morbidity, and subsequently reduce the need for further psychotropic treatment. GPs and other health care professionals should take a cautious approach when managing mental illness in pregnant women. The findings in this thesis provide vital information for this purpose, namely helping communicate the magnitude of risk of major congenital anomalies to women with the use of different psychotropic drugs in the context of the baseline risk in the general population

Maternal perinatal mental illnesses and adverse pregnancy outcomes: population-based studies using data from United Kingdom primary care

Background: Perinatal mental illness, especially depression, is a leading cause of maternal morbidity and mortality in high-income countries. In the United Kingdom (UK), mental illness commonly presents to and is treated at primary care level; however there are no up-to-date estimates of the burden of different mental illnesses in women in and around pregnancy. The potential impact of mental illness with or without psychotropic medication on the risk of non-live pregnancy outcomes is unclear. In this context, the safety of psychotropic drugs, especially antidepressants, remains controversial. Aim and objectives: To estimate the clinical burden of depression, anxiety and serious mental illness (defined as bipolar disorder, schizophrenia and other related psychotic disorders) presenting to and/or being treated in UK primary care, and to investigate the effects on pregnancy outcomes while trying to differentiate the effects of psychotropic medication from mental illness itself. Methods: Women aged 15-45 years from 1990 to 2009 were identified from The Health Improvement Network, a UK primary care database. Coding of mental illness diagnoses and psychotropic drug prescriptions were examined by separately assessing the proportions of women with recordings of diagnoses, symptoms, and drug prescriptions over the study period. Three separate studies were then carried out. A cross-sectional study was firstly conducted to estimate the prevalence and diagnostic overlap of mental illnesses before, during and after pregnancy and the variation by maternal age, socioeconomic status and other maternal factors. The second study examined the risks of non-live pregnancy outcomes (defined as perinatal death, miscarriage, and termination) in women with no history of depression and anxiety, a diagnosis of such illness prior to pregnancy, illness during pregnancy or illness during pregnancy with use of medication (stratified by medication type). Multinomial logistic regression models were used to compare risks of non-live outcomes across these groups, adjusting for important socio-demographic and lifestyle characteristics. The third study examined the risks of major and system-specific congenital anomalies in children born to women with depression or anxiety that was untreated or treated with psychotropic medication. Logistic regression with a generalised estimating equation was used to compare risks of major congenital anomalies in children exposed and unexposed to psychotropic medication during the first trimester of pregnancy, adjusting for important socio-demographic, lifestyle and chronic comorbidity in the mother. Results: There were 344,042 women who had one or more singleton pregnancies identified between age 15 and 45 from 1990 to 2009. Recording of mental illness and prescriptions of psychotropic drugs increased considerably over the study period. There was high prevalence and overlap of different maternal mental illnesses, especially depression and anxiety, during and after pregnancy, and the prevalence was generally highest in younger, socioeconomically deprived women who had smoked before childbirth, were outside the normal range of BMI and had other chronic medical conditions, such as diabetes. Socioeconomic deprivation was associated with increased risk of all mental illnesses, although the impact of deprivation was more marked in older women. Those aged 35-45 in the most deprived group had 2.63 times the odds of antenatal depression (95% confidence interval [CI] 2.22-3.13) compared with the least deprived; in women aged 15-25 the increased odds associated with deprivation was more modest (odds ratio [OR]=1.35, 95%CI 1.07-1.70). Similar patterns were found for anxiety and serious mental illness. Women with antenatal exposure to antidepressant or anti-anxiety drugs showed the greatest increased risks for non-live pregnancy outcomes, relative to those with no history of depression or anxiety, although women with prior (but currently un-medicated) illness also showed modest increased risks. Compared with un-medicated antenatal morbidity, there was weak evidence of an excess risk in women taking tricyclic antidepressants (TCAs), and stronger evidence for other medications. The absolute risks of major and system-specific congenital anomalies were small in the general population (269 per 10,000 children for major congenital anomalies). Compared with un-medicated antenatal depression or anxiety (278 per 10,000 children for major congenital anomalies), the use of antidepressants during early pregnancy was associated with excess risks, especially for selective serotonin reuptake inhibitors (SSRIs) (290 per 10,000 children for major congenital anomalies). Compared with children born to women with no depression or anxiety, there was an increased risk of heart anomalies in children with antenatal exposure to SSRIs (adjusted OR=1.25, 95% 95%CI 1.02-1.53), particularly in those exposed to paroxetine (adjusted OR=1.89, 95%CI 1.24-2.88). Children exposed to sertraline and escitalopram also had similar increased risks, although fewer women were exposed to these drugs. No increased risks of major congenital anomalies were found in children exposed to TCAs or benzodiazepines; however, the risks of right ventricular outflow tract anomalies were notably higher for all drug classes. Conclusion: Strong socioeconomic inequalities in perinatal mental illnesses occur and persist with increasing maternal age. Women with depression or anxiety have higher risks of miscarriage, perinatal death and therapeutic terminations than women without these diagnoses and the risks are even higher if prescribed psychotropic medication during early pregnancy than if not. There is also an increased risk of congenital heart anomalies in children exposed to paroxetine and other SSRIs during the first trimester compared with those who are unexposed, although the absolute risk is small. There could be other associated factors also related to depression, anxiety or use of medications, which yet unlikely fully explain the observed excess risks. Whilst medicated depression or anxiety could be a marker of more severe illness than un-medicated ones, my findings indicate there may be some specific drug effects Targeting detection and effective interventions to women at risk of mental illness during pregnancy may reduce inequity and avoid substantial psychiatric morbidity, and subsequently reduce the need for further psychotropic treatment. GPs and other health care professionals should take a cautious approach when managing mental illness in pregnant women. The findings in this thesis provide vital information for this purpose, namely helping communicate the magnitude of risk of major congenital anomalies to women with the use of different psychotropic drugs in the context of the baseline risk in the general population

L-carnitine supplementation in non-alcoholic fatty liver disease: A systematic review and meta-analysis

BACKGROUNDNon-alcoholic fatty liver disease (NAFLD) dominates the landscape of modern hepatology. Affecting 25% of the general population, there is critical unmet need to identify broadly available, safe and cost-effective treatments. Cumulative evidence in animal and human models suggests that intrahepatic and skeletal muscle fatty acid oxidation is impaired in NAFLD, such that lipid accretion is not matched by efficient utilisation. L-carnitine is a crucial mediator of fatty acid metabolism in vivo, promoting mitochondrial lipid β-oxidation and enhancing tissue metabolic flexibility. These physiological properties have generated research interest in L-carnitine as a potentially effective adjunctive therapy in NAFLD.AIMTo systematically review randomised trials reporting effects of dietary L-carnitine supplementation on liver biochemistry, liver fat and insulin sensitivity in NAFLD.METHODSSearch strategies, eligibility criteria and analytic methods were specified a priori (PROSPERO reference: CRD42018107063). Ovid MEDLINE, Ovid EMBASE, PubMed, Web of Science and the Cochrane Library were searched from their inception until April 2019. Outcome measures included serum concentrations of alanine and aspartate aminotransferase (ALT and AST), liver fat and insulin sensitivity assessed by the homeostasis model of insulin resistance (HOMA-IR). A random effects meta-analysis was performed for, ALT, AST and HOMA-IR measures separately. Between-study heterogeneity was measured using I2 statistics.RESULTSFive eligible randomised trials were included in the qualitative and quantitative synthesis (n = 338). All of the 5 included trials assessed the effect of L-carnitine on serum ALT, identified from Italy, South Korea and Iran. Weighted mean difference (WMD) for ALT between L-carnitine and control groups after intervention was -25.34 IU/L [95%CI: -41.74-(-8.94); P = 0.002]. WMD for AST between L-carnitine and control groups was -13.68 IU/L (95%CI: -28.26-0.89; P = 0.066). In three studies (n = 204), HOMA-IR was evaluated. WMD for HOMA-IR between L-carnitine and control groups was -0.74 units [95%CI: -1.02-(-0.46); P < 0.001]. Two studies using validated outcome measures reported a significant reduction in liver fat in L-carnitine vs control groups post-intervention (P < 0.001).CONCLUSIONPooled results indicate that L-carnitine supplementation attenuates ALT, liver fat and insulin resistance in NAFLD cohorts, confirming a beneficial effect of L-carnitine for a highly prevalent condition with a growing economic burden

First trimester exposure to anxiolytic and hypnotic drugs and the risks of major congenital anomalies: a United Kingdom population-based cohort study.

BACKGROUND: Despite their widespread use the effects of taking benzodiazepines and non-benzodiazepine hypnotics during pregnancy on the risk of major congenital anomaly (MCA) are uncertain. The objectives were to estimate absolute and relative risks of MCAs in children exposed to specific anxiolytic and hypnotic drugs taken in the first trimester of pregnancy, compared with children of mothers with depression and/or anxiety but not treated with medication and children of mothers without diagnosed mental illness during pregnancy. METHODS: We identified singleton children born to women aged 15-45 years between 1990 and 2010 from a large United Kingdom primary care database. We calculated absolute risks of MCAs for children with first trimester exposures of different anxiolytic and hypnotic drugs and used logistic regression with a generalised estimating equation to compare risks adjusted for year of childbirth, maternal age, smoking, body mass index, and socioeconomic status. RESULTS: Overall MCA prevalence was 2.7% in 1,159 children of mothers prescribed diazepam, 2.9% in 379 children with temazepam, 2.5% in 406 children with zopiclone, and 2.7% in 19,193 children whose mothers had diagnosed depression and/or anxiety but no first trimester drug exposures. When compared with 2.7% in 351,785 children with no diagnosed depression/anxiety nor medication use, the adjusted odds ratios were 1.02 (99% confidence interval 0.63-1.64) for diazepam, 1.07 (0.49-2.37) for temazepam, 0.96 (0.42-2.20) for zopiclone and 1.27 (0.43-3.75) for other anxiolytic/hypnotic drugs and 1.01 (0.90-1.14) for un-medicated depression/anxiety. Risks of system-specific MCAs were generally similar in children exposed and not exposed to such medications. CONCLUSIONS: We found no evidence for an increase in MCAs in children exposed to benzodiazepines and non-benzodiazepine hypnotics in the first trimester of pregnancy. These findings suggest that prescription of these drugs during early pregnancy may be safe in terms of MCA risk, but findings from other studies are required before safety can be confirmed

Maternal depression, antidepressant prescriptions, and congenital anomaly risk in offspring: a population-based cohort study

OBJECTIVE: To estimate risks of major congenital anomaly (MCA) among children of mothers prescribed antidepressants during early pregnancy or diagnosed with depression but without antidepressant prescriptions. DESIGN: Population-based cohort study. SETTING: Linked UK maternal–child primary care records. POPULATION: A total of 349 127 singletons liveborn between 1990 and 2009. METHODS: Odds ratios adjusted for maternal sociodemographics and comorbidities (aORs) were calculated for MCAs, comparing women with first-trimester selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) and women with diagnosed but unmedicated depression, or women without diagnosed depression. MAIN OUTCOME MEASURES: Fourteen system-specific MCA groups classified according to the European Surveillance of Congenital Anomalies and five specific heart anomaly groups. RESULTS: Absolute risks of MCA were 2.7% (95% confidence interval, 95% CI, 2.6–2.8%) in children of mothers without diagnosed depression, 2.8% (95% CI 2.5–3.2%) in children of mothers with unmedicated depression, and 2.7% (95% CI 2.2–3.2%) and 3.1% (95% CI 2.2–4.1%) in children of mothers with SSRIs or TCAs, respectively. Compared with women without depression, MCA overall was not associated with unmedicated depression (aOR 1.07, 95% CI 0.96–1.18), SSRIs (aOR 1.01, 95% CI 0.88–1.17), or TCAs (aOR 1.09, 95% CI 0.87–1.38). Paroxetine was associated with increased heart anomalies (absolute risk 1.4% in the exposed group compared with 0.8% in women without depression; aOR 1.78, 95% CI 1.09–2.88), which decreased marginally when compared with women with diagnosed but unmedicated depression (aOR 1.67, 95% CI 1.00–2.80). CONCLUSIONS: Overall MCA risk did not increase with maternal depression or with antidepressant prescriptions. Paroxetine was associated with increases of heart anomalies, although this could represent a chance finding from a large number of comparisons undertaken

The incidence of first stroke in and around pregnancy: A population-based cohort study from Sweden

Introduction: Research has suggested that delivery is associated with an increased risk of stroke in women; however, there is a lack of contemporary estimates on the incidence of stroke in and after pregnancy compared with the baseline risk in women of childbearing age in Sweden. Patients and methods: All women aged 15–49 years with live births/stillbirths in 1992–2011 were identified from the Swedish Medical Birth Registry linked with the National Patient Registry. First stroke during the study period was identified. Incidence rates per 100,000 person-years and adjusted incidence rate ratios (IRRs) were calculated for antepartum, peripartum and early and late postpartum periods, compared with all other available follow-up time (time before pregnancy and after postpartum) using Poisson regression adjusted for maternal age, education attainment and calendar time. Results: Of 1,124,541 women, 3094 had a first incident stroke (331 occurred during pregnancy or first 12 weeks postpartum), about half having ischaemic stroke. The incidence was 15.0 per 100,000 person-years (95% confidence interval 14.5–15.6) in non-pregnant time. The incidence was lower antepartum (7.3/100,000 person-years, 6.0–8.9; adjusted IRR = 0.7, 0.5–0.8) but higher peripartum (314.4/100,000 person-years, 247.5–399.5; adjusted IRR = 27.3, 21.4–34.9) and early postpartum (64.0/100,000 person-years, 54.1–75.7; adjusted IRR = 5.5, 4.6–6.6). The increased risk in peripartum was more evident for intracerebral haemorrhage than other types of stroke. Conclusion: Overall risk of stroke was low in women of childbearing age, but stroke risk peaks in the peripartum and early postpartum periods. Future work should address factors that contribute to this increased risk in order to develop approaches to attenuate risk

Pregnancy complications and adverse birth outcomes among women with celiac disease: a population-based study from England

OBJECTIVES: Evidence-based information about adverse birth outcomes and pregnancy complications is crucial when counseling women with celiac disease (CD); however, limited population-based data on such risks exist. We estimated these for pregnant women with CD diagnosed before and after delivery. METHODS: We included all singleton pregnancies between 1997 and 2012 using linked primary care data from the Clinical Practice Research Datalink and secondary care Hospital Episode Statistics data. Risks of pregnancy complications (antepartum and postpartum hemorrhage, pre-eclampsia, and mode of delivery) and adverse birth outcomes (preterm birth, stillbirth, and low birth weight) were compared between pregnancies of women with and without CD using logistic/multinomial regression. Risks were stratified on the basis of whether women were diagnosed or yet undiagnosed before delivery. RESULTS: Of 363,930 pregnancies resulting in a live birth or stillbirth, 892 (0.25%) were among women with CD. Diagnosed CD was not associated with an increased risk of pregnancy complications or adverse birth outcomes compared with women without CD. However, the risk of postpartum hemorrhage and assisted delivery was slightly higher among pregnant women with diagnosed CD (adjusted odds ratio (aOR)=1.34). We found no increased risk of any pregnancy complication among those with undiagnosed CD. We only observed a 1% absolute excess risk of preterm birth and low birth weight among undiagnosed CD mothers corresponding to aOR=1.24 (95% confidence interval (CI)=0.82–1.87) and aOR=1.36 (95% CI=0.83–2.24), respectively. CONCLUSIONS: Whether diagnosed or undiagnosed during pregnancy, CD is not associated with a major increased risk of pregnancy complications and adverse birth outcomes. These findings are reassuring to both women and clinicians

Risk of cardiovascular disease in Chinese patients with rheumatoid arthritis: a cross sectional study based on hospital medical records in 10 years

Objective: Though the risk of cardiovascular disease (CVD) in rheumatoid arthritis (RA) has been established in Western population, little is known about the risk in Chinese people with RA. Our objective was to estimate the risk of CVD in Chinese people with RA using hospital medical records data. Methods The inpatients medical record database 2005‐2015 of Sichuan provincial people’s hospital was examined. All individuals with a primary diagnosis of RA were included as cases, and those of osteoarthritis (OA) were included as controls, which consisted of the unmatched dataset. Then, RA cases and OA controls were matched by sex and age at 1:1 ratio, forming the matched dataset. The morbidity of CVD (including ischemia heart disease (IHD), congestive heart failure (CHF), et al), stroke and arthrosclerosis were extracted from the database, so as the demographic data and comorbidities related to CVD. Multiple logistic regression analysis was used to estimate the risk of CVD in RA adjusted for demographics and comorbidities using the unmatched dataset. Sensitivity analysis was conducted 1) considering interaction terms between RA and comorbidities, and 2) using multivariable conditional logistic regression for the matched dataset. Results: The unmatched data set comprised of 1824RA cases and 1995 OA controls and the matched dataset comprised of 1022 pairs of sex and age matched RA and OA patients. RA exhibited increased odds of prevalent CVD compared with OA, and the adjusted ORs (95%CIs) for CVD, stroke, IHD, CHF, and atherosclerosis were1.86(1.42‐2.43), 1.11(0.71‐1.74), 1.47(0.97‐2.24), 2.09(1.03‐4.22), and 2.49 (1.97‐3.13), respectively, and was 2.26 (1.29‐3.96) for IHD further adjusted for interaction term. The matched dataset analysis found similar results. Conclusions: Chinese people with RA were approximated 2 times more 1 likely to have CVD, IHD, CHF and atherosclerosis compared with those with OA. The findings justified the need of further longitudinal study to establish the causal‐relationship between RA and CVD and to estimate the precise risk in this population