Adverse pregnancy outcomes and subsequent development of connective tissue disease in the UK: an epidemiological study.

OBJECTIVE: This study assessed prevalence of connective tissue disease (CTDs), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS) and antiphospholipid antibodies (aPL) in women with previous adverse pregnancy outcome compared with uncomplicated livebirths. DESIGN: Retrospective case-control study. SETTING: UK Primary Care. POPULATION OR SAMPLE: Records of women, 18 years and older, within the Clinical Practice Research Datalink (CPRD) (1 January 2000-31 December 2013). METHODS: Clinical Practice Research Datalink was searched for pregnancy terms to identify adverse pregnancy outcome. Each identified case was matched to five livebirths. MAIN OUTCOME MEASURES: Diagnosis of SLE, CTD, APS or autoimmune antibodies. Poisson regression was performed to calculate relative risk ratios (RR), comparing adverse pregnancy outcome with livebirth cohorts. RESULTS: Clinical Practice Research Datalink identified 20 123 adverse pregnancy outcomes matched to 97 323 livebirths, with a total of 875 590 person-years follow up. Median follow up from study entry was 7.29 years (SD 4.39). Compared with women with an uncomplicated livebirth, women with adverse pregnancy outcome had an increased risk of developing CTD or autoimmune antibodies (RR 3.20, 95% CI 2.90-3.51). Risk was greatest following a stillbirth (RR 5.82, 95% CI 4.97-6.81). For CTD and SLE, the risk was greatest within the first 5 years of adverse pregnancy outcome. Risk for aPL and APS diagnosis was highest ≥5 years from adverse pregnancy outcome. CONCLUSIONS: Adverse pregnancy outcome is associated with increased risk of developing maternal CTD, including SLE. Either immunological factors predispose women to adverse pregnancy outcome and subsequent CTD diagnosis or, alternatively, adverse pregnancy outcome initiates autoimmune events which culminate in CTD in later life. TWEETABLE ABSTRACT: Stillbirth is associated with increased maternal risk of developing systemic lupus erythematosus (SLE).

Pregnancy outcomes in women with mechanical prosthetic heart valves: a prospective descriptive population based study using the United Kingdom Obstetric Surveillance System (UKOSS) data collection system.

OBJECTIVE: To describe the incidence of mechanical prosthetic heart valves (MPHV) in pregnancy in the UK; rates of maternal and fetal complications in this group of women, and whether these vary with the anticoagulation used during pregnancy. DESIGN: Prospective descriptive population-based study. SETTING: All consultant-led maternity units in the UK. POPULATION: All women with an MPHV who were pregnant between 1 February 2013 and 31 January 2015. METHODS: Collection and analysis of anonymous data relating to pregnancy management and outcome, using the UKOSS notification and data collection system. MAIN OUTCOME MEASURES: Maternal death, serious maternal morbidity, poor fetal outcome. RESULTS: Data were obtained for 58 women giving an estimated incidence of 3.7 (95% CI 2.7-4.7) per 100 000 maternities. There were five maternal deaths (9%); a further 24 (41%) suffered serious maternal morbidity. There was a poor fetal outcome from 26 (47%) pregnancies. Only 16 (28%) women had a good maternal and good fetal outcome. Low-molecular-weight heparin (LMWH) was used throughout pregnancy by 71% of women. Of these, 83% required rapid dose escalation in the first trimester. Monitoring regimens lacked consistency. CONCLUSIONS: This study has estimated the incidence of MPHV in pregnant women in the UK. It includes the largest cohort managed with LMWH throughout pregnancy reported to date. It demonstrates a high rate of maternal death, and serious maternal and fetal morbidity. Women with MPHVs, and their clinicians need to appreciate the significant maternal and fetal risks involved in pregnancy. Care should be concentrated in specialist centres. TWEETABLE ABSTRACT: High rates of poor maternal and fetal outcomes in pregnant women with mechanical prosthetic heart valves.

Syncytin 1 in the human placenta.

This study characterises HERV-W (syncytin 1) expression in normal and pathologic placenta and in BeWo cells. HERV-W mRNA levels were higher in the first trimester than at term, and similar patterns were observed with another retrovirally-derived mRNA species, ERV-3. N-glycosylated syncytin 1 precursor (73 kDa) is cleaved to surface-associated (SU) and transmembrane (TM) subunits. Both were evident in villous trophoblast, where perinuclear and punctate cytoplasmic deposits were observed, and linear TM subunit immunoreactivity was seen at the syncytial microvillous membrane. Punctate immunoreactivity was seen in BeWo cells with antibodies to SU and TM, and the two were co-localised. SU immunoreactivity was observed in association with fetal endothelium, and this effect was increased in tissue from pre-eclamptic placentas, which also showed a higher level of total SU protein. Absence of the TM subunit from endothelium suggests it is not a biosynthetic source. We suggest that SU is released from trophoblast into fetal circulation where it may bind vascular endothelium.

Maternal deaths in women with lupus nephritis: a review of published evidence.

BACKGROUND AND OBJECTIVES: Pregnancies in women with systemic lupus erythematosus (SLE) and lupus nephritis are considered high-risk due to high rates of maternal and fetal complications. However, there has not been a formal analysis addressing the issue of maternal deaths in these women. The aim of this study was to perform a literature review of the maternal deaths in women with SLE and lupus nephritis to: (1) identify the main causes of death and (2) discuss possible reasons for these causes, and strategies that may improve patient care and outcomes. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENT: We performed an extensive electronic literature search from 1962 to 2009 using online databases (PubMed, Embase, Lilacs, Cochrane Controlled Trials Register, Medline, and Science Citation Index). Studies were included if they reported pregnancies in patients with SLE and lupus nephritis with at least one reported maternal death. RESULTS: We identified 13 studies that reported a total of 17 deaths in the 6 week post-partum period that were attributable to SLE and lupus nephritis. In all cases, death occurred in the setting of active disease, and was attributed either to infection in 41.2% (n = 7), or disease activity in 29.4% (n = 5). The remaining deaths were due to pulmonary embolus in 11.8% (n = 2), pregnancy-associated cardiomyopathy in 5.9% (n = 1), adrenal failure due to abrupt steroid withdrawal in 5.9% (n = 1), and undefined in 5.9% (n = 1). CONCLUSIONS: All maternal deaths in patients with SLE and lupus nephritis occurred in those with active disease, with disease activity/complications and infections (mainly opportunistic) being the two major causes. The presented evidence further supports timing of pregnancy relative to SLE activity, and the judicious use of immunosuppressive agents in pregnant patients.

Differential expression of angiotensin II type 1 and type 2 receptors at the maternal-fetal interface: potential roles in early placental development.

Angiotensin II (Ang II) is locally generated in the placenta and regulates syncytial transport, vascular contractility and trophoblast invasion. It acts through two receptor subtypes, AGTR1 and AGTR2 (AT1 and AT2), which typically mediate antagonising actions. The objectives of this study are to characterise the cellular distribution of AGTR1 and AGTR2 at the maternal-fetal interface and explore the effects on cytotrophoblast turnover. Low levels of AGTR2 mRNA were detected in first trimester placental homogenates using real-time PCR. Immunohistochemistry using polyclonal antibodies against AGTR1 and AGTR2 detected the receptors in first trimester placenta, decidua basalis and villous tip outgrowths in culture. Serial staining with cytokeratin-7 was used to identify extravillous trophoblasts (EVTs). AGTR1 was found in the syncytiotrophoblast microvillous membrane, in a subpopulation of villous cytotrophoblasts, and in Hofbauer cells. AGTR1 was strongly upregulated in cytotrophoblasts in cell columns and villous tip outgrowths, but was absent in interstitial and endovascular EVTs within the decidua. AGTR2 immunostaining was present in Hofbauer cells and villous cytotrophoblasts, but was absent from syncytiotrophoblast. Faint staining was detected in cell column cytotrophoblasts and villous outgrowths, but not in EVTs within the decidua. Both receptors were detected in placental homogenates by western blotting. Ang II significantly increased proliferation of cytotrophoblasts in both villous explants and villous tip outgrowths, but did not affect apoptosis. Blockade of AGTR1 and AGTR2 together abrogated this effect. This study shows specific expression patterns for AGTR1 and AGTR2 in distinct trophoblast populations at the maternal-fetal interface and suggests that Ang II plays a role in placental development and generation of EVTs.

Cytomegalovirus infection in association with early onset pre-eclampsia.

This case describes a woman who presented with raised α-fetoprotein (AFP) on second trimester screening, and developed early onset fetal growth restriction (FGR) and severe pre-eclampsia (PET) before 24 weeks' gestation requiring magnesium sulphate and intravenous antihypertensives. Ultrasonography revealed a structurally normal fetus with estimated weight <3rd centile, abnormal uterine artery Dopplers and deteriorating fetal arterial Dopplers over the following 2 weeks. The pregnancy ended in fetal death before a viable weight was reached. Postmortem examination revealed a growth restricted fetus (birth weight <0.4th centile) and chronic villitis secondary to placental cytomegalovirus (CMV) infection. CMV has previously been associated with PET and FGR. This case highlights its potential role in the pathogenesis of placental failure and has relevance for counselling and management for future pregnancies. Furthermore, raised AFP may represent ongoing placental damage and offers potential for future therapeutic measures--for example, antivirals or immunisations to alter the natural history and prognosis of placental infection.

Prognosis in isolated gastroschisis with bowel dilatation: a systematic review.

OBJECTIVES: To investigate prognosis of the fetus with isolated gastroschisis and bowel dilatation from a systematic review of the literature. We aimed to compare the incidence of (a) intrauterine death, (b) death within 4 weeks of delivery, (c) bowel resection, (d) length of time to oral feeds and (e) time as inpatient in fetuses with gastroschisis with and without evidence of bowel dilatation. METHODS: Literature was identified by searching two bibliographical databases between 1980 and 2007. Studies were assessed for quality and stratified according to the definition of bowel dilatation. The data extracted were inspected for clinical and methodological heterogeneity. RESULTS: The search strategy yielded 1335 potentially relevant citations. Full manuscripts were retrieved for 92 citations. 10 studies (273 patients) were finally included in the systematic review. No difference was found between groups for death within 4 weeks of delivery (OR = 0.62 (95% CI 0.11 to 3.32); heterogeneity p = 0.39) or bowel resection (OR = 3.35 (95% CI 0.82 to 13.74); heterogeneity p = 0.39). There were insufficient data to compare the risk of intrauterine death and length of time to oral feeds. The mean inpatient stay was not significantly different between groups (OR = 16.63 (95% CI 0.98 to 32.28); heterogeneity p = 0.23). CONCLUSION: Current available evidence suggests that fetuses with isolated gastroschisis and bowel dilatation are not at increased risk of adverse perinatal outcome compared to those without bowel dilatation. However, there is a paucity of studies, and a randomised controlled trial is urgently needed.

Polymorphism in the epidermal growth factor gene is associated with birthweight in Sinhalese and white Western Europeans.

Birthweight predicts health later in life and is influenced by inherited factors. We investigated the association of the c.61G > A, and c.2566G > A polymorphisms in the epidermal growth factor (EGF) gene [GenBank NM_001963] with birthweight in three groups of healthy pregnant women, and in women with pregnancies affected by fetal growth restriction (FGR). Subjects comprised 171 Sinhalese women with normal pregnancies (Group A), 64 white Western European women with normal pregnancies (Group B), 101 white Western European women with normal pregnancies and their babies (Group C) and 107 women with pregnancies affected by FGR, their partners and their babies (Group D). Maternal EGF genotypes were associated with birthweight of healthy babies of women in Groups A (P = 0.03), B (P = 0.001) and C (P = 0.01). The association persisted following adjustment for confounding by gestational age, sex, maternal weight, parity and smoking habit. The trend from heaviest to lightest birthweights in all these groups was c.61AA > c.61GA > c.61GG and c.2566GG > c.2566GA > c.2566AA. The EGF haplotype associated with lower birthweight (c.61G, c.2566A) was transmitted at increased frequency from heterozygous parents to babies affected by FGR in Group D (P = 0.02). These findings support the hypothesis that growth factors expressed by the feto-maternal unit affect birthweight, and implicates polymorphism in the EGF gene in the aetiology of birthweight variability.

Angiotensinogen gene variants and small-for-gestational-age infants.

In 2003, the angiotensinogen (AGT) gene was found to be associated with infants small for gestational age (SGA). The present study of 107 pregnancies affected by SGA infants and 101 normal pregnancies was designed to further investigate this association. Maternal or fetal AGT genotype or haplotype frequencies did not differ between SGA and normal pregnancies (P > 0.35). Quantitative trait analysis of mothers with normal pregnancies demonstrated an association between AGT haplotype and blood pressure and body mass index at antenatal booking (P = 0.04), suggesting that AGT may play a role in the complex relationship between body mass and blood pressure in healthy pregnant women.

Transforming growth factor beta1 regulates angiotensin II type I receptor gene expression in the extravillous trophoblast cell line SGHPL-4.

The angiotensin II type 1 (AT1) receptor, transforming growth factor beta1 (TGFbeta1) and Oncostatin M (OSM) control key pathways that may be important during placentation. Although interactions between them exist in other tissues, trophoblast cells have not been investigated. Extravillous trophoblast cells, SGHPL-4, were stimulated with 10 ng/ml TGFbeta1 +/- 100 ng/ml OSM for 24 h. Real-time PCR showed that AT1 expression increased 2.76-fold [95% confidence interval (CI) = 1-6.74, P = 0.05] in response to TGFbeta1 and 4.21-fold (95% CI = 1.33-11.76, P = 0.03) with TGFbeta1 + OSM. Luciferase reporter gene constructs containing three haplotypes of the 59 flanking region of the AT1 receptor gene were transfected into SGHPL-4 and HepG2 cells and stimulated with 0.1, 1 and 10 ng/ml TGFbeta1 and 50 ng/ml OSM. Responses were dose and cell dependent. Luciferase activity increased in HepG2 cells in response to TGFbeta1 alone or together with OSM (P < 0.001); transcriptional activation differed between AT1 receptor gene haplotypes. In SGHPL-4 cells, luciferase activity was reduced on exposure to low concentrations of TGFbeta1 or high concentrations of TGFbeta1 combined with OSM (P = 0.003); the response was unaffected by haplotype. Interaction between AT1 and TGFbeta1 is a novel observation in trophoblast and suggests new avenues for the study of placentation.

Intrauterine haematomas in a recurrent miscarriage population.

BACKGROUND: This study examines the effect of intrauterine haematomas (IUH) discovered during early pregnancy ultrasound scanning in patients with recurrent miscarriage. Previous studies of IUHs have reported conflicting findings, and none studied women with recurrent miscarriage. METHODS: A total of 341 women with a viable pregnancy was included. Women with an IUH (n = 41) were compared with those without (n = 300). RESULTS: An IUH was identified by ultrasound in 12% (41/341) women. There were no differences in the number of live births between the two groups (25/41, 61% in the IUH group compared with 169/300, 56% without an IUH) or the number of miscarriages (6/41, 15% with an IUH compared with 72/300, 24% without an IUH). Anti-phospholipid antibodies were more common in the IUH group (21/31, 68% compared with 103/244, 42% P < 0.01). More women with haematomas experienced vaginal bleeding (16/31, 52% compared with 47/244, 19%, P < 0.01). These associations did not affect pregnancy outcome. Also, no increase in the rate of pregnancy complications was observed in the IUH group. CONCLUSIONS: The presence of an IUH in this potentially high risk patient group does not have a deleterious effect on pregnancy outcome.

Long-term implications of caesarean section.

Previous reports have linked caesarean section with subsequent reduced fertility, increased rates of miscarriage/ectopic, time delay to next baby and lower fetal weight. However, most reports studied women delivering before 1980. The aim of this study was to assess whether these findings still apply. Five hundred and seventy-six primiparous women delivered by caesarean section during 1992-93 and 576 controls were identified and followed for five years. No difference was observed for the time (months) to next pregnancy/delivery, proportion suffering miscarriage or ectopic or the number of subsequent children (P > 0.05, Mann-Whitney U/chi-squared). Subgroup analysis by indication for caesarean section yielded similar results. Subsequent babies in the caesarean section group were statistically smaller and delivered earlier (median 3.4 kg/39 weeks, P <0.01, Mann-Whitney U) compared with the control group (median 3.5 kg/40 weeks). These differences are probably due to an increased rate of elective caesarean section in the caesarean section group. This study has largely refuted the findings of previous publications. Women delivered by caesarean section in the 1990s can be reassured that future fertility and miscarriage/ectopic risk will not be affected.