Fetal Loss and Preterm Birth Caused by Intraamniotic Haemophilus influenzae Infection, New Zealand.

Invasive Haemophilus influenzae infection during pregnancy can cause preterm birth and fetal loss, but the mechanism is unclear. We investigated 54 cases of pregnancy-associated invasive H. influenzae disease in 52 unique pregnancies in the Auckland region of New Zealand during October 1, 2008‒September 30, 2018. Intraamniotic infection was identified in 36 (66.7%) of 54 cases. Outcome data were available for 48 pregnancies. Adverse pregnancy outcomes, defined as fetal loss, preterm birth, or the birth of an infant requiring intensive/special care unit admission, occurred in 45 (93.8%) of 48 (pregnancies. Fetal loss occurred in 17 (35.4%) of 48 pregnancies, before 24 weeks' gestation in 13 cases, and at >24 weeks' gestation in 4 cases. The overall incidence of pregnancy-associated invasive H. influenzae disease was 19.9 cases/100,000 births, which exceeded the reported incidence of pregnancy-associated listeriosis in New Zealand. We also observed higher rates in younger women and women of Maori ethnicity.

The use of biologics for autoimmune rheumatic diseases in fertility and pregnancy.

In an age where autoimmune rheumatic diseases are successfully managed with biologics, their discontinuation in pregnancy is inadvisable without careful forethought; maternal disease activity is associated with adverse pregnancy outcomes, which has long-term implications for both mother and offspring. We aim to provide clinicians with the necessary tools to facilitate decision-making - when a biologic should be used, when it can be discontinued in pregnancy if appropriate. The pathophysiology of these biologic molecules and their effect on fertility, pregnancy and parturition are discussed. A summary of the 2016 international guidelines (European League Against Rheumatism and British Society in Rheumatology) on biologics in pregnancy has been tabulated; more recent publications are discussed in depth. Data on transplacental-transfer ratios and breastmilk excretion rates are also included. Biologic effects on organogenesis, their implications for the exposed infant in terms of infection risks and vaccination requirements are included, and future directions for research proposed.

Biomarkers for Adverse Pregnancy Outcomes in Rheumatic Diseases.

Pregnancy is a delicate balance of angiogenic factors. Adverse pregnancy outcomes in the form of placental insufficiency occur when antiangiogenic factors predominate, which manifests as maternal-placental syndrome (MPS). Women with rheumatic disease are at increased risk of MPS. Endothelial damage from circulating antiangiogenic factors and other inflammatory molecules in combination with preexisting maternal vascular risk factors is the likely underlying pathophysiological process for MPS. It is likely that these changes persist, and additional "insults" from ongoing inflammation, medications, and disease damage contribute to the development of accelerated cardiovascular disease seen in young women with rheumatic disease.

Cytomegalovirus may mimic the presentation of intrahepatic cholestasis and hemolysis, elevated liver enzymes and low platelets in immunosuppressed pregnant women.

Most published cases of cytomegalovirus infection in pregnancy relate to congenital abnormalities in neonates infected in early pregnancy, while the mother remains asymptomatic. We describe a diagnostically challenging case of an immunosuppressed woman with scleroderma who developed deranged liver function tests attributed to intrahepatic cholestasis of pregnancy and haemolysis, elevated liver enzymes and low platelets syndrome but was ultimately found to have disseminated cytomegalovirus. Cytomegalovirus can present in a myriad of ways. Clinicians caring for immunocompromised pregnant women should consider cytomegalovirus as a possible differential diagnosis when reviewing abnormal liver function tests.

Maternal-placental syndrome and future risk of accelerated cardiovascular events in Parous Swedish women with systemic lupus erythematosus - a population-based retrospective cohort study with time-to-event analysis.

OBJECTIVES: Women with SLE are at increased risk of cardiovascular events (CVEs), but a relationship with traditional cardiovascular and SLE-specific risk factors has not been established. In unselected populations, adverse pregnancy outcomes linked to maternal-placental syndrome (MPS) are associated with an increased risk of CVEs. However, the effect of MPS on CVEs is unknown in women with SLE. The aim of this study was to determine if MPS increased the risk and accelerated the development of CVEs in women with SLE. METHODS: Utilizing Swedish population registries, parous women with SLE were identified. Exposures were the following: MPS defined as hypertensive disorders of pregnancy; small-for-gestational-age; placental abruption and stillbirth; and preterm delivery <34 weeks. Outcomes were CVE encompassing cardiovascular morbidity and mortality. Risk of an event was modelled using Cox proportional hazards adjusted for year of delivery, age at CVE, severity of SLE and cardiovascular risk factors. Time-to-CVE was estimated using Kaplan-Meier methods. RESULTS: Over the 38-year study period, there were 3977 women with 7410 pregnancies, of whom 413 (10.2%) suffered a CVE. Hazard of CVE was higher in those with MPS, particularly when MPS (adjusted HR = 1.64; 95% CI: 1.31, 2.05) was combined with preterm delivery < 34 weeks' gestation (adjusted HR 1.99; 95% CI 1.39, 2.84). There was accelerated development of CVEs in women with MPS of 10.5% (vs 7.3% in uncomplicated pregnancies) over the 38-year interval (P < 0.05). CONCLUSION: Pregnancy complicated by MPS and preterm delivery exerts an independent effect to increase the risk and accelerate the development of CVEs in parous women with SLE.

Brief Report: Association Between Pregnancy Outcomes and Death From Cardiovascular Causes in Parous Women With Systemic Lupus Erythematosus: A Study Using Swedish Population Registries.

OBJECTIVE: To determine if maternal placental syndromes (MPS) are associated with an increased risk of death from cardiovascular causes in women with systemic lupus erythematosus (SLE). METHODS: Between 1973 and 2011, women with SLE and a history of pregnancy were identified using linked Swedish population registries. The outcome was death from primarily cardiovascular causes, defined as death from acute coronary syndrome or coronary artery disease, stroke, or peripheral vascular disease. The exposure was MPS, defined as any hypertensive disorders in pregnancy, stillbirth, placental abruption, or delivery of a small-for-gestational-age infant. The association of preterm delivery (delivery at <34 weeks of gestation) with death from cardiovascular causes was also explored. Risk of death from cardiovascular causes was determined using logistic regression, adjusting for the year of first delivery, duration of SLE, number of inpatient admissions, and cardiovascular risk factors. RESULTS: A total of 3,977 women with SLE had 7,410 pregnancies during the study interval. Death from primarily cardiovascular causes occurred in 44 of the 325 women who died (13.5%). The median age at death from cardiovascular causes was 54 years (interquartile range 48-58 years), and these women were more likely to have had hypertension and renal disease. MPS was associated with an increased risk of death from primarily cardiovascular causes (adjusted odds ratio [OR] 2.19 [95% confidence interval (95% CI) 1.14-4.22]), specifically, a history of placental abruption (adjusted OR 5.78 [95% CI 1.61-20.72]). Delivery at <34 weeks of gestation, particularly when combined with MPS, was also associated with an increased risk of death from primarily cardiovascular causes (adjusted OR 2.49 [95% CI 1.06-5.85]). CONCLUSION: MPS in pregnancy is associated with a higher risk of death from primarily cardiovascular causes in women with SLE.

High-risk pregnancy and the rheumatologist.

Rheumatologists are increasingly involved in the care of young women who, in the age of biologic therapy, are now gaining control of their rheumatic diseases and attempting pregnancy. With careful planning, most women with rheumatic diseases have successful pregnancies. This article focuses specifically on the highest-risk pregnancies and controversial areas. We discuss the women at risk of complications, the types of maternal and fetal complications, the treatments that can be used in pregnancy (and breastfeeding) and longer-term outcomes that could affect the mother. SLE, RA, ANCA-associated vasculitides, large vessel vasculitis (e.g. Takayasu's) and other CTDs (e.g. scleroderma) are among the conditions covered. The evidence and controversies regarding the recommendations for the use of biologics in pregnancy are discussed. The role of the rheumatologist in pregnancy planning and caring for the pregnant and post-partum woman as part of the multidisciplinary team is discussed.

Persistent antiphospholipid antibodies do not contribute to adverse pregnancy outcomes.

OBJECTIVE: To determine whether women with persistent aPL (>12 weeks apart on at least two separate occasions) without a history of thrombosis or adverse pregnancy outcome had the same adverse pregnancy outcomes as those with obstetric APS or unmatched controls. METHODS: This was a case-control study between 2005 and 2011 where we identified 73 women with persistent aPL and coincidentally the same number with obstetric APS. Unmatched controls were identified from low-risk clinics (ratio 1:4). Women with multiple pregnancies, fetal anomalies, SLE, thrombotic APS and other thrombophilias were excluded. RESULTS: Cases and controls were demographically similar, with the exception of younger controls with fewer medical comorbidities. aPL profiles were similar between aPL and APS. In women with aPL, risk of APS-type complications (odds ratio 1.3; 95% CI 0.6, 2.9) and birthweight distribution (median birthweight on a customized centile was 50.8, interquartile range 26.4-68.9; P < 0.05) were similar to controls. These findings persisted even after adjustment for maternal age and medical comorbidities. CONCLUSION: Women with persistent aPL on aspirin had pregnancy outcomes that were similar to controls. These data suggest that in the absence of other risk factors, women with aPL do not need intense antenatal surveillance or modified management in pregnancy.

The combined impact of CYP2C19 and CYP2B6 pharmacogenetics on cyclophosphamide bioactivation.

AIMS: The role of CYP pharmacogenetics in the bioactivation of cyclophosphamide is still controversial. Recent clinical studies have suggested a role for either CYP2C19 or CYP2B6. The aim of this study was to clarify the role of these pharmacogenes. METHODS: We used a combined in vitro-in vivo approach to determine the role of these pharmacogenes in the bioactivation of the prodrug to 4-hydroxy cyclophosphamide (4-OHCP). Cyclophosphamide metabolism was determined in a human liver biobank (n= 14) and in patients receiving the drug for treatment of lupus nephritis (n= 16) RESULTS: In livers of known CYP2C19 and CYP2B6 genotype and protein expression we observed that there was a combined role for both CYP2C19 and CYP2B6 in the bioactivation of cyclophosphamide in vitro. The presence of at least one loss of function (LoF) allele at either CYP2C19 or CYP2B6 resulted in a significant decrease in both V(max) (P= 0.028) and CL(int) (P= 0.0017) compared with livers with no LoF alleles. This dual genotype relationship was also observed in a preliminary clinical study, with patients who had ≥1 LoF allele at either CYP2C19 or CYP2B6 also displaying significantly (P= 0.0316) lower bioactivation of cyclophosphamide. The mean 4-OHCP : CP bioactivation ratio was 0.0014 (95% CI 0.0007, 0.002) compared with 0.0071 (95% CI 0.0001, 0.014) in patients with no LoF alleles at either of these genes. CONCLUSIONS: The presence of ≥1 LoF allele(s) at either CYP2B6 or CYP2C19 appeared to result in decreased bioactivation of cyclophosphamide both in vitro and in patients. Further clinical studies to confirm this relationship are warranted.

Bartonella henselae aortic valve endocarditis mimicking systemic vasculitis.

A 28-year-old man with a bicuspid aortic valve presented with facial droop and slurred speech with several months of constitutional symptoms of night sweats, weight loss and productive cough. Examination confirmed aortic regurgitation, palpable spleen and left facial droop. Multiple peripheral blood cultures were negative. Inflammatory markers, cytoplasmic staining antineutrophil cytoplasmic antibodies (cANCA) and anti-PR3 antibody were all elevated. MRI of the brain and CT of the chest and abdomen confirmed embolic infarcts to brain, kidney and spleen. Transoesophageal echocardiogram (ECG) showed valve vegetations and severe aortic regurgitation. Endocardial Wegener's granulomatosis was considered. Aortic valve replacement was performed. Grindings from aortic valve leaflets were analysed for rpoB gene, which confirmed the presence of Bartonella henselae. Serological assays demonstrated B henselae IgM 20 (normal <20) and IgG >2048 (normal < 64). The patient completely recovered after prolonged antibiotic treatment. Culture-negative infective endocarditis may mimic vasculitis and be associated with positive cANCA. Serology and molecular techniques may aid diagnosis.

Pregnancy complicating Wegener's granulomatosis.

Pregnancy associated with Wegener's granulomatosis is rare. Therapeutic options are limited. There is a paucity of published literature to guide clinical decision-making in these complex patients. Two cases are presented. Firstly, a 33-year-old woman with generalized Wegener's in remission and off all medications presented with a flare in the third trimester with haemoptysis, raised C-reactive protein and c-anti-neutrophilic cytoplasmic antibody (c-ANCA) levels. Her care was complicated by florid steroid-induced psychosis. With deteriorating disease control, she was treated with pulsed-intravenous cyclophosphamide with a good response. She delivered a healthy baby at 38 weeks. She had a severe postpartum flare. Secondly, a 37-year-old woman with limited Wegener's in remission for the last two years and off all treatment became pregnant after pre-conception counselling. A normal baby was delivered at term. An exhaustive review of all published literature on Wegener's activity in pregnancy is presented along with therapeutic options and recommendations.

Pericardial effusions with tamponade and visceral constriction in patients with rheumatoid arthritis on tumour necrosis factor (TNF)-inhibitor therapy.

Tumour necrosis factor-inhibitor (TNF-inhibitor) therapy is increasingly used for the treatment of rheumatoid arthritis. While it is effective for the articular manifestations of rheumatoid arthritis we have reason to believe that it is less effective for extra-articular disease. We present two cases of life-threatening cardiac tamponade in two patients with well-controlled rheumatoid arthritis on adalimumab. An extensive literature search was carried out and three other patients were found. We believe that these cases highlight the need for rheumatologists to be vigilant for extra-articular manifestations of rheumatoid arthritis even in the presence of quiescent joint disease while on TNF-inhibitors.