Pre-eclampsia is associated with complement pathway activation in the maternal and fetal circulation, and placental tissue.

OBJECTIVES: Pre-eclampsia (PE) is a leading cause of obstetric morbidity, with no definitive therapy other than delivery. We aimed to compare complement markers in maternal and fetal circulation, and placental tissue, between women with PE and healthy pregnant controls. STUDY DESIGN: Maternal and umbilical cord blood was tested for iC3b, C3, C4, properdin, Ba and C5b-9, and placental tissue for C3d, C4d, C9 and C1q, from women with PE (n = 34) and healthy pregnant controls (n = 33). Maternal properdin and Ba tests were repeated in a separate validation cohort (PE n = 35; healthy pregnant controls n = 35). MAIN OUTCOME MEASURES: Complement concentrations in maternal and umbilical cord blood, and placental immunohistochemical complement deposition. RESULTS: Women with PE had significantly lower concentrations of properdin (mean: 4828 vs 6877 ng/ml, p < 0.001) and C4 (mean: 0.20 vs 0.31 g/l, p < 0.001), and higher Ba (median: 150 vs 113 ng/ml, p = 0.012), compared to controls. After controlling for gestational age at blood draw, average properdin concentration was 1945 ng/ml lower in PE vs controls (95 % CI: 1487-2402, p < 0.001). Of the cord blood markers assessed, only Ba differed significantly between PE and controls (median: 337 vs 233 ng/ml, p = 0.004). C4d staining of the syncytiotrophoblast membrane was increased in PE vs controls (median immunoreactivity score 3 vs 0, p < 0.001). Maternal properdin and C4 were significantly negatively correlated with placental C4d staining. CONCLUSIONS: Our data confirm excessive placental complement deposition associated with significant concurrent changes in maternal and fetal circulating complement biomarkers in PE. Inhibition of complement activation is a potential therapeutic target.

Care of pregnant women with epilepsy in the United Kingdom: A national survey of healthcare professionals.

OBJECTIVES: To map the care provided to pregnant women with epilepsy in UK maternity units and identify future research priorities by conducting a nationwide survey of healthcare professionals. STUDY DESIGN: A prospective cross-sectional electronic survey was conducted between 29 April and 30 October 2021. The survey included 23 questions developed and refined with relevant stakeholders, including a woman with lived experience of epilepsy and pregnancy. We used descriptive analyses to summarise responses and estimated proportions with medians and interquartile ranges. RESULTS: 144 individual healthcare professionals from 94 hospitals, representing 77 NHS Trusts, participated in the survey. Obstetricians were the most common responders (45%, 65/144) and almost half (47%, 7/15) of regions had a survey response rate per NHS Trust greater than 50%. Six pregnant women with epilepsy, on average, were booked into antenatal care per hospital per month, and 49% (46/94) of hospitals saw women for specialist antenatal care in the first trimester. The care provided across healthcare systems varied, with multiple pathways for referral to specialist care within regions. Midwife referral was the most used care pathway (80%, 75/94). Less than a third of hospitals (31%, 29/94) ran joint obstetric/neurology clinics for pregnant women with epilepsy. Most survey respondents (81%, 117/144) were confident talking to pregnant women about their risk of seizures but only a minority (20%, 29/144) used validated calculators to assess this risk. There was broad agreement across healthcare professionals that the priorities for research should focus on how to improve communication and address pregnant women's concerns regarding epilepsy and pregnancy, and to develop further understanding on the optimal use and long-term effects of anti-seizure medication. CONCLUSION: Our UK nationwide survey of hospital-based maternity services for pregnant women with epilepsy identified wide variation in when, how and by whom these women are seen, with differences between and within the UK regions. This survey highlights areas for improvement in the care of pregnant women with epilepsy.

Type 2 Autoimmune Hepatitis and Nonadherence to Medication Correlate With Premature Birth and Risk of Postpartum Flare.

Autoimmune hepatitis (AIH) is an immune-mediated chronic liver disease that affects all ages, including women of childbearing age. Optimal management during pregnancy is poorly defined. We aimed to explore the clinical and biochemical course of AIH in the antenatal and postpartum periods, and assess factors associated with premature birth and postpartum flares. Pregnant women with AIH reviewed in the autoimmune liver disease clinic at the Queen Elizabeth Hospital Birmingham between 2009 and 2020 were identified retrospectively, and clinical, biochemical, and immunological data 1 year before conception to 1 year postpartum were collected. Analysis was performed to identify trends in blood markers over the antenatal period, with an interrupted time series approach used to assess postpartum trends. Data were available for n = 27 pregnancies (n = 20 women), with median gestation of 38 weeks (30% premature) and most having type 1 AIH (78%) and delivering via caesarean section (63%). Levels of alanine transaminase, aspartate transaminase, and immunoglobulin G all declined significantly during gestation, followed by significant step-change increases after delivery. Postpartum flare developed in 58% of pregnancies. AIH type 2 was associated with a higher rate of premature births (67% vs. 19%, P = 0.044), and a trend toward a higher rate of postpartum flare (100% vs. 48%, P = 0.053). Although not significant, medication nonadherence was associated with almost double the risk of prematurity (40% vs. 24%, P = 0.415) and postpartum flare (80% vs. 44%, P = 0.109). Conclusion: Biochemical and immunological remission of AIH occurs during pregnancy, although subsequent postpartum flare is common. Type 2 AIH is associated with a higher risk of premature birth and postpartum flare, although further research is required to validate and explain this finding.

Review article: chronic liver disease and pregnancy.

BACKGROUND: The prevalence of chronic liver disease in women of child bearing age is increasing, leading to a higher incidence of pregnancy in this cohort. Chronic medical conditions have a significant adverse effect on maternal morbidity and mortality. To date, reviews on this topic have been written either from a hepatology or obstetrics viewpoint, and no specific guidelines are available solely for the management of chronic liver disease in pregnancy. AIMS: To produce a comprehensive review on the clinical management of women with chronic liver disease during pregnancy, addressing the risks of pregnancy to mother and child, how these risks can be ameliorated, and what additional considerations are required for management of chronic liver disease in pregnancy. METHODS: Data were collected up to May 2020 from the biomedical database PubMed, national and international guidelines in gastroenterology and hepatology. RESULTS: During pregnancy, women with cirrhosis are more likely to develop decompensated disease, worsening of portal hypertension, and to deliver premature infants. CONCLUSIONS: The risks associated with pregnancy can be ameliorated by advanced planning, assessing risk using the model for end stage liver disease score and risk reduction through varices screening. A multidisciplinary approach is paramount in order to minimise complications and maximise the chance of a safe pregnancy and birth for mother and baby.

Pregnancy in women with cystinosis.

Cystinosis is a rare autosomal recessive disease causing cystine deposition in all tissues, primarily affecting the kidneys. There are few published reports of pregnancy in women with cystinosis, and little evidence is available regarding optimal management. Kidney transplantation and cystine-depleting therapy have transformed the prognosis of cystinosis, and pregnancy is increasingly considered. The evidence base for cystinosis management in pregnancy, therefore, requires expansion. We report three successful pregnancy outcomes and five early pregnancy losses in two women with cystinosis. The challenges of pregnancy in patients with cystinosis are discussed. Pre-pregnancy planning and antenatal management in a specialist renal obstetric clinic are paramount.

Humoral immunity in late-onset Pre-eclampsia and linkage with angiogenic and inflammatory markers.

PROBLEM: Pre-eclampsia (PE) is a leading cause of maternal and foetal morbidity worldwide. Given the implication of immune mechanisms, we compared markers of humoral immunity in PE and their relationship to circulating markers of inflammation, angiogenic factors, and renal function. METHOD OF STUDY: Serum samples from 88 previously healthy women admitted to hospital with PE and 107 healthy pregnant controls at term were analysed for serum immunoglobulins (Ig), including IgG subclasses and free light chain (sFLC) levels, beta-2 microglobulin (B2-M), high-sensitivity C-reactive protein (HS-CRP), albumin, complement proteins (C3 & C4), creatinine, cystatin-C and the ratio of soluble fms-like tyrosine kinase-1 (sFLT-1) and placental growth factor (PlGF). RESULTS: Compared to the controls, women with PE had significantly reduced renal function, serum IgG (subclass 1 & 3), albumin, and C4 levels, whilst concentrations of total sFLC, HS-CRP, B2-M, and sFLT-1:PlGF were raised. On multivariable analysis, sFLT-1:PlGF ratio (P < 0.001), sFLC (P < 0.001) and IgG1 (P < 0.024) were found to be independently associated with PE, after accounting for renal function, patient age, BMI, ethnicity, and parity. B2-M and sFLT-1:PlGF had comparable diagnostic association with PE (P = 0.184), and correlated strongly with each other (ρ = 0.588, P < 0.001) as well as with renal function and adverse clinical outcome. CONCLUSION: We describe for the first time that PE is independently associated with activation of the humoral immune system independent of deranged kidney function and angiogenic markers. The role of B2-M as a potential predictive marker of PE remains to be determined.

Patterns of opioid use during initial buprenorphine/naloxone treatment in relation to changes in opioid management laws in Kentucky.

BACKGROUND AND OBJECTIVES: There is limited information on the most commonly used opioid reported at the time of presentation for treatment with buprenorphine/naloxone and the extent to which state policy may impact type of opioid use reported. METHODS: Retrospective study, total N = of 595 from four different medical locations from January 1, 2009 to July 1, 2016 that provided buprenorphine/naloxone treatment in Louisville, Kentucky. Study aims included identifying the most commonly used opioid at the time of treatment before and after the creation of a state-wide opioid prescribing surveillance system (ie, the 2012 House Bill 1 [HB1]), and determine the extent to which clinical setting, sex, age, and insurance type impacted type of opioid reported during the intake appointment. RESULTS: Non-heroin opioid use decreased in the academic and private practice settings following passage of HB1, while heroin use increased in all three settings. After controlling for clinical setting and demographic characteristics, there was a significant increase in patients who reported using heroin (vs. non-heroin opioid) (RR = 25.00, p ≤ .001, CI = 12.08-51.73) and a significant increase in patients who reported using opioid agonists (vs. non-heroin opioid) (RR = 6.56, p ≤ .001, CI = 4.10-10.50) following enactment of HB1. DISCUSSION AND CONCLUSIONS: After the passage of HB1, there was a significant increase in patients reporting heroin use and opioid agonists compared to non-heroin opioids when presenting for treatment. SIGNIFICANT SIGNIFICANCE: There has been a notable shift in the opioid epidemic, which is evident in the outpatient treatment settings. (Am J Addict 2018;27:560-566).

Outcomes of pregnancy in patients with known Budd-Chiari syndrome.

AIM: To analyse the risk of pregnancy (a prothrombotic state) in patients with Budd-Chiari Syndrome (BCS). METHODS: Retrospective study of pregnancy in women with known BCS at single center from January 2001 to December 2015. RESULTS: Out of 53 females with BCS, 7 women had 16 pregnancies. Median age at diagnosis of BCS in these women was 25 years (range 21-34 years). At least one causal factor for BCS was identified in 6 women (86%). Six women had undergone radiological decompressive treatment. All patients had anticoagulation. Six fetuses were lost before 20 wk gestation in 2 women. There were 9 deliveries over 32 wk gestation and one delivery at 27 wk. All infants did well. Seven babies were born by emergency caesarean section. There were no cases of thrombosis. Two patients had notable vaginal (PV) bleeding in 3 pregnancies. None of the patients had variceal haemorrhage. Two patients were diagnosed with pulmonary hypertension, one during pregnancy and the other in the post-partum period. There was no maternal mortality. CONCLUSION: Maternal outcomes in patients with treated BCS are favourable and fetal outcomes beyond 20 wk gestation are good. There has been increased rate of caesarean section. Pulmonary hypertension is an important finding that needs further validation. These patients should be managed in centers experienced in treating high-risk pregnancies.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in women of childbearing age: risks versus benefits.

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are effective and widely used antihypertensive drugs. Exposure to these agents is known to be harmful to the fetus in the second and third trimesters of pregnancy. Concerns have also been raised about the risk of congenital malformations if ACEIs or ARBs are taken during the first trimester of pregnancy. The evidence to date, however, is conflicting and observed malformations may be due to confounders such as undiagnosed diabetes or maternal obesity, other antihypertensive medications or the hypertension itself. Nonetheless, in women who become pregnant while taking an ACEI or ARB, the drug should be stopped as soon as possible. In women with chronic kidney disease and proteinuria, it may be appropriate to continue taking an ACEI or ARB until the pregnancy is confirmed because of the significant benefit to their kidney function and the lower fertility rate in these patients.

Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence.

OBJECTIVES: To evaluate the association between thyroid autoantibodies and miscarriage and preterm birth in women with normal thyroid function. To assess the effect of treatment with levothyroxine on pregnancy outcomes in this group of women. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, Cochrane Library, and SCISEARCH (inception-2011) without any language restrictions. We used a combination of key words to generate two subsets of citations, one indexing thyroid autoantibodies and the other indexing the outcomes of miscarriage and preterm birth. STUDY SELECTION: Studies that evaluated the association between thyroid autoantibodies and pregnancy outcomes were selected in a two stage process. Two reviewers selected studies that met the predefined and explicit criteria regarding population, tests, and outcomes. DATA SYNTHESIS: Odds ratios from individual studies were pooled separately for cohort and case-control studies with the random effects model. RESULTS: 30 articles with 31 studies (19 cohort and 12 case-control) involving 12,126 women assessed the association between thyroid autoantibodies and miscarriage. Five studies with 12,566 women evaluated the association with preterm birth. Of the 31 studies evaluating miscarriage, 28 showed a positive association between thyroid autoantibodies and miscarriage. Meta-analysis of the cohort studies showed more than tripling in the odds of miscarriage with the presence of thyroid autoantibodies (odds ratio 3.90, 95% confidence interval 2.48 to 6.12; P < 0.001). For case-control studies the odds ratio for miscarriage was 1.80, 1.25 to 2.60; P = 0.002). There was a significant doubling in the odds of preterm birth with the presence of thyroid autoantibodies (2.07, 1.17 to 3.68; P = 0.01). Two randomised studies evaluated the effect of treatment with levothyroxine on miscarriage. Both showed a fall in miscarriage rates, and meta-analysis showed a significant 52% relative risk reduction in miscarriages with levothyroxine (relative risk 0.48, 0.25 to 0.92; P=0.03). One study reported on the effect of levothyroxine on the rate of preterm birth, and noted a 69% relative risk reduction (0.31, 0.11 to 0.90). CONCLUSION: The presence of maternal thyroid autoantibodies is strongly associated with miscarriage and preterm delivery. There is evidence that treatment with levothyroxine can attenuate the risks.

Multiples clinic: a model for antenatal care.

Antenatal care has become more focused in recent years with an increase in the number of specialist clinics providing care in a multidisciplinary manner. Multiple pregnancies are complex with complications for the mother and babies arising frequently. As a group they lend themselves well to a specialist clinic model where interested doctors and midwives can provide care tailored to the individual. This makes it less likely that complications will be missed and provides a consistent approach to care that patients desire. This article aims to describe models of care that can be given in such a clinic, acknowledging that one model will not fit all. The scant evidence that exists is presented along with selected examples of individual complications.

Prenatal detection of pulmonary hypoplasia in fetuses with congenital diaphragmatic hernia: a systematic review and meta-analysis of diagnostic studies.

BACKGROUND: Fetuses with congenital diaphragmatic hernia (CDH) are at risk of death from pulmonary hypoplasia at birth. OBJECTIVE: To determine the value of prenatal imaging parameters for predicting lethal pulmonary hypoplasia in fetuses with CDH. SEARCH STRATEGY: Relevant papers were identified by searching MEDLINE (1966-2008), EMBASE (1988-2008) and the Cochrane Library (2008 issue 3). SELECTION CRITERIA: Selected studies examined diagnostic tests for the prenatal prediction of lethal pulmonary hypoplasia in fetuses with CDH. The primary outcome measure was perinatal survival. RESULTS: Twenty-one studies fulfilled the entry criteria, of which six examined entirely unique heterogeneous parameters and the remaining 15 examined lung-head ratios (LHR) and/or the presence of liver in the fetal thorax. The strongest association was that of LHR > or = 0.6 compared to <0.6 (OR: 17.02; 95% CI: 2.10-137.89), although more clinically relevant was that of LHR >1.0 (OR: 5.07; 95% CI: 2.94-8.74). The finding of liver in the fetal chest was a poor prognostic feature (survival OR: 0.32; 95% CI: 0.21-0.49). CONCLUSION: In CDH, LHR and the presence of liver in the fetal thorax may be a useful predictive indicator of perinatal survival. Future usage of developing techniques needs careful evaluation prior to usage to guide therapy.

A review of the methodological features of systematic reviews in fetal medicine.

Systematic reviews of fetal medicine can serve as a tool for translation of research findings from a few expert centres to a wider healthcare specialty. The extent to which reviews of fetal medicine research are systematic and unbiased is not known. In this review of systematic reviews in fetal medicine, we have searched without language restrictions, Medline, Embase, DARE (Database of Abstracts of Reviews of Effectiveness), Cochrane Library (from database inception to 2005) and bibliographies of known reviews, and contacted experts to identify potentially relevant citations of literature for reviews of fetal medicine studies. The selected reviews were assessed for information on framing of questions, literature search and methods of review. The search yielded 659 citations of which 84 reviews met the inclusion criteria. Most of the reviews were in the field of fetal pathology (49/84, 59%). A majority of reviews (58/84, 69%) specified the question to be answered but only half (44/84, 52%) addressed a focussed question. Although 57/84 (68%) reviews had a detailed search description, only 32/84 (38%) searched without language restriction. 45/84 (54%) searched in multiple databases and 27/84 (32%) assessed for the risk of missing studies. There was no difference in quality between reviews of fetal pathology, screening for aneuploidy, fetal growth and fetal therapy, except with respect to specifying the question (p<0.03), search without language restriction (p<0.004), assessment of risk of missing studies (p<0.006) and study quality assessment (p<0.002) where reviews of fetal growth performed better than other domains. Our study reflects the paucity of good quality reviews in fetal medicine research. Existing reviews tend to be poor in reporting methodological features. Particularly, not enough attention is paid to assessment of validity of included studies and means to improving reliability of results through appropriate use of meta-analysis. There is a need for conducting further reviews and for rigour when reviewing fetal medicine research.

The accuracy of various tests for bacterial vaginosis in predicting preterm birth: a systematic review.

OBJECTIVE: To determine the accuracy with which various types of tests for bacterial vaginosis predict spontaneous preterm birth in pregnant women. DATA SOURCES: Studies were identified without language restrictions through nine different databases, and manual searching of bibliographies of known primary and review articles. STUDY SELECTION AND DATA EXTRACTION: There are four different bacterial vaginosis testing methods: Gram staining tests using either Nugent's or Spiegel's criteria, and gas liquid chromatography are laboratory based, and the fourth method uses clinical (Amsel's) criteria to diagnose bacterial vaginosis. Two reviewers independently selected studies and extracted data on their characteristics, quality and accuracy. Accuracy data were used to form 2 x 2 contingency tables of the bacterial vaginosis test results with spontaneous preterm birth as the reference standard. DATA SYNTHESIS: Data on asymptomatic women and women with symptoms of threatened preterm labour were analysed separately. Data were pooled to produce summary estimates of likelihood ratios for positive (LR+) and negative (LR-) test results for the various types of tests. RESULTS: There were 18 primary articles, involving altogether 17,868 women. There was unexplained heterogeneity in the meta-analyses of the accuracy results, which requires caution in their interpretation. Meta-analyses of studies testing asymptomatic women in the second trimester showed that clinical criteria had a LR+ of 0.98 (95% confidence interval 0.59 to 1.6) and a LR- of 1.00 (0.93 to 1.1), Gram staining (Nugent's criteria) had a LR+ of 1.6 (1.4 to 1.9) and a LR- of 0.9 (0.8 to 0.9), and Gram staining (Spiegel's criteria) had a LR+ of 2.4 (1.4 to 4.9) and a LR- of 0.81 (0.64 to 1.0). Among symptomatic women, Gram staining (Spiegel's criteria) had a LR+ of 1.3 (1.0 to 1.6) and LR- of 0.9 (0.7 to 1.0). CONCLUSION: There was a lack of difference in the accuracy of the various bacterial vaginosis tests for predicting preterm birth in both asymptomatic and symptomatic women of threatened preterm labour.

Effectiveness of nifedipine versus atosiban for tocolysis in preterm labour: a meta-analysis with an indirect comparison of randomised trials.

OBJECTIVE: To explore the effectiveness of nifedipine compared with atosiban for tocolysis in preterm labour. DESIGN: A systematic review of randomised controlled trials with meta-analysis using adjusted indirect comparison. POPULATION: Six hundred and seventy-nine women recruited in nine randomised trials evaluating the effectiveness of nifedipine versus beta-agonists, and 852 women recruited in four trials of atosiban versus beta-agonists. There were no trials comparing nifedipine directly with atosiban. METHODS: We performed meta-analysis with a technique involving an adjusted indirect comparison between nifedipine and atosiban using beta-agonists as the common comparator. This approach preserves the benefit accrued by randomisation in the original comparisons. MAIN OUTCOME MEASURES: Reduction in neonatal respiratory distress syndrome and delay in delivery by 48 hours. RESULTS: Nifedipine tocolysis was associated with a significant reduction in respiratory distress syndrome compared with atosiban (OR 0.55, 95% CI 0.32-0.97). It also increased the number of women whose delivery was delayed by 48 hours (OR 1.20, 95% CI 0.73-1.95), although this result was not statistically significant. CONCLUSIONS: When indirectly compared with atosiban, nifedipine tocolysis is more effective. In the absence of a direct comparison, our analysis provides a way to explore the potential benefits of nifedipine versus atosiban.

Oxytocin antagonists for tocolysis in preterm labour -- a systematic review.

BACKGROUND: Oxytocin antagonists have been shown to inhibit uterine contractions and delay preterm delivery. Our objective was to examine the clinical effectiveness and safety of oxytocin antagonists for tocolysis in preterm labour. MATERIAL/METHODS: We searched MEDLINE, EMBASE, the Cochrane Controlled Trials Register and Science Citation Index using the following Medical Subject Headings and textwords: oxytocin (antagonists and inhibitors), atosiban, antocin, oxytocin antagonists, oxytocin receptor antagonists and oxytocin inhibitors. All randomised controlled trials that compared effectiveness and safety of atosiban with a placebo or another tocolytic in women with threatened or actual preterm labour were included. The primary outcome measure was the proportion of women undelivered by 48 hours from the commencement of treatment. RESULTS: Six articles met the inclusion criteria - two compared atosiban to placebo and four atosiban to a beta-agonist. Meta-analysis showed a significant increase in the proportion of women undelivered by 48 hours in women receiving atosiban compared to placebo (RR 1.13, 95%CI 1.02, 1.26). When compared with beta-agonists, atosiban increased the proportion of women undelivered by 48 hours, but this trend did not reach statistical significance (RR 1.07, 95%CI 0.98, 1.17). Side effect profile was substantially better for atosiban compared to beta-agonists. CONCLUSIONS: Oxytocin antagonists appear to be effective and safe for tocolysis in preterm labour.