A novel methodology for personalized simulations of ventricular hemodynamics from noninvasive imaging data.

Current state-of-the-art imaging techniques can provide quantitative information to characterize ventricular function within the limits of the spatiotemporal resolution achievable in a realistic acquisition time. These imaging data can be used to personalize computer models, which in turn can help treatment planning by quantifying biomarkers that cannot be directly imaged, such as flow energy, shear stress and pressure gradients. To date, computer models have typically relied on invasive pressure measurements to be made patient-specific. When these data are not available, the scope and validity of the models are limited. To address this problem, we propose a new methodology for modeling patient-specific hemodynamics based exclusively on noninvasive velocity and anatomical data from 3D+t echocardiography or Magnetic Resonance Imaging (MRI). Numerical simulations of the cardiac cycle are driven by the image-derived velocities prescribed at the model boundaries using a penalty method that recovers a physical solution by minimizing the energy imparted to the system. This numerical approach circumvents the mathematical challenges due to the poor conditioning that arises from the imposition of boundary conditions on velocity only. We demonstrate that through this technique we are able to reconstruct given flow fields using Dirichlet only conditions. We also perform a sensitivity analysis to investigate the accuracy of this approach for different images with varying spatiotemporal resolution. Finally, we examine the influence of noise on the computed result, showing robustness to unbiased noise with an average error in the simulated velocity approximately 7% for a typical voxel size of 2mm(3) and temporal resolution of 30ms. The methodology is eventually applied to a patient case to highlight the potential for a direct clinical translation.

Towards a fast and efficient approach for modelling the patient-specific ventricular haemodynamics.

Computer modelling of the heart has emerged over the past decade as a powerful technique to explore the cardiovascular pathophysiology and inform clinical diagnosis. The current state-of-the-art in biophysical modelling requires a wealth of, potentially invasive, clinical data for the parametrisation and validation of the models, a process that is still too long and complex to be compatible with the clinical decision-making time. Therefore, there remains a need for models that can be quickly customised to reconstruct physical processes difficult to measure directly in patients. In this paper, we propose a less resource-intensive approach to modelling, whereby computational fluid-dynamics (CFD) models are constrained exclusively by boundary motion derived from imaging data through a validated wall tracking algorithm. These models are generated and parametrised based solely on ultrasound data, whose acquisition is fast, inexpensive and routine in all patients. To maximise the time and computational efficiency, a semi-automated pipeline is embedded in an image processing workflow to personalise the models. Applying this approach to two patient cases, we demonstrate this tool can be directly used in the clinic to interpret and complement the available clinical data by providing a quantitative indication of clinical markers that cannot be easily derived from imaging, such as pressure gradients and the flow energy.

Automated registration of optical coherence tomography and dermoscopy in the assessment of sub-clinical spread in basal cell carcinoma.

Optical coherence tomography (OCT) has been shown to be of clinical value in imaging basal cell carcinoma (BCC). A novel dual OCT-video imaging system, providing automated registration of OCT and dermoscopy, has been developed to assess the potential of OCT in measuring the degree of sub-clinical spread of BCC. Seventeen patients selected for Mohs micrographic surgery (MMS) for BCC were recruited to the study. The extent of BCC infiltration beyond a segment of the clinically assessed pre-surgical border was evaluated using OCT. Sufficiently accurate (<0.5 mm) registration of OCT and dermoscopy images was achieved in 9 patients. The location of the OCT-assessed BCC border was also compared with that of the final surgical defect. Infiltration of BCC across the clinical border ranged from 0 mm to >2.5 mm. In addition, the OCT border lay between 0.5 mm and 2.0 mm inside the final MMS defect in those cases where this could be assessed. In one case, where the final MMS defect was over 17 mm from the clinical border, OCT showed >2.5 mm infiltration across the clinical border at the FOV limit. These results provide evidence that OCT allows more accurate assessment of sub-clinical spread of BCC than clinical observation alone. Such a capability may have clinical value in reducing the number of surgical stages in MMS for BCC. There may also be a role for OCT in aiding the selection of patients most suitable for MMS.

Registering preprocedure volumetric images with intraprocedure 3-D ultrasound using an ultrasound imaging model.

For many image-guided interventions there exists a need to compute the registration between preprocedure image(s) and the physical space of the intervention. Real-time intraprocedure imaging such as ultrasound (US) can be used to image the region of interest directly and provide valuable anatomical information for computing this registration. Unfortunately, real-time US images often have poor signal-to-noise ratio and suffer from imaging artefacts. Therefore, registration using US images can be challenging and significant preprocessing is often required to make the registrations robust. In this paper we present a novel technique for computing the image-to-physical registration for minimally invasive cardiac interventions using 3-D US. Our technique uses knowledge of the physics of the US imaging process to reduce the amount of preprocessing required on the 3-D US images. To account for the fact that clinical US images normally undergo significant image processing before being exported from the US machine our optimization scheme allows the parameters of the US imaging model to vary. We validated our technique by computing rigid registrations for 12 cardiac US/magnetic resonance imaging (MRI) datasets acquired from six volunteers and two patients. The technique had mean registration errors of 2.1-4.4 mm, and 75% capture ranges of 5-30 mm. We also demonstrate how the same approach can be used for respiratory motion correction: on 15 datasets acquired from five volunteers the registration errors due to respiratory motion were reduced by 45%-92%.

Respiratory motion correction for image-guided cardiac interventions using 3-D echocardiography.

In this paper, we investigate the use of 3-D echocardiography (echo) data for respiratory motion correction of roadmaps in image-guided cardiac interventions. This is made possible by tracking and calibrating the echo probe and registering it to the roadmap coordinate system. We compare two techniques. The first uses only echo-echo registration to predict a motion-correction transformation in roadmap coordinates. The second combines echo-echo registration with a model of the respiratory motion of the heart. Using experiments with cardiac MRI and 3-D echo data acquired from eight volunteers, we demonstrate that the second technique is more robust than the first, resulting in motion-correction transformations that were accurate to within 5mm in 60% of cases, compared to 42% for the echo-only technique, based on subjective visual assessments. Objective validation showed that the model-based technique had an accuracy of 3.3 + or - 1.1mm, compared to 4.1 + or - 2.2mm for the echo only technique. The greater errors of the echo-only technique were mostly found away from the area of echo coverage. The model-based technique was more robust away from this area, and also has significant benefits in terms of computational cost.

Learning from adverse clinical outcomes: major obstetric haemorrhage in Scotland, 2003-05.

OBJECTIVE: To describe a system for learning from cases of major obstetric haemorrhage. DESIGN: Prospective critical incident audit. SETTING: All consultant-led maternity units in Scotland, between 1 January 2003 and 31 December 2005. POPULATION: Women suffering from major obstetric haemorrhage (estimated blood loss > or = 2500 ml or transfused > or = 5 units of blood or received treatment for coagulopathy during the acute event). METHODS: Hospital clinical risk management teams reviewed local cases using a standard, national assessment pro forma. MAIN OUTCOME MEASURES: Standard of care provided and learning points identified. RESULTS: Rate of major haemorrhage was 3.7 (3.4-4.0) per 1000 births. Pro formas returned for 517 of 581 reported cases (89%); 41% were delivered by emergency caesarean section (compared with 15% of all Scottish births). Uterine atony was the most common cause (250 women, 48%); 32% had multiple causes. A consultant obstetrician gave hands-on care to 368 (71%) and a consultant anaesthetist to 262 (50%). Placenta praevia as a cause was independently associated with consultant presence. Central venous pressure monitoring was used in 164 (31%) women, and 108 (21%) women were admitted to intensive care. Parity, blood loss, and placenta praevia as a cause were independently associated with peripartum hysterectomy (performed in 62 women, 12%). Balloon tamponade and haemostatic uterine suturing were successful in 92 of 116 women (79%). Most cases were assessed as well managed, with 'major suboptimal' care identified in only 14 cases (3%). CONCLUSIONS: It is feasible to identify and assess cases of major obstetric haemorrhage prospectively on a national basis. Most women received appropriate care, but many learning points and action plans were identified.

Birth weight and maternal glycated haemoglobin in pregnancies complicated by type 1 diabetes.

AIM: To re-examine the relationships between birth weight and maternal glycated haemoglobin (HbAlc) concentration at different time points in pregnancies complicated by pre-gestational type 1 diabetes. METHODS: A dataset was collected prospectively on all deliveries in Scotland to women with pre-gestational type 1 diabetes occurring during two 12 month periods (01/04/98 to 31/03/99 and 01/04/03 to 31/03/04). Relationships between standardised measures of birth weight and HbAlc at each time point were examined using correlation analysis. RESULTS: Standardised birth weights (Z scores) were calculated for 338 singleton live born infants. HbA1c concentrations were available for: 204 women (pre-pregnancy), 297 women (1st trimester), 314 women (2nd trimester) and 303 women (3rd trimester). Standardised birth weight showed a unimodal distribution shifted to the right relative to a reference population (Mean, +1.62 S.D). There was a significant negative correlation between pre-pregnancy HbAlc and birth weight (Spearman's Rho -0.138; p=0.049). CONCLUSIONS: Standardised birth weights of the infants of diabetic mothers are higher than those of a reference population. There is no simple relationship between maternal glycaemic control and birth weight, but the previously described paradoxical inverse relationship between pre-pregnancy glycaemic control and birth weight has been confirmed using a larger dataset.

The relationship between pre-pregnancy care and early pregnancy loss, major congenital anomaly or perinatal death in type I diabetes mellitus.

The relationships between markers of pregnancy planning and pre-pregnancy care and adverse outcomes (early pregnancy loss, major congenital anomaly and perinatal death) were examined in 423 singleton pregnancies in women with pre-gestational type I diabetes mellitus. Pregnancy planning and markers of pre-pregnancy care were associated with reduced risks of adverse pregnancy outcomes. 'Documentation of achievement of an optimal haemoglobin A1c prior to discontinuation of contraception' was the marker associated with the lowest rate of adverse outcome (OR 0.2; 95% CI 0.06-0.67) and might serve as an appropriate definition of pre-pregnancy care for research and audit purposes.

Do panels vary when assessing intrapartum adverse events? The reproducibility of assessments by hospital risk management groups.

INTRODUCTION: A national audit project, Scotland-wide Learning from Intrapartum Critical Events (SLICE), included local assessment of quality of care in cases of perinatal death and neonatal encephalopathy due to intrapartum events. Concerns had been raised about interobserver variation in case assessment by different panels. We therefore studied the extent of agreement and disagreement between assessment panels, and examined the areas in which agreement and disagreement tended to occur. METHODS: 8 cases were randomly selected from all 42 cases identified during a 6-month period (1 January-1 July 2005). Each case was independently reviewed by three panels: the local hospital clinical risk-management group and two specially convened external panels. Panels assessed quality of care in three areas: admission assessment, recognition of incident, and method and timing of delivery. Predefined standards of care were provided for these three areas. Panels were also asked to assess the overall quality of care. RESULTS: For each area of care, agreement between the two external panels was lowest. The lowest levels of agreement between panels were seen in assessment of overall care (50% crude agreement between external panel 1 and the hospital (kappa = 0.24, AC(1) = 0.36); 29% crude agreement between external panels 1 and 2 (kappa = -0.11, AC(1) = 0.1); 47% crude agreement between external panel 2 and the hospital (kappa = 0.36, AC(1) = 0.46). The lowest level of agreement among all three panels was also in the assessment of overall care (crude agreement 48%; kappa = 0.16, AC(1) = 0.34). CONCLUSION: Moderate to substantial agreement among the three panels was achieved for the three areas in which explicit standards were provided. Therefore, a systematic approach to analysis of adverse events in perinatal care improves reproducibility.

Cadaver validation of intensity-based ultrasound to CT registration.

A method is presented for the rigid registration of tracked B-mode ultrasound images to a CT volume of a femur and pelvis. This registration can allow tracked surgical instruments to be aligned with the CT image or an associated preoperative plan. Our method is fully automatic and requires no manual segmentation of either the ultrasound images or the CT volume. The parameter which is directly related to the speed of sound through tissue has also been included in the registration optimisation process. Experiments have been carried out on six cadaveric femurs and three cadaveric pelves. Registration results were compared with a "gold standard" registration acquired using bone implanted fiducial markers. Results show the registration method to be accurate, on average, to 1.6 mm root-mean-square target registration error.

An evaluation of the impact of a national health demonstration project on testing and management for Chlamydia trachomatis infections in two regions of Scotland.

OBJECTIVES: To compare clinical practice relating to testing for, and management of, genital Chlamydia trachomatis infection in the Lothian and Grampian regions of Scotland as part of an evaluation of a Government-funded health demonstration project in Lothian, Healthy Respect. STUDY DESIGN: Clinical audit against standards developed from a national clinical guideline. METHODS: Clinical practice relating to testing for, and management of, genital C. trachomatis infection was assessed against standards for good quality care developed from a national clinical guideline (Scottish Intercollegiate Guidelines Network Guideline 42). Audit methods comprised: postal survey of primary care clinicians; review of referral letters from primary to secondary care; and review of primary and secondary care patient case records. Findings from Lothian and Grampian were compared. RESULTS: Questionnaires were returned by 167 primary care clinicians in Lothian and 96 in Grampian. Clinicians in Lothian and Grampian gave similar responses relating to: testing of symptomatic patients (87 vs 88%); offer of testing for asymptomatic young patients (55 vs 55%); choice of antichlamydial agent (47 vs 42% azithromycin as first line); and follow-up strategies (50 vs 51% offer follow-up in primary care). Clinicians in Lothian were significantly more likely to participate in partner notification work (57 vs 44%; P=0.04) and to agree with statements reflecting 'perceived self-efficacy' in chlamydia-related care (57 vs 48%; P=0.006). Referral letters from primary to secondary care were reviewed for 31 women with genital symptoms in Lothian and 28 in Grampian. More women in Lothian were tested for chlamydia prior to referral (65 vs 39%; difference not significant). Review of primary care records for consultations in young people (145 in Lothian; 203 in Grampian) showed a higher level of chlamydia testing in Grampian (Lothian, 14%; Grampian, 34%; P<0.0001). However, review of secondary care records (n=39) showed a much higher level of testing in Lothian (Lothian, 75%; Grampian, 9%; P<0.0001). Review of secondary care records relating to proven chlamydia-positive women (n=159) suggested better care in Lothian in relation to ensuring antibiotic treatment (Lothian, 91%; Grampian, 74%; P=0.004), and use of the preferred antibiotic, azithromycin (Lothian, 78%; Grampian, 37%; P<0.0001). However, documented referral to a health adviser appeared to be better in Grampian (Lothian, 32%; Grampian, 48%; P=0.048). CONCLUSIONS: During the period of activity of the Healthy Respect demonstration project, few differences were detected between clinicians in Lothian and Grampian with regard to chlamydia-related practice. In both regions, clinicians appeared to be very aware of the need to test for chlamydia in patients with relevant symptoms, but were less likely to offer opportunistic testing to young patients without specific symptoms. These findings suggest that Healthy Respect in Lothian has had little impact on clinicians. However, these findings must be considered within the context of a broader evaluation, and it is noteworthy that the few significant differences that were detected tended to suggest better practice in Lothian.

Economic modelling of antenatal screening and ultrasound scanning programmes for identification of fetal abnormalities.

OBJECTIVE: Within the framework of a health technology assessment and using an economic model, to determine the most clinically and cost effective policy of scanning and screening for fetal abnormalities in early pregnancy. DESIGN: A discrete event simulation model of 50,000 singleton pregnancies. SETTING: Maternity services in Scotland. POPULATION: Women during the first 24 weeks of their pregnancy. METHODS: The mathematical model was populated with data on uptake of screening, prevalence, detection and false positive rates for eight fetal abnormalities and with costs for ultrasound scanning and serum screening. Inclusion of abnormalities was based on the relative prevalence and clinical importance of conditions and the availability of data. Six strategies for the identification of abnormalities prenatally including combinations of first and second trimester ultrasound scanning and first and second trimester screening for chromosomal abnormalities were compared. MAIN OUTCOME MEASURES: The number of abnormalities detected and missed, the number of iatrogenic losses resulting from invasive tests, the total cost of strategies and the cost per abnormality detected were compared between strategies. RESULTS: First trimester screening for chromosomal abnormalities costs more than second trimester screening but results in fewer iatrogenic losses. Strategies which include a second trimester ultrasound scan result in more abnormalities being detected and have lower costs per anomaly detected. CONCLUSIONS: The preferred strategy includes both first and second trimester ultrasound scans and a first trimester screening test for chromosomal abnormalities. It has been recommended that this policy is offered to all women in Scotland.

Fertility and ageing.

The late 20th century trend to delay birth of the first child until the age at which female fecundity or reproductive capacity is lower has increased the incidence of age-related infertility. The trend and its consequences have also stimulated interest in the possible factors in the female and the male that may contribute to the decline in fecundity with age; in the means that exist to predict fecundity; and in the consequences for pregnancy and childbirth. In the female, the number of oocytes decreases with age until the menopause. Oocyte quality also diminishes, due in part to increased aneuploidy because of factors such as changes in spindle integrity. Although older male age affects the likelihood of conception, abnormalities in sperm chromosomes and in some components of the semen analysis are less important than the frequency of intercourse. Age is as accurate as any other predictor of conception with assisted reproductive technology. The decline in fecundity becomes clinically relevant when women reach their mid-30s, when even assisted reproduction treatment cannot compensate for the decline in fecundity associated with delaying attempts at conceiving. Pregnancies among women aged >40 years are associated with more non-severe complications, more premature births, more congenital malformations and more interventions at birth.

Tissue deformation and shape models in image-guided interventions: a discussion paper.

This paper promotes the concept of active models in image-guided interventions. We outline the limitations of the rigid body assumption in image-guided interventions and describe how intraoperative imaging provides a rich source of information on spatial location of anatomical structures and therapy devices, allowing a preoperative plan to be updated during an intervention. Soft tissue deformation and variation from an atlas to a particular individual can both be determined using non-rigid registration. Established methods using free-form deformations have a very large number of degrees of freedom. Three examples of deformable models--motion models, biomechanical models and statistical shape models--are used to illustrate how prior information can be used to restrict the number of degrees of freedom of the registration algorithm and thus provide active models for image-guided interventions. We provide preliminary results from applications for each type of model.

Registration-based interpolation.

A method is presented to interpolate between neighboring slices in a grey-scale tomographic data set. Spatial correspondence between adjacent slices is established using a nonrigid registration algorithm based on B-splines which optimizes the normalized mutual information similarity measure. Linear interpolation of the image intensities is then carried out along the directions calculated by the registration algorithm. The registration-based method is compared to both standard linear interpolation and shape-based interpolation in 20 tomographic data sets. Results show that the proposed method statistically significantly outperforms both linear and shape-based interpolation.

A randomised controlled trial of a tailored multifaceted strategy to promote implementation of a clinical guideline on induced abortion care.

OBJECTIVE: To evaluate the effectiveness and efficiency of a tailored multifaceted strategy, delivered by a national clinical effectiveness programme, to implement a guideline on induced abortion. DESIGN: Cluster randomised controlled trial. SETTING AND PARTICIPANTS: All 26 hospital gynaecology units in Scotland providing induced abortion care. INTERVENTION: Following the identification of barriers to guideline implementation, intervention units received a package comprising audit and feedback, unit educational meetings, dissemination of structured case records and promotion of a patient information booklet. Control units received printed guideline summaries alone. MAIN OUTCOME MEASURES: Compliance with five key guideline recommendations (primary outcomes) and compliance with other recommendations, patient satisfaction and costs of the implementation strategy (secondary outcomes). RESULTS: No effect was observed for any key recommendation: appointment with a gynaecologist within five days of referral (odds ratio 0.89; 95% confidence interval 0.50 to 1.58); ascertainment of cervical cytology history (0.93; 0.36 to 2.40); antibiotic prophylaxis or screening for lower genital tract infection (1.70; 0.71 to 5.99); use of misoprostol as an alternative to gemeprost (1.00; 0.27 to 1.77); and offer of contraceptive supplies at discharge (1.11; 0.48 to 2.53). Median pre-intervention compliance was near optimal for antibiotic prophylaxis and misoprostol use. No intervention benefit was observed for any secondary outcome. The intervention costs an average of pound 2607 per gynaecology unit. CONCLUSIONS: The tailored multifaceted strategy was ineffective. This was possibly attributable to high pre-intervention compliance and the limited impact of the strategy on factors outside the perceived control of clinical staff.

Assessment of a technique for 2D-3D registration of cerebral intra-arterial angiography.

This study assesses the ability of a computer algorithm to perform automated 2D-3D registrations of digitally subtracted cerebral angiograms. The technique was tested on clinical studies of five patients with intracranial aneurysms. The automated procedure was compared against a gold standard manual registration, and achieved a mean registration accuracy of 1.3 mm (SD 0.6 mm). Two registration strategies were tested using coarse (128 x 128 pixel) or fine (256 x 256 pixel) images. The mean registration errors proved similar but registration of the lower resolution images was 3 times quicker (mean registration times 33 s, SD 13 s for low and 150 s SD 48 s for high resolution images). The automated techniques were considerably faster than manual registrations but achieved similar accuracy. The technique has several potential uses but is particularly applicable to endovascular treatment techniques.

Registration of freehand 3D ultrasound and magnetic resonance liver images.

We present a method to register a preoperative MR volume to a sparse set of intraoperative ultrasound slices. Our aim is to allow the transfer of information from preoperative modalities to intraoperative ultrasound images to aid needle placement during thermal ablation of liver metastases. The spatial relationship between ultrasound slices is obtained by tracking the probe using a Polaris optical tracking system. Images are acquired at maximum exhalation and we assume the validity of the rigid body transformation. An initial registration is carried out by picking a single corresponding point in both modalities. Our strategy is to interpret both sets of images in an automated pre-processing step to produce evidence or probabilities of corresponding structure as a pixel or voxel map. The registration algorithm converts the intensity values of the MR and ultrasound images into vessel probability values. The registration is then carried out between the vessel probability images. Results are compared to a "bronze standard" registration which is calculated using a manual point/line picking algorithm and verified using visual inspection. Results show that our starting estimate is within a root mean square target registration error (calculated over the whole liver) of 15.4 mm to the "bronze standard" and this is improved to 3.6 mm after running the intensity-based algorithm.

Is midwife workload associated with quality of process of care (continuous electronic fetal monitoring [CEFM]) and neonatal outcome indicators? A prospective study in consultant-led labour wards in Scotland.

Evidence for staffing recommendations in labour wards is scant. This study aimed to test association between midwife workload with adjusted process of continuous electronic fetal monitoring (CEFM) and neonatal outcome indicators. This was a prospective workload study in 23 consultant-led labour wards in Scotland. There were 3489 livebirths during September 2000, and 1561 consecutively delivered women with CEFM case review during the mid-two weeks. Process measures were: adjusted rates of CEFM, appropriate CEFM, and time to medical response for a serious fetal heart trace abnormality. Neonatal outcome indicators were: Apgar score < 7 at 5 minutes, admission to neonatal unit (NNU) > 48 hours, and neonatal resuscitation. Complete information was available for 99% (2553/2576) of workload time points, 99% (1559) of CEFM process, and 3083 eligible neonates. There were no associations between occupancy or staffing ratios and adjusted CEFM process, Apgar < 7 at 5 minutes (0.98 [0.83, 1.15]) or admission to NNU for > 48 hours (0.97 [0.95, 1.00]). However, there was association between increasing staffing ratios and lower odds of adjusted neonatal resuscitation (excluding bag and mask only) (0.97 [0.94, 0.99]). The direction of effect of increasing workload suggests detriment to outcome indicators, although the size of effect may be small.

The relationship between birth weight and maternal glycated haemoglobin (HbA1c) concentration in pregnancies complicated by Type 1 diabetes.

AIM: To examine the relationships between maternal HbA1c concentration at different time points and birth weight in pregnancies complicated by pre-existing Type 1 diabetes. METHODS: A comprehensive audit dataset was collected prospectively on all deliveries in Scotland to women with pre-existing Type 1 diabetes occurring between 1 April 1998 and 31 March 1999. Data items included HbA1c concentrations prior to conception and in each of the three trimesters of pregnancy, and birth weight. Relationships between standardized birth weight and HbA1c concentrations at each of the four time points were examined using correlation analysis. RESULTS: Standardized birth weight (Z scores) could be calculated for 203 of 208 singleton liveborn infants. HbA1c concentrations, standardized to correct for assay differences among hospitals, at different time points were available for between 134 (pre-pregnancy) and 192 (third trimester) cases. Standardized birth weight, relative to a reference population, showed a unimodal distribution, shifted to the right (mean, +1.57 sd). There was a significant negative correlation between pre-pregnancy HbA1c and birth weight (Spearman's R, -0.208; P = 0.016). There were no statistically significant correlations for other time points. CONCLUSIONS: Standardized birth weight scores of the infants of diabetic mothers are higher than those of a reference population. There is no simple relationship between maternal glycaemic status and birth weight, but there appears to be a paradoxical inverse relationship between pre-pregnancy glycaemic control and standardized birth weight.