Accuracy of PE rule-out strategies in pregnancy : secondary analysis of the DiPEP study prospective cohort

ObjectiveRecent studies suggest that combinations of clinical probability assessment (the YEARS algorithm or Geneva score) and D-dimer can safely rule out suspected pulmonary embolism (PE) in pregnant women. We performed a secondary analysis of the DiPEP (Diagnosis of Pulmonary Embolism in Pregnancy) study data to determine the diagnostic accuracy of these strategies.MethodsThe DiPEP study prospectively recruited and collected data and blood samples from pregnant/postpartum women with suspected PE across 11 hospitals and retrospectively collected data from pregnant/postpartum women with diagnosed PE across all UK hospitals (15 February 2015 to 31 August 2016). We selected prospectively recruited pregnant women who had definitive diagnostic imaging for this analysis. We used clinical data and D-dimer results to determine whether the rule out strategies would recommend further investigation. Two independent adjudicators used data from imaging reports, treatments and adverse events up to 30 days to determine the reference standard.ResultsPEs were diagnosed in 12/219 (5.5%) women. The YEARS/D-dimer strategy would have ruled out PE in 96/219 (43.8%) but this would have included 5 of the 12 with PEs. Sensitivity for PE was 58.3% (95% CI 28.6% to 83.5%) and specificity 44.0% (37.1% to 51.0%). The Geneva/D-dimer strategy would have ruled out PE in 46/219 (21.0%) but this would have included three of the 12 with PE. Sensitivity was 75.0% (95% CI 42.8% to 93.3%) and specificity 20.8% (95% CI 15.6% to 27.1%). Administration of anticoagulants prior to blood sampling may have reduced D-dimer sensitivity for small PE.ConclusionStrategies using clinical probability and D-dimer have limited diagnostic accuracy and do not accurately rule out all PE in pregnancy. It is uncertain whether PE missed by these strategies lead to clinically important consequences.</jats:sec

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 INTEREST(S): 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

Successful pregnancies with thiopurine-allopurinol co-therapy for inflammatory bowel disease

Background: Thiopurines are an effective treatment for moderate to severe inflammatory bowel disease [IBD] and can be used safely in pregnancy. Combining allopurinol with a lower dose of thiopurine can improve clinical efficacy and bypass some adverse reactions associated with thiopurine monotherapy. Data on allopurinol in pregnancy are scarce. We report on a total of 13 cases where thiopurine and allopurinol co-therapy was used successfully to manage IBD during pregnancy without attributable adverse fetal effects. Methods: Patients were retrospectively identified at our two hospitals, one in the UK and one in Australia, using local IBD databases. Data regarding pregnancy and fetal outcomes including in utero fetal ultrasound scans, APGAR scores, fetal birthweights and neonate checks were collected from patient notes. Results: We identified 12 women with a total of 13 pregnancies treated with co-therapy before conception and for the duration of pregnancy. There were no miscarriages or spontaneous pre-term deliveries. There were 14 live births [seven vaginal deliveries; six caesarean sections]. Except for a primagravid twin pregnancy complicated by pre-eclampsia and twin-to-twin transfusion syndrome requiring caesarean section at 25 weeks, there were no low birthweight [< 2.5 kg] babies born and the APGAR scores of all babies were normal. No congenital malformations were identified. Conclusions: Adverse pregnancy outcomes attributable to thiopurine and allopurinol co-therapy were not detected in our case series. Our study provides reassurance for clinicians and patients who wish to continue the thiopurine-allopurinol co-therapy combination before conception and during pregnancy to maintain remission of IBD

Pregnancies in older women living with HIV in the UK and Ireland.

OBJECTIVES: The aim of the study was to compare maternal characteristics and pregnancy outcomes in women aged < 40 years and ≥ 40 years in a large unselected population of HIV-positive women delivering in the UK and Ireland between 2000 and 2014. METHODS: Comprehensive population-based surveillance data on all HIV-positive pregnant women and their children seen for care in the UK and Ireland are collected through the National Study of HIV in Pregnancy and Childhood. All singleton and multiple pregnancies reported by the end of June 2015 resulting in live birth or stillbirth to women diagnosed with HIV infection before delivery and delivering in 2000-2014 were included. Logistic regression models were fitted in analyses examining the association between older maternal age and specific outcomes (preterm delivery and stillbirth). RESULTS: Among 15 501 pregnancies in HIV-positive women, the proportion in older women (≥ 40 years) increased from 2.1% (73 of 3419) in 2000-2004 to 8.9% (510 of 5748) in 2010-2014 (P < 0.001). Compared with pregnancies in younger women, those in older women were more likely to result in multiple birth (3.0 vs. 1.9% in younger women; P = 0.03), stillbirth (adjusted odds ratio 2.39; P = 0.004) or an infant with a chromosomal abnormality (1.6 vs. 0.2%, respectively; P < 0.001). However, there was no increased risk of preterm delivery, low birth weight or mother-to-child HIV transmission among older mothers. CONCLUSIONS: There has been a significant increase over time in the proportion of deliveries to women living with HIV aged ≥ 40 years, which has implications for pregnancy management, given their increased risk of multiple births, stillbirth and chromosomal anomalies, as also apparent in the general population

Pathways of association between maternal haemoglobin and stillbirth: Path-analysis of maternity data from two hospitals in England

© 2018 The Authors. Published by BMJ Publishing Group. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: http://dx.doi.org/10.1136/bmjopen-2017-020149© 2018 Article author(s) (or their employer(s) unless otherwise stated in the text of the article). Objective To investigate the mechanisms that link maternal haemoglobin concentration with stillbirth. Design A retrospective cohort analysis using anonymised maternity data from two hospitals in England. Setting The Royal Wolverhampton NHS Trust and Guy's and St Thomas' NHS Foundation Trust. Study population 12 636 women with singleton pregnancies ≥24 weeks of gestation giving birth in the two hospitals during 2013-2015. Method A conceptual framework of hypothesised pathways through birth weight-for-gestational age and maternal infection including potential confounders and other risk factors was developed and examined using path-analysis. Path-analysis was performed by fitting a set of regression equations using weighted least squares adjusted for mean and variance. Goodness-of-fit indices were estimated. Main outcome measures Coefficient of association (β) for relationship between each parameter, and direct, indirect and total effects via the postulated pathways. Results The path-model showed a significant adjusted indirect negative effect of maternal haemoglobin on stillbirth mediated via birth weight-for-gestational age (standardised estimate (SE)=-0.01; 95% CI=-0.01 to-0.001; P=0.028). The effect through maternal infection was not significant at P<0.05 (SE=0.001; 95% CI=-0.004 to 0.01; P=0.610). There was a residual direct negative effect of maternal haemoglobin on stillbirth (SE=-0.12; 95% CI-0.23 to-0.02; P=0.020) after accounting for the two pathways. Total indirect SE=-0.004; 95% CI-0.01 to 0.003; P=0.267; total direct and indirect SE=-0.13; 95% CI-0.23 to-0.02; P=0.016. The goodness-of-fit indices showed a good fit between the model and the data. Conclusion While some of the influence on risk of stillbirth acts through low birth weight-for-gestational age, the majority does not. Several new mechanisms have been suggested for how haemoglobin may be exerting its influence on the risk of stillbirth possibly involving genetic, epigenetic and/or alternative obstetric and nutritional pathologies, but much more research is needed.MK is funded by a National Institute for Health Research (NIHR) Research Professorship (NIHR-RP-011-032).Published versio

Assessment of discharge treatment prescribed to women admitted to hospital for hyperemesis gravidarum

Aims: Prescribing drug treatment for the management of hyperemesis gravidarum (HG), the most severe form of nausea and vomiting in pregnancy, remains controversial. Since most manufacturers do not recommend prescribing antiemetics during pregnancy, little is known regarding which treatments are most prevalent among pregnant patients. Here we report for the first time, evidence of actual treatments prescribed in English hospitals.Methods: A retrospective pregnancy cohort was constructed using anonymised electronic records in the Nottingham University Hospitals Trust system for all women who delivered between January 2010 and February 2015. For women admitted to hospital for HG, medications prescribed on discharge were described and variation by maternal characteristics was assessed. Compliance with local and national HG treatment guidelines was evaluated.Results: Of 33,567 pregnancies (among 30,439 women), the prevalence of HG was 1.7%. Among 530 HG admissions with records of discharge drugs, Cyclizine was the most frequently prescribed (almost 73% of admissions). Prochlorperazine and metoclopramide were prescribed mainly in combination with other drugs, however, ondansetron was more common than metoclopramide at discharge from first and subsequent admissions. Steroids were only prescribed following readmissions. Thiamine was most frequently prescribed following readmission while high dose of folic acid was prescribed equally after first or subsequent admissions. Prescribing showed little variation by maternal age, ethnicity, weight, socioeconomic deprivation, or comorbidities.Conclusion: Evidence that management of HG in terms of discharge medications mainly followed local and national recommendations provides reassurance within the health professional community. Wider documentation of drugs prescribed to women with HG is required to enable full assessment of whether optimal drug management is being achieved

The DiPEP (Diagnosis of PE in Pregnancy) biomarker study: An observational cohort study augmented with additional cases to determine the diagnostic utility of biomarkers for suspected venous thromboembolism during pregnancy and puerperium

This study aimed to estimate the diagnostic utility of biomarkers for suspected venous thromboembolism (VTE) in pregnancy and the puerperium. Research nurses/midwives collected blood samples from 310 pregnant/postpartum women with suspected pulmonary emboli (PE) and 18 with diagnosed deep vein thrombosis (DVT). VTE was diagnosed using imaging, treatment and adverse outcome data. Primary analysis was limited to women with conclusive imaging (36 with VTE, 247 without). The area under the curve (AUC) for each biomarker was: activated partial thromboplastin time 0·669 (95% confidence interval 0·570-0·768), B-type natriuretic peptide 0·549 (0·453-0·645), C-reactive protein 0·542 (0·445-0·639), Clauss fibrinogen 0·589 (0·476-0·701), D-Dimer (by enzyme-linked immunosorbent assay) 0·668 (0·561-0·776), near-patient D-Dimer 0·651 (0·545-0·758), mid-regional pro-atrial natriuretic peptide 0·524 (0·418-0·630), prothrombin fragment 1 + 2 0·562 (0·462-0·661), plasmin-antiplasmin complexes 0·639 (0·536-0·742), prothombin time 0·613 (0·508-0·718), thrombin generation lag time 0·702 (0·598-0·806), thrombin generation endogenous potential 0·559 (0·437-0·681), thrombin generation peak 0·596 (0·478-0·715), thrombin generation time to peak 0·655 (0·541-0·769), soluble tissue factor 0·531 (0·424-0·638) and serum troponin 0·597 (0·499-0·695). No diagnostically useful threshold for diagnosing or ruling out VTE was identified. In pregnancy and the puerperium, conventional and candidate biomarkers have no utility either for their negative or positive predictive value in the diagnosis of VTE

The incidence of first stroke in pregnant and non-pregnant women of childbearing age: a population-based cohort study from England

Background: Pregnant women may have an increased risk of stroke compared to non-pregnant women of similar age, but the magnitude and the timing of such risk are unclear. We examined the risk of first stroke event in women of childbearing age and compared the risk during pregnancy and in the early postpartum period to background risk outside these periods. Methods and Results: We conducted an open cohort study of 2,046,048 women aged 15-49 years between 1st April 1997 and 31th March 2014 using linked primary (Clinical Practice Research Datalink) and secondary (Hospital Episode Statistics) care records in England. Risk of first stroke was assessed by calculating the incidence rate of stroke in antepartum, peripartum (2 days before until 1 day after delivery), early (first six weeks) and late (second six weeks) postpartum periods, compared with non-pregnant time using a Poisson regression model with adjustment for maternal age, socioeconomic group and calendar time. A total of 2,511 women had a first stroke. The incidence rate of stroke was 25.0 per 100,000 person-years (95% confidence interval 24.0-26.0) in non-pregnant time. The rate was lower antepartum (10.7/100,000 person-years, 7.6-15.1), but 9-fold higher peripartum (161.1/100,000 person-years, 80.6-322.1) and 3-fold higher early postpartum (47.1/100,000 person-years, 31.3-70.9). Rates of ischaemic and haemorrhagic stroke both increased peripartum and early postpartum. Conclusions: Although the absolute risk of first stroke is low in women of childbearing age, health care professionals should be aware of a considerable increase in relative risk during the peripartum and early postpartum periods

Physiological changes in pregnancy

Physiological changes occur in pregnancy to nurture the developing foetus and prepare the mother for labour and delivery. Some of these changes influence normal biochemical values while others may mimic symptoms of medical disease. It is important to differentiate between normal physiological changes and disease pathology. This review highlights the important changes that take place during normal pregnancy.http://www.cvja.co.zaam2016Obstetrics and Gynaecolog