Low CD4 + T cell count is related to specific anti-nuclear antibodies, IFNα protein positivity and disease activity in systemic lupus erythematosus pregnancy.

BACKGROUND: Lymphopenia, autoantibodies and activation of the type I interferon (IFN) system are common features in systemic lupus erythematosus (SLE). We speculate whether lymphocyte subset counts are affected by pregnancy and if they relate to autoantibody profiles and/or IFNα protein in SLE pregnancy. METHODS: Repeated blood samples were collected during pregnancy from 80 women with SLE and 51 healthy controls (HC). Late postpartum samples were obtained from 19 of the women with SLE. Counts of CD4 + and CD8 + T cells, B cells and NK cells were measured by flow cytometry. Positivity for anti-nuclear antibodies (ANA) fine specificities (double-stranded DNA [dsDNA], Smith [Sm], ribonucleoprotein [RNP], chromatin, Sjögren's syndrome antigen A [SSA] and B [SSB]) and anti-phospholipid antibodies (cardiolipin [CL] and ß2 glycoprotein I [ß2GPI]) was assessed with multiplexed bead assay. IFNα protein concentration was quantified with Single molecule array (Simoa) immune assay. Clinical data were retrieved from medical records. RESULTS: Women with SLE had lower counts of all lymphocyte subsets compared to HC throughout pregnancy, but counts did not differ during pregnancy compared to postpartum. Principal component analysis revealed that low lymphocyte subset counts differentially related to autoantibody profiles, cluster one (anti-dsDNA/anti-Sm/anti-RNP/anti-Sm/RNP/anti-chromatin), cluster two (anti-SSA/anti-SSB) and cluster three (anti-CL/anti-ß2GPI), IFNα protein levels and disease activity. CD4 + T cell counts were lower in women positive to all ANA fine specificities in cluster one compared to those who were negative, and B cell numbers were lower in women positive for anti-dsDNA and anti-Sm compared to negative women. Moreover, CD4 + T cell and B cell counts were lower in women with moderate/high compared to no/low disease activity, and CD4 + T cell count was lower in IFNα protein positive relative to negative women. Finally, CD4 + T cell count was unrelated to treatment. CONCLUSION: Lymphocyte subset counts are lower in SLE compared to healthy pregnancies, which seems to be a feature of the disease per se and not affected by pregnancy. Our results also indicate that low lymphocyte subset counts relate differentially to autoantibody profiles, IFNα protein levels and disease activity, which could be due to divergent disease pathways.

Low-density granulocytes are related to shorter pregnancy duration but not to interferon alpha protein blood levels in systemic lupus erythematosus.

BACKGROUND: An increased risk of pregnancy complications is seen in women with systemic lupus erythematosus (SLE), but the specific immunopathological drivers are still unclear. Hallmarks of SLE are granulocyte activation, type I interferon (IFN) overproduction, and autoantibodies. Here we examined whether low-density granulocytes (LDG) and granulocyte activation increase during pregnancy, and related the results to IFNα protein levels, autoantibody profile, and gestational age at birth. METHODS: Repeated blood samples were collected during pregnancy in trimesters one, two, and three from 69 women with SLE and 27 healthy pregnant women (HC). Nineteen of the SLE women were also sampled late postpartum. LDG proportions and granulocyte activation (CD62L shedding) were measured by flow cytometry. Plasma IFNα protein concentrations were quantified by single molecule array (Simoa) immune assay. Clinical data were obtained from medical records. RESULTS: Women with SLE had higher LDG proportions and increased IFNα protein levels compared to HC throughout pregnancy, but neither LDG fractions nor IFNα levels differed during pregnancy compared to postpartum in SLE. Granulocyte activation status was higher in SLE relative to HC pregnancies, and it was increased during pregnancy compared to after pregnancy in SLE. Higher LDG proportions in SLE were associated with antiphospholipid positivity but not to IFNα protein levels. Finally, higher LDG proportions in trimester three correlated independently with lower gestational age at birth in SLE. CONCLUSION: Our results suggest that SLE pregnancy results in increased peripheral granulocyte priming, and that higher LDG proportions late in pregnancy are related to shorter pregnancy duration but not to IFNα blood levels in SLE.

The complexity of kidney disease and diagnosing it - cystatin C, selective glomerular hypofiltration syndromes and proteome regulation.

Estimation of kidney function is often part of daily clinical practice, mostly done by using the endogenous glomerular filtration rate (GFR)-markers creatinine or cystatin C. A recommendation to use both markers in parallel in 2010 has resulted in new knowledge concerning the pathophysiology of kidney disorders by the identification of a new set of kidney disorders, selective glomerular hypofiltration syndromes. These syndromes, connected to strong increases in mortality and morbidity, are characterized by a selective reduction in the glomerular filtration of 5-30 kDa molecules, such as cystatin C, compared to the filtration of small molecules <1 kDa dominating the glomerular filtrate, for example water, urea and creatinine. At least two types of such disorders, shrunken or elongated pore syndrome, are possible according to the pore model for glomerular filtration. Selective glomerular hypofiltration syndromes are prevalent in investigated populations, and patients with these syndromes often display normal measured GFR or creatinine-based GFR-estimates. The syndromes are characterized by proteomic changes promoting the development of atherosclerosis, indicating antibodies and specific receptor-blocking substances as possible new treatment modalities. Presently, the KDIGO guidelines for diagnosing kidney disorders do not recommend cystatin C as a general marker of kidney function and will therefore not allow the identification of a considerable number of patients with selective glomerular hypofiltration syndromes. Furthermore, as cystatin C is uninfluenced by muscle mass, diet or variations in tubular secretion and cystatin C-based GFR-estimation equations do not require controversial race or sex terms, it is obvious that cystatin C should be a part of future KDIGO guidelines.

Variation of Complement Protein Levels in Maternal Plasma and Umbilical Cord Blood during Normal Pregnancy: An Observational Study.

The complement system constitutes a crucial part of the innate immunity, mediating opsonization, lysis, inflammation, and elimination of potential pathogens. In general, there is an increased activity of the complement system during pregnancy, which is essential for maintaining the host's defense and fetal survival. Unbalanced or excessive activation of the complement system in the placenta is associated with pregnancy complications, such as miscarriage, preeclampsia, and premature birth. Nonetheless, the actual clinical value of monitoring the activation of the complement system during pregnancy remains to be investigated. Unfortunately, normal reference values specifically for pregnant women are missing, and for umbilical cord blood (UCB), data on complement protein levels are scarce. Herein, complement protein analyses (C1q, C3, C4, C3d levels, and C3d/C3 ratio) were performed in plasma samples from 100 healthy, non-medicated and non-smoking pregnant women, collected during different trimesters and at the time of delivery. In addition, UCB was collected at all deliveries. Maternal plasma C1q and C3d/C3 ratio showed the highest mean values during the first trimester, whereas C3, C4, and C3d had rising values until delivery. We observed low levels of C1q and C4 as well as increased C3d and C3d/C3 ratio, particularly during the first trimester, as a sign of complement activation in some women. However, the reference limits of complement analyses applied for the general population appeared appropriate for the majority of the samples. As expected, the mean complement concentrations in UCB were much lower than in maternal plasma, due to the immature complement system in neonates.

A prospective study of the relationships between movement and glycemic control during day and night in pregnancy.

Both disturbed sleep and lack of exercise can disrupt metabolism in pregnancy. Accelerometery was used to objectively assess movement during waking (physical activity) and movement during sleeping (sleep disturbance) periods and evaluated relationships with continuous blood glucose variation during pregnancy. Data was analysed prospectively. 15-women without pre-existing diabetes mellitus wore continuous glucose monitors and triaxial accelerometers from February through June 2018 in Sweden. The relationships between physical activity and sleep disturbance with blood glucose rate of change were assessed. An interaction term was fitted to determine difference in the relationship between movement and glucose variation, conditional on waking/sleeping. Total movement was inversely related to glucose rate of change (p < 0.001, 95% CI (- 0.037, - 0.026)). Stratified analyses showed total physical activity was inversely related to glucose rate of change (p < 0.001, 95% CI (- 0.040, - 0.028)), whereas sleep disturbance was not related to glucose rate of change (p = 0.07, 95% CI (< - 0.001, 0.013)). The interaction term was positively related to glucose rate of change (p < 0.001, 95% CI (0.029, 0.047)). This study provides temporal evidence of a relationship between total movement and glycemic control in pregnancy, which is conditional on time of day. Movement is beneficially related with glycemic control while awake, but not during sleep.

Activated low-density granulocytes in peripheral and intervillous blood and neutrophil inflammation in placentas from SLE pregnancies.

OBJECTIVE: Women with SLE face an increased risk of adverse pregnancy outcomes compared with healthy women, but the underlying immunological mechanisms are unknown. Given the recognised association of neutrophil activation with SLE pathogenesis, we examined whether there is increased neutrophil activation and inflammation in blood and placenta in SLE relative to healthy pregnancy. METHODS: At delivery, peripheral blood, maternal-derived intervillous blood and placentas were collected from 12 SLE and 10 healthy control pregnancies. The proportion of low-density granulocytes (LDGs) and the activation status of LDG and normal-density granulocytes were examined with flow cytometry. The chemokines CXCL8 and CXCL1 were quantified with a cytometric bead-based assay and interferon alpha (IFNα) protein levels with a Simoa method. IFNα-stimulated maternal-derived decidual stromal cells were examined for CXCL8 gene expression with qPCR. A pathologist, blinded to the patient background, examined all placentas. RESULTS: Women with SLE had significantly higher proportions of LDG in peripheral blood compared with controls (p=0.02), and LDG in both peripheral and intervillous blood were more activated in SLE relative to healthy pregnancies (peripheral blood: p=0.002 and intervillous blood: p=0.05). There were higher levels of CXCL8 and CXCL1 in intervillous compared with peripheral blood in women with SLE (p=0.004 and p=<0.0001, respectively) but not in controls. In SLE pregnancy, IFNα was detectable in 6 out of 10 intervillous blood samples but only in one control. Stimulation with IFNα upregulated CXCL8 gene expression in decidual stromal cells from both SLE and healthy pregnancy. Histological chorioamnionitis was present in 6 out of 12 placentas from women with SLE and in 1 out of 10 controls. CONCLUSIONS: In women with SLE, locally produced chemokines in the placenta are increased and may attract and activate neutrophils. This in turn could contribute to placental inflammation and dysfunction and increased risk of placenta-related pregnancy complications.

A novel non-antimicrobial treatment of bacterial vaginosis: An open label two-private centre study.

BACKGROUND: Bacterial vaginosis (BV) is the most common cause of vaginal discharge. It is caused by an imbalance in the normal vaginal microbiota. Symptoms include an offensive odour. Standard oral or vaginal antimicrobial treatments have high immediate cure rates but almost as high recurrence rates. pHyph, a vaginal pessary, contains glucono-delta-lactone (GDL) and sodium gluconate (NaG) which restore normal pH and disrupt the associated biofilm. AIM: To investigate the clinical performance of pHyph, for both treatment and recurrence prevention. Design An open-label, single arm, multi-centre first in women study. SETTING: Two private gynaecology clinics in Skåne County, Southern Sweden. METHODS: Twenty four adult women with confirmed bacterial vaginosis received the investigational product for self-administration on days 0, 2, 4, and 6 and were assessed on day 7. Clinical cure was defined as absence of three of four Amsel's criteria (pH excluded) on day 7. Safety and tolerability were also recorded. Those not cured by day 7 received a prolonged treatment protocol. Results There were three withdrawals, two before the day 7 assessment. 18/22 (82 %) were clinically cured at day 7. The pessary was well tolerated. Recurrence rates at 14 days in patients cured at day 7 after receiving standard study treatment (n = 18) were 1/18 (5.6 %) with no additional recurrences reported at 35 days. Three of four patients not cured at 7 days received continued treatment (day 7, 9, 11, and 13), but none were cured at 14 days. CONCLUSION: pHyph has the potential for both high cure rates and a reduction in recurrence.

Adverse Pregnancy Outcomes after Multi-Professional Follow-Up of Women with Systemic Lupus Erythematosus: An Observational Study from a Single Centre in Sweden.

While the management of pregnant patients with systemic lupus erythematosus (SLE) has improved over the last decades, the risk of maternal, foetal, and neonatal complications is still substantial. We evaluated the occurrence of adverse pregnancy outcomes (APO) occurring in 2002-2018 among patients with SLE from the catchment area of the Department of Rheumatology in Lund, Sweden. Longitudinal clinical and laboratory data were collected and analysed. Results were stratified according to the sequence of conception. We investigated a total of 59 pregnancies in 28 patients. Prior lupus nephritis was the clinical feature that, in a multivariable regression analysis, displayed the strongest association with APO overall (OR 6.0, p = 0.02). SLE combined with antiphospholipid syndrome (APS) was associated with the risk of miscarriage (OR 3.3, p = 0.04). The positivity of multiple antiphospholipid antibodies (aPL) was associated with APO overall (OR 3.3, p = 0.05). IgG anti-cardiolipin during pregnancy resulted in a higher risk of preterm delivery (OR 6.8, p = 0.03). Hypocomplementaemia was associated with several APO, but only in the first pregnancies. We conclude that, despite the close follow-up provided, a majority of pregnancies resulted in ≥1 APO, but a few of them were severe. Our study confirms the importance of previous lupus nephritis as a main risk factor for APO in patients with SLE.

Pregnancy outcome in women with gestational diabetes - A longitudinal study of changes in demography and treatment modalities.

INTRODUCTION: Gestational diabetes is on the rise and demographics are changing in many countries due to increased migration. Simultaneously, the treatment of gestational diabetes in our clinic has shifted towards metformin with substantially less insulin treatment. The aim was to study the impact of these changes on metabolic control and pregnancy outcome by comparing women diagnosed with gestational diabetes during 2012-2013 and 2016-2017. MATERIAL AND METHODS: Our universal Oral Glucose Tolerance Test screening program for gestational diabetes diagnosed 199 women with singleton pregnancies during 2012-2013 and 203 during 2016-2017. Treatment and achieved metabolic control in the two different time periods were compared. Pregnancy outcome data related to gestational diabetes were retrieved from case notes and compared between the different time periods. RESULTS: When comparing results from 2016-2017 with 2012-2013 there was no difference in maternal weight or weight gain. There was a higher frequency of heredity (52.6 vs 35.4%; P = 0.001) and non-Scandinavian ethnicity (46.5 vs 33.8%; P = 0.011).The frequency of smoking during pregnancy was significantly lower (2.6 vs 7.7%; P = 0.023) There was an improved metabolic control as measured by median glucose in 2016-2017 compared with 2012-2013 (5.8 vs 6.2 mmol/L; P < 0.001). Insulin was less frequently used in 2016-2017 than in 2012-2013 (32.5 vs 44.7%; P = 0.012). There was a significant increase in the use of metformin (14.8 vs 0%; P < 0.001). There were no differences regarding the frequency of large-for-gestational-age infants (8.2% vs 7.3%; P = 0.762) or macrosomia (16.3 vs 15.1%; P = 0.745), median birthweight (3510 vs 3521; P = 0.879), frequency of cesarean section (28.1 vs 27.8%; P = 0.951) or Apgar scores at 10 minutes (10 [3-10] vs 10 [7-10]; P = 0.290). CONCLUSIONS: In an increasing but changing population of gestational diabetes women in our region, with more hereditary and non-Scandinavian origins, but with fewer smokers, metabolic control has improved with maintained favorable pregnancy outcomes, with more frequent use of metformin and substantially less use of insulin treatment.

Changing diagnostic criteria for gestational diabetes in Sweden - a stepped wedge national cluster randomised controlled trial - the CDC4G study protocol.

BACKGROUND: The optimal criteria to diagnose gestational diabetes mellitus (GDM) remain contested. The Swedish National Board of Health introduced the 2013 WHO criteria in 2015 as a recommendation for initiation of treatment for hyperglycaemia during pregnancy. With variation in GDM screening and diagnostic practice across the country, it was agreed that the shift to new guidelines should be in a scientific and structured way. The aim of the Changing Diagnostic Criteria for Gestational Diabetes (CDC4G) in Sweden ( www.cdc4g.se/en ) is to evaluate the clinical and health economic impacts of changing diagnostic criteria for GDM in Sweden and to create a prospective cohort to compare the many long-term outcomes in mother and baby under the old and new diagnostic approaches. METHODS: This is a stepped wedge cluster randomised controlled trial, comparing pregnancy outcomes before and after the switch in GDM criteria across 11 centres in a randomised manner. The trial includes all pregnant women screened for GDM across the participating centres during January-December 2018, approximately two thirds of all pregnancies in Sweden in a year. Women with pre-existing diabetes will be excluded. Data will be collected through the national Swedish Pregnancy register and for follow up studies other health registers will be included. DISCUSSION: The stepped wedge RCT was chosen to be the best study design for evaluating the shift from old to new diagnostic criteria of GDM in Sweden. The national quality registers provide data on the whole pregnant population and gives a possibility for follow up studies of both mother and child. The health economic analysis from the study will give a solid evidence base for future changes in order to improve immediate pregnancy, as well as long term, outcomes for mother and child. TRIAL REGISTRATION: CDC4G is listed on the ISRCTN registry with study ID ISRCTN41918550 (15/12/2017).

Evidence of Augmented Intrarenal Angiotensinogen Associated With Glomerular Swelling in Gestational Hypertension and Preeclampsia: Clinical Implications.

Background AGT (angiotensinogen) synthesis occurs in renal proximal tubular epithelial cells, independent from systemic AGT , as a component of the intrarenal renin-angiotensin system. We investigated urinary AGT , as a biomarker for renin-angiotensin system activation, and electrolyte concentrations, in relation to glomerular volume, as a proxy for glomerular endotheliosis in renal biopsy tissue from pregnant normotensive control and hypertensive women. Methods and Results Urine samples were collected from normotensive control (n=10), gestational hypertensive (n=6), and pre-eclamptic (n=16) women at the time a renal biopsy was obtained. Samples were collected from Lund University Hospital between November 1999 and June 2001. Urinary AGT , potassium, and sodium were measured, normalized to urinary creatinine. Mean glomerular volume was estimated from biopsy sections. AGT protein expression and localization were assessed in renal biopsies by immunohistochemistry. Urinary AGT concentrations were higher in hypertensive pregnancies (median, gestational hypertension: 11.3 ng/mmol [interquartile range: 2.8-13.6]; preeclampsia: 8.4 ng/mmol [interquartile range: 4.2-29.1]; normotensive control: 0.6 ng/mmol [interquartile range: 0.4-0.8]; P<0.0001) and showed a positive relationship with estimated mean glomerular volume. Urinary potassium strongly correlated with urinary AGT ( P<0.0001). Although numbers were small, AGT protein was found in both glomeruli and proximal tubules in normotensive control but was present only in proximal tubules in women with hypertensive pregnancy. Conclusions This study shows that pregnant women with gestational hypertension or preeclampsia have increased urinary AGT and potassium excretion associated with signs of glomerular swelling. Our data suggest that the kidneys of women with hypertensive pregnancies and endotheliosis have inappropriate intrarenal renin-angiotensin system activation, which may contribute toward the pathogenesis of hypertension and renal injury.

Soluble CD163 and TWEAK in early pregnancy gestational diabetes and later glucose intolerance.

Gestational diabetes mellitus (GDM) is today universally diagnosed during late pregnancy. Treating hyperglycaemia during pregnancy reduces the risk of complications, the effect of interventions is however limited due to the late diagnosis. It is thus important to identify biomarkers reaching a high precision for GDM development in early pregnancy. Here we aim to investigate soluble CD163 (sCD163) and soluble tumour necrosis factor-like weak inducer of apoptosis (sTWEAK) in early pregnancy GDM and their association to the development of later glucose intolerance. In this case-control study, women diagnosed with GDM in early pregnancy (n = 70) at Lund University Hospital, Lund, Sweden in 2011-2015 were age- and BMI matched to pregnant volunteers without diabetes (n = 70) recruited in early pregnancy from maternal health care centres in 2014-2015. Plasma levels of sCD163 and sTWEAK were analysed using commercial ELISA. Plasma levels of sCD163 did not differ between patients with and without GDM in early pregnancy (p = 0.86), plasma levels of sTWEAK however was decreased in women with GDM (0.71 [0.4-1.75] ng/ml) compared to controls (1.38 [0.63-4.86] ng/ml; p = 0.003). Women with sTWEAK levels in the lowest tertile had an increased risk of GDM in early pregnancy (p = 0.014). Neither sCD163 nor sTWEAK were associated with later glucose intolerance in women with GDM. This study reports decreased levels of sTWEAK in women with early pregnancy GDM, independent of age and BMI. Neither sCD163 nor sTWEAK were found to be associated to later glucose intolerance.

The use of polyhydroxylated carboxylic acids and lactones to diminish biofilm formation of the pathogenic yeast Candida albicans.

The vaginal microbiome of healthy women is a diverse and dynamic system of various microorganisms. Any sudden change in microbe composition can increase the vaginal pH and thus lead to vaginal infections, conditions that affect a large percentage of women each year. The most common fungal strains involved in infections belong to the yeast species Candida albicans. The main virulence factor of C. albicans is the ability to transform from planktonic yeast-form cells into a filamentous form (hyphae or pseudohyphae), with the subsequent formation of biofilm. The hyphal form, constituted by filamentous cells, has the ability to invade tissue and induce inflammation. Our hypothesis is that certain polyhydroxylated carboxylic acids, that may serve as an alternative carbohydrate source and at the same time lower the pH, function as an indicator of a nutrient-rich environment for C. albicans, which favors planktonic cells over hyphae, and thus diminish the formation of biofilm. We have shown that the biofilm formation in C. albicans and other Candida species can be significantly reduced by the addition of glucono-δ-lactone (GDL).

IgG4 subclass glutamic acid decarboxylase antibodies (GADA) are associated with a reduced risk of developing type 1 diabetes as well as increased C-peptide levels in GADA positive gestational diabetes.

Some women with gestational diabetes (GDM) present with autoantibodies associated with type 1 diabetes. These are usually directed against glutamic acid decarboxylase (GADA) and suggested to predict development of type 1 diabetes. The primary aim of this study was to investigate if GADA IgG subclasses at onset of GDM could assist in predicting postpartum development. Of 1225 women diagnosed with first-time GDM only 51 were GADA-positive. Total GADA was determined using ELISA. GADA subclasses were determined with radioimmunoassay. Approximately 25% of GADA-positive women developed type 1 diabetes postpartum. Titers of total GADA were higher in women that developed type 1 diabetes (142.1 vs 74.2u/mL; p=0.04) and they also had lower titers of GADA IgG4 (index=0.01 vs 0.04; p=0.03). In conclusion we found that that women with high titers of total GADA but low titers of GADA IgG4 were more prone to develop type 1 diabetes postpartum.

Outcomes of women with gestational diabetes mellitus in Sweden.

OBJECTIVE: The number of women with gestational diabetes mellitus (GDM) during pregnancy is increasing around the world and in our region in the south Sweden 1.2% of all pregnant women received the GDM diagnosis in the 90s and now it is about 2.2%. The aim of this study was to compare women with GDM 1995-99 against women with GDM 2012-13 regarding eventual differences in demographics and pregnancy outcome. STUDY DESIGN: In our region in Sweden, all pregnant women are tested for GDM with a 2-h 75g oral glucose tolerance test and the 2-h cut off value for GDM is ≥10.0mmol/l in capillary plasma glucose. 1995-99 there were 131 women with GDM and their medical journals were compared against the 210 women with GDM during 2012-13. The same screening and diagnostic method was uses during the whole time period. RESULTS: In the 2012-13 GDM pregnancies there were more non-Scandinavian women, more women with insulin treatment during pregnancy and a higher frequency of cesarean deliveries compared to 1995. First weight of the women during GDM pregnancy 2012-13 was significantly higher than the weight of women with GDM 1995-99, 71kg (43-138; n=201) and 65kg (43-133; n=125) (p=0.008) respectively. However, there was no significant difference in weight of the mother at delivery. Birth weight of the child in GDM pregnancies 1995-99 was 3722.4g±578.2 (n=109; p=0.009), and in GDM pregnancies 2012-13 3555.6g±465.8 (n=162). CONCLUSION: Even though women with GDM 2012-13 weigh more when they start the pregnancy there is no difference in weight at delivery compared to women with GDM 1995-99. This is also reflected on the newborn, that 2012-13 had significantly lower birth weight but with the same gestational length as 1995-1999. We believe that this is due to a more active and intense treatment of women with GDM during pregnancy together with higher frequency of cesarean delivery. Prevention of large infants is crucial to avoid complications during delivery.

Towards normalized birthweight in gestational diabetes mellitus.

INTRODUCTION: The objective was to describe pregnancy outcomes in gestational diabetes mellitus (GDM) in comparison with general population in Sweden. MATERIAL AND METHODS: A population-based retrospective study using University hospital records and Swedish Medical Birth Register was carried out on pregnant women with well-monitored GDM (n = 870) and pregnancies in the Swedish Medical Birth Register (n = 1 553 420). Data from GDM pregnancies was compared to pregnancies in the whole of Sweden during 1995-2010. The main outcome measures were age, first bodyweight in and weight gain during pregnancy, birthweight, gestational length, percentage of cesarean deliveries. RESULTS: First maternal bodyweight during the GDM pregnancy was higher than in the general population, 72.4 ± 17.4 kg (n = 837) vs. 67.3 ± 12.6 kg (n = 1 383 000; p < 0.0001). Women with GDM gained less weight during pregnancy 9.9 ± 5.8 kg (n = 703) compared to the general population, 13.2 ± 5.7 kg (n = 482 860; p < 0.0001). Mean birthweight in GDM pregnancies was 3564 ± 500 g (n = 743) compared to 3580 ± 483 g for the general population (n = 1 316 364; p = ns). Gestational length was slightly shorter, 39.4 weeks in the GDM pregnancies (n = 683) vs. 39.5 weeks (n = 1 319 876; p = 0.02) in the general population and the percentage of cesarean deliveries higher in the GDM pregnancies at 18.4% (n = 712) vs. 13.3% (n = 1 322 242; p < 0.0001). CONCLUSIONS: Though many studies have shown an increased risk of macrosomia in GDM pregnancies, remaining even after ambitious management programs, we show no difference in birthweight. This may be due to a combination of intense efforts to achieve good metabolic control during pregnancy and shorter pregnancy duration. Preventing unduly large babies is crucial to minimize adverse pregnancy outcomes.

PP038. Renal ETK/BMX activation decreased in preeclampsia.

INTRODUCTION: Vascular endothelial growth factors (VEGF's) are essential to angiogenesis and play a central role in the pathophysiology of preeclampsia. Specifically, antagonists of VEGFR2 cause a preeclampsia-like syndrome, in humans and rats[1]. ETK/BMX is a receptor tyrosine kinase (RTK) which induces VEGF expression and forms a complex with VEGFR2, whereby VEGF and TNF can induce a reciprocal activation of both kinases. OBJECTIVES: To determine the levels of phosphorylation, and thus activation, of VEGFR2 and ETK/BMX in renal tissue from women with preeclampsia and with healthy pregnancies. METHODS: Renal tissue was obtained with consent from six preeclamptic and six healthy pregnant women included in a previous renal needle biopsy study[2] and a RayBio® Phosphorylation Antibody Array was used according to instructions. RESULTS: Phosphorylated ETK/BMX was significantly reduced in the preeclamptic women compared to in the healthy pregnant women. There was no difference in phosphorylated VEGFR2 between groups. CONCLUSION: These data suggest that ETK/BMX could be an important mediator of VEGF function in healthy pregnancy, in the kidneys more so than VEGFR2, and that absence of the positive feedforward signalling that ETK/BMX and VEGF together accomplish, and/or a TNF induced activation of this, may play a role in the pathophysiology of preeclampsia.

PP039. ETK/BMX and renin-angiotensin system (RAS) components are differentially expressed in renal tissue in both normal and preeclamptic pregnancy.

INTRODUCTION: Renal ETK/BMX activity is reduced in preeclampsia. Systemic RAS has been studied in preeclampsia; the renal RAS has not. None of the proteins in either pathway have previously been located in renal tissue from human pregnancy. OBJECTIVES: To determine renal expression and distribution of proteins involved in the ETK/BMX and RAS pathways in normal and preeclamptic pregnancy. METHODS: Limited residual tissue was available from renal biopsies in eight preeclamptic and seven healthy pregnant women. Immunohistochemistry was performed for AT1R, AT2R, angiotensinogen (AGT), prorenin, unphosphorylated ETK/BMX (uBMX) and phosphorylated ETK/BMX (pBMX). Immunohistochemical scoring was performed semiquantatively by a nephropathologist blinded to the original diagnosis. Results All proteins were renally expressed, AT1R equally in glomeruli and tubules, AT2R and prorenin more strongly in the tubules. If at all, uBMX was weakly expressed in glomeruli, and no glomerular pBMX expression was detected. Both uBMX and pBMX were strongly expressed in distal tubules. The material was too limited to detect differences between groups. CONCLUSION: The presence of prorenin, and both angiotensin receptors in the proximal tubule may indicate activation of the intra-renal RAS. Angiotensin II promotes sodium retention at the proximal tubule independently of aldosterone. Activated ETK/BMX in injured tubular epithelial cells is associated with cell repair and regeneration, proliferation and motility.