Linda Fiaschi

Risk factors for first venous thromboembolism around pregnancy: a population-based cohort study from the United Kingdom

Knowledge of the absolute risk (AR) for venous thromboembolism (VTE) in women around pregnancy and how potential risk factors modify this risk is crucial in identifying women who would benefit most from thromboprophylaxis. We examined a large primary care database containing 376 154 pregnancies ending in live birth or stillbirth from women aged 15 to 44 years between 1995 and 2009 and assessed the effect of risk factors on the incidence of antepartum and postpartum VTE in terms of ARs and incidence rate ratios (IRR), using Poisson regression. During antepartum, varicose veins, inflammatory bowel disease (IBD), urinary tract infection, and preexisting diabetes were associated with an increased risk for VTE (ARs, ≥139/100 000 person-years; IRRs, ≥1.8/100 000 person-years). Postpartum, the strongest risk factor was stillbirth (AR, 2444/100 000 person-years; IRR, 6.2/100 000 person-years), followed by medical comorbidities (including varicose veins, IBD, or cardiac disease), a body mass index (BMI) of 30 kg/m(2) or higher, obstetric hemorrhage, preterm delivery, and caesarean section (ARs, ≥637/100 000 person-years; IRRs, ≥1.9/100 000 person-years). Our findings suggest that VTE risk varies modestly by recognized factors during antepartum; however, women with stillbirths, preterm births, obstetric hemorrhage, caesarean section delivery, medical comorbidities, or a BMI of 30 kg/m(2) or higher are at much higher risk for VTE after delivery. These risk factors should receive careful consideration when assessing the potential need for thromboprophylaxis during the postpartum period.

Limited Risks of Major Congenital Anomalies in Children of Mothers With IBD and Effects of Medications

BACKGROUND & AIMS Concerns persist about the risk of major congenital anomalies in children of women with inflammatory bowel disease (IBD), and whether medication use affects risk. We assessed these risks, and variations in use of medications by women with IBD before, during, and after pregnancy. METHODS We accessed data on children born to women 15-45 y old from 1990 through 2010, using a mother-child linked dataset from an electronic database of primary care records containing medical diagnoses, events, and drug prescriptions from across the United Kingdom. We identified pregnant women with IBD, and all prescriptions for 5-aminosalicylates azathioprine/6-mercaptopurine, and corticosteroids were extracted from their primary care records. We calculated risks of major congenital anomaly in children of mothers with and without IBD, and in children exposed or not exposed to 5-aminosalicylates, azathioprine/6-mercaptopurine, or corticosteroids during their first trimester of fetal development. Logistic regression with a generalized estimating equation was used to provide risk estimates adjusted for confounders. We calculated proportions of women taking medications before, during, and after pregnancy and assessed whether cessation was associated with subsequent disease flares. RESULTS Risks of a major congenital anomaly in 1703 children of mothers with IBD and 384,811 children of mothers without IBD were 2.7% and 2.8%, respectively. This corresponded to an adjusted odds ratio of 0.98 (95% confidence interval [CI], 0.73-1.31). In children of women with IBD, the adjusted odds ratios of a major congenital anomaly associated with drug use were 0.82 (95% CI, 0.42-1.61) for 5-aminosalicylates 0.48 (95% CI, 0.15-1.50) for corticosteroids, and 1.27 (95% CI, 0.48-3.39) for azathioprine/6-mercaptopurine. No increases in heart, limb, or genital anomalies were found in children of women with IBD; 31.2% of women discontinued 5-aminosalicylates and 24.6% discontinued azathioprine/6-mercaptopurine in early pregnancy. The risk of flares later in pregnancy was not related to cessation of medication. CONCLUSIONS We found no evidence that IBD during pregnancy or medical therapy for IBD during pregnancy increases the risk of a major congenital anomaly in children. Patients should receive appropriate guidance on use of medication before and during pregnancy.

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

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.

Impact of socioeconomic deprivation on maternal perinatal mental illnesses presenting to UK general practice

BACKGROUND Although maternal perinatal mental illnesses commonly present to and are primarily treated in general practice, few population-based estimates of this burden exist, and the most affected socioeconomic groups of pregnant women remain unclear. AIM To provide estimates of maternal depression, anxiety and serious mental illness (SMI) in UK general practice and quantify impacts of socioeconomic deprivation. DESIGN AND SETTING Cross-sectional analysis of prospectively recorded general practice records from a UK-wide database. METHOD A pregnancy ending in live birth was randomly selected for every woman of childbearing age, 1994-2009. Prevalence and diagnostic overlap of mental illnesses were calculated using a combination of medical diagnoses and psychotropic drug prescriptions. Socioeconomic deprivation was assessed using multivariate logistic regression, adjusting for calendar period and pregnancy history. RESULTS Among 116 457 women, 5.1% presented with antenatal depression and 13.3% with postnatal depression. Equivalent figures for anxiety were 2.6% and 3.7% and for SMI 1/1000 and 2/1000 women. Socioeconomic deprivation increased the risk of all mental illnesses, although this was more marked in older women. Those age 35-45 years in the most deprived group had 2.63 times the odds of antenatal depression (95% confidence interval [CI] = 2.22 to 3.13) compared with the least deprived; in women aged 15-25 years the increased odds associated with deprivation was more modest (odds ratio = 1.35, 95% CI = 1.07 to 1.70). Similar patterns were found for anxiety and SMI. CONCLUSION Strong socioeconomic inequalities in perinatal mental illness persist with increasing maternal age. Targeting detection and effective interventions to high-risk women may reduce inequity and avoid substantial psychiatric morbidity.

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.

Live and non-live pregnancy outcomes among women with depression and anxiety: a population-based study.

Background Women taking antidepressant or anti-anxiety medications during early pregnancy have high risks of non-live pregnancy outcomes, although the contribution of the underlying illnesses to these risks remains unclear. We examined the impacts of antenatal depression and anxiety and of commonly prescribed treatments on the risks of non-live pregnancy outcomes. Methods We identified all pregnancies and their outcome (live birth, perinatal death, miscarriage or termination) among women aged 15–45 years between 1990 and 2009 from a large primary care database in the United Kingdom. Women were grouped according to whether they had no history of depression and anxiety, a diagnosis of such illness prior to pregnancy, illness during pregnancy and illness during pregnancy with use of medication (stratified by medication type). Multinomial logistic regression models were used to compare risks of non-live outcomes among these groups, adjusting for major socio-demographic and lifestyle characteristics. Results Among 512,574 pregnancies in 331,414 women, those with antenatal drug exposure showed the greatest increased risks for all non-live pregnancy outcomes, relative to those with no history of depression or anxiety, although women with prior (but not currently 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, and stronger evidence for other medications. Conclusions Women with depression or anxiety have higher risks of miscarriage, perinatal death and decisions to terminate a pregnancy if prescribed psychotropic medication during early pregnancy than if not. Although underlying disease severity could also play a role, avoiding or reducing use of these drugs during early pregnancy may be advisable.

Decreased fertility rates in 9639 women diagnosed with inflammatory bowel disease: a United Kingdom population-based cohort study.

Clinical studies have reported reduced fertility in women with inflammatory bowel disease (IBD).

Occurrence of fertility problems presenting to primary care: population-level estimates of clinical burden and socioeconomic inequalities across the UK

STUDY QUESTION What are the age-specific incident rates of clinically recorded fertility problems in women aged 15-49 years and how do they vary by socioeconomic group and geographic area. SUMMARY ANSWER The incident rate of recorded fertility problems was highest in women age 30-34 years: about 1% of women per annum. Overall rates did not vary by socioeconomic group; however, age-specific rates varied substantially by socioeconomic deprivation quintile; among younger women, deprivation was associated with higher infertility rates. WHAT IS KNOWN ALREADY AND WHAT THIS PAPER ADDS The rates of infertility in the UK range from 2 to 26%. Infertility definitions and denominators vary widely, and most current evidence is based on questionnaire studies that are subject to recall, reporting and selection bias. The current paper presents population-based estimates of clinically recorded fertility problems in women of reproductive age and the variation by age and socioeconomic deprivation quintile across different regions of the UK, using a nationally representative cohort of women that is larger than any previous study. Although infertility overall does not vary by socioeconomic status, consultation for fertility problems is closely related to socioeconomic patterns of womens age at first conception, demonstrating that many couples have pre-existing, rather than specifically age-related, infertility. STUDY DESIGN, SIZE, DURATION This cohort study used data from The Health Improvement Network, a computerized primary care database of anonymized patient records from general practices across the UK, with prospective health records on over 1.7 million women between 1990 and 2010. PARTICIPANTS/MATERIALS, SETTING AND METHODS Our cohort included 1,776,746 women of reproductive age (age 15-49 years) who contributed one or more years of active general practice registration. We estimated rates of new clinically recorded fertility problems in these women using medical records and medications exclusively used to treat infertility. We assessed variation in age-specific incidence by socioeconomic deprivation quintile and geographic area using Poisson regression. MAIN RESULTS AND THE ROLE OF CHANCE The rate of incident recorded fertility problems was highest in women in the 30-34 year age group (10.9 per 1000 person-years), which equates to approximately 1% of women per annum in this age group. Lowest rates were in women in the 15-19 and 45-49 year age groups (0.7 and 0.4 per 1000 person-years, respectively). Overall rates did not vary by socioeconomic group, measured using quintiles of the Townsend index. Age-specific rates, however, varied substantially with socioeconomic deprivation quintile (P-value for interaction < 0.0001) such that up to age 25, women with more deprivation had more recorded fertility problems [rate ratio (RR) comparing most to least deprived 5.6, 95% confidence interval (CI) 4.4-7.2 at 15-20 years of age]. This reversed from age 25 to 39, when women with more deprivation had fewer recorded fertility problems (RR 0.6 95% CI 0.5-0.6 at age 30-34). After age 40, there was no socioeconomic gradient in absolute rates. LIMITATIONS, REASONS FOR CAUTION This is by far the largest population-based study to estimate clinically recorded fertility problems in women and the first in the UK to assess variation across such a broad age group from 15 to 49 years. Our data, however, did not capture women who experience difficulty in conceiving, but do not consult their general practitioner (GP) regarding fertility problems. WIDER IMPLICATIONS OF THE FINDINGS Compared with existing estimates, our measures of the extent and distribution of recorded fertility problems in primary care are more useful for GPs, primary care trusts and policy makers for the planning and delivery of fertility services. We have shown a high burden of infertility with little geographic variation; however, the significant burden in young, more deprived women needs recognition in light of age restrictions for treatment availability for infertility in the UK. Not only does treatment access need to be universal and more equitably allocated across socioeconomic groups, but also more resources are required to reduce fertility problems by targeting modifiable risk factors. STUDY FUNDING/COMPETING INTEREST(S) There was no direct source of funding for this research work. N.N.D. completed the work as part of an M.Sc., which was funded by Developing Solutions Scholarship provided by the International Office, University of Nottingham. J.W. is supported by a University of Nottingham/National Institute for Health Research (NIHR) Senior Clinical Research Fellowship. TRIAL REGISTRATION NUMBER Not applicable.

Hospital admission for hyperemesis gravidarum: a nationwide study of occurrence, reoccurrence and risk factors among 8.2 million pregnancies.

STUDY QUESTION What are the maternal risk factors for hyperemesis gravidarum (HG) hospital admission, readmission and reoccurrence in a following pregnancy? SUMMARY ANSWER Young age, less socioeconomic deprivation, nulliparity, Asian or Black ethnicity, female fetus, multiple pregnancy, history of HG in a previous pregnancy, thyroid and parathyroid dysfunction, hypercholesterolemia and Type 1 diabetes are all risk factors for HG. WHAT IS KNOWN ALREADY Women with Black or Asian ethnicity, of young age, carrying multiple babies or singleton females, with Type 1 diabetes or with a history of HG were previously reported to be at higher risk of developing HG; however, most evidence is from small studies. Little is known about associations with other comorbidities and there is controversy over other risk factors such as parity. Estimates of HG prevalence vary and there is a little understanding of the risks of HG readmission in a current pregnancy and reoccurrence rates in subsequent pregnancies, all of which are needed for planning measures to reduce onset or worsening of the condition. STUDY DESIGN, SIZE, DURATION We performed a population-based cohort study of pregnancies ending in live births and stillbirths using prospectively recorded secondary care records (Hospital Episode Statistics) from England. We analysed those computerized and anonymized clinical records from over 5.3 million women who had one or more pregnancies between 1997 and 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS We obtained 8 215 538 pregnancies from 5 329 101 women of reproductive age, with a total of 186 800 HG admissions occurring during 121 885 pregnancies. Multivariate logistic regression with generalized estimating equations was employed to estimate odds ratios (aOR) to assess sociodemographic, pregnancy and comorbidity risk factors for HG onset, HG readmission within a pregnancy and reoccurrence in a subsequent pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE Being younger, from a less socioeconomically deprived status, of Asian or Black ethnicity, carrying a female fetus or having a multiple pregnancy all significantly increased HG and readmission risk but only ethnicity increased reoccurrence. Comorbidities most strongly associated with HG were parathyroid dysfunction (aOR = 3.83, 95% confidence interval 2.28-6.44), hypercholesterolemia (aOR = 2.54, 1.88-3.44), Type 1 diabetes (aOR = 1.95, 1.82-2.09), and thyroid dysfunction (aOR = 1.85, 1.74-1.96). History of HG was the strongest independent risk factor (aOR = 4.74, 4.46-5.05). Women with higher parity had a lower risk of HG compared with nulliparous women (aOR = 0.90, 0.89-0.91), which was not explained by women with HG curtailing further pregnancies. LIMITATIONS, REASONS FOR CAUTION Although this represents the largest population-based study worldwide on the topic, the results could have been biased by residual and unmeasured confounding considering that some potential important risk factors such as smoking, BMI or prenatal care could not be measured with these data. Underestimation of non-routinely screened comorbidities such as hypercholesterolemia or thyroid dysfunction could also be a cause of selection bias. WIDER IMPLICATIONS OF THE FINDINGS The estimated prevalence of 1.5% from our study was similar to the average prevalence reported in the literature and the representativeness of our data has been validated by comparison to national statistics. Also the prevalence of comorbidities was mostly similar to other studies estimating these in the UK and other developed countries. Women with Black or Asian ethnicity, of young age, carrying multiple babies or singleton females, with Type 1 diabetes or with history of HG were confirmed to be at higher risk of HG with an unprecedented higher statistical power. We showed for the first time that socioeconomic status interacts with maternal age, that hypercholesterolemia is a potential risk factor for HG and that carrying multiple females increases risk of hyperemesis compared with multiple males. We also provided robust evidence for the association of parity with HG. Earlier recognition and management of symptoms via gynaecology day-case units or general practitioner services can inform prevention and control of consequent hospital admissions. STUDY FUNDING/COMPETING INTERESTS The work was founded by The Rosetrees Trust and the Stoneygate Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. C.N.-P. reports personal fees from Sanofi Aventis, Warner Chilcott, Leo Pharma, UCB and Falk, outside the submitted work and she is one of the co-developers of the RCOG Green Top Guideline on HG; all other authors did not report any potential conflicts of interest. TRIAL REGISTRATION NUMBER Not applicable.

Nicotine Replacement Therapy in Pregnancy and Major Congenital Anomalies in Offspring

BACKGROUND AND OBJECTIVES: Nicotine replacement therapy (NRT) is now being used as a smoking cessation aid during pregnancy, although little is known about fetal safety. We assessed the relationship between early pregnancy exposure to NRT or smoking with major congenital anomalies (MCA) in offspring. METHODS: We studied 192 498 children born in the United Kingdom between 2001 and 2012 with linked mother–child primary care records. The absolute risks of MCAs in the NRT group (women prescribed NRT during the first trimester or 1 month before conception [and therefore likely consumed during the first trimester]) and odds ratios (ORs) and 99% confidence intervals (CIs) were compared with those of women who smoked during pregnancy and with a control group (women who neither smoked nor were prescribed NRT); logistic regression models adjusted for maternal morbidities that increase MCA risk were used for analysis. RESULTS: MCA prevalence was 288 per 10 000 live births (5535 children with ≥1 MCA). Maternal morbidities were most common in the NRT group (35%) followed by smokers (27%) and the control group (20%). Compared with the control group, adjusted ORs for MCAs in the NRT group and smokers were 1.12 (99% CI: 0.84–1.48) and 1.05 (99% CI: 0.89–1.23), respectively. The OR comparing the NRT group directly with smokers was 1.07 (99% CI: 0.78–1.47). There were no statistically significant associations between maternal NRT and system-specific anomalies except for respiratory anomalies (OR: 4.65 [99% CI: 1.76–12.25]; absolute risk difference: 3 per 1000 births), which was based on 10 exposed cases. CONCLUSIONS: For most system-specific MCAs, we found no statistically significant increased risks associated with maternal NRT prescribed during pregnancy, except for respiratory anomalies. Although this study is the largest published to date, NRT use in pregnancy remains rare; thus, the statistical power was limited. Higher morbidities in those women prescribed NRT may also be an explanatory factor. Nevertheless, absolute MCA risks were similar between women who smoked and those prescribed NRT during pregnancy.