Pregnancy outcome after TNF-α inhibitor therapy during the first trimester: a prospective multicentre cohort study.

AIMS: TNF-α inhibitors are considered relatively safe in pregnancy but experience is still limited. The aim of this study was to evaluate the risk of major birth defects, spontaneous abortion, preterm birth and reduced birth weight after first trimester exposure to TNF-α inhibitors. METHODS: Pregnancy outcomes of women on adalimumab, infliximab, etanercept, certolizumab pegol or golimumab were evaluated in a prospective observational cohort study and compared with outcomes of a non-exposed random sample. The samples were drawn from pregnancies identified by institutes collaborating in the European Network of Teratology Information Services. RESULTS: In total, 495 exposed and 1532 comparison pregnancies were contributed from nine countries. The risk of major birth defects was increased in the exposed (5.0%) compared with the non-exposed group (1.5%; adjusted odds ratio (ORadj ) 2.2, 95% CI 1.0, 4.8). The risk of preterm birth was increased (17.6%; ORadj 1.69, 95% CI 1.1, 2.5), but not the risk of spontaneous abortion (16.2%; adjusted hazard ratio [HRadj ] 1.06, 95% CI 0.7, 1.7). Birth weights adjusted for gestational age and sex were significantly lower in the exposed group compared to the non-exposed cohort (P = 0.02). As a diseased comparison group was not possible to ascertain, the influence of disease and treatment on birth weight and preterm birth could not be differentiated. CONCLUSIONS: TNF-α inhibitors may carry a risk of adverse pregnancy outcome of moderate clinical relevance. Considering the impact of insufficiently controlled autoimmune disease on the mother and the unborn child, TNF-α inhibitors may nevertheless be a treatment option in women with severe disease refractory to established immunomodulatory drugs.

Observational cohort study of pregnancy outcome after first-trimester exposure to fluoroquinolones.

Fluoroquinolones are avoided during pregnancy due to developmental toxicity in animals. The aim of this study was to assess the fetal risk after intrauterine fluoroquinolone exposure. We performed an observational study of a prospectively ascertained cohort of pregnant women exposed to a fluoroquinolone during the first trimester. Pregnancy outcomes were compared to those of a cohort exposed to neither fluoroquinolones nor teratogenic or fetotoxic drugs. The outcomes evaluated were major birth defects (structural abnormalities of medical, surgical, or cosmetic relevance), spontaneous abortion, and elective termination of pregnancy. Pregnancy outcomes of 949 women with fluoroquinolone treatment were compared with those of 3,796 nonexposed controls. Neither the rate of major birth defects (2.4%; adjusted odds ratio [OR(adj)], 0.91; 95% confidence interval [CI], 0.6 to 1.5) nor the risk of spontaneous abortion (adjusted hazard ratio [HR(adj)], 1.01; 95% CI, 0.8 to 1.3) was increased. However, there was a nonsignificant increase in major birth defects after exposure to moxifloxacin (6/93, 6.5%; crude odds ratio [OR(crude)], 2.40; 95% CI, 0.8 to 5.6). Neither a critical exposure time window within the first trimester nor a specific pattern of birth defects was demonstrated for any of the fluoroquinolones. The rate of electively terminated pregnancies was increased among the fluoroquinolone-exposed women (HR(adj), 1.32; 95% CI, 1.03 to 1.7). The gestational ages at delivery and birth weights did not differ between groups. Our study did not detect an increased risk of spontaneous abortion or major birth defects. These reassuring findings support the recommendation to allow fluoroquinolone use in early pregnancy in selected cases. After the use of moxifloxacin, a detailed fetal ultrasound examination should be considered.

Angiotensin-II receptor 1 antagonist fetopathy--risk assessment, critical time period and vena cava thrombosis as a possible new feature.

AIMS: Angiotensin-II receptor 1 antagonists (AT1-antagonists) may cause severe and even lethal fetopathy in late pregnancy. However, exposure still occurs in spite of warnings in package leaflets. This study aimed to assess the risk of fetopathy, the sensitive time window, and possible new symptoms in prospective as well as retrospective cases with AT1-antagonist treatment during the second or third trimester of pregnancy. METHODS: Patients were enrolled by the Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy between 1999 and 2011 through risk consultation. Symptoms defined as indicative of AT1-antagonist fetopathy were: oligo-/anhydramnios, renal insufficiency, lung hypoplasia, joint contractures, skull hypoplasia and fetal/neonatal death. RESULTS: In 5/29 (17%) prospectively enrolled cases with AT1-antagonist exposure beyond the first trimester oligo-/anhydramnios was diagnosed. Two infants showed additional symptoms of fetopathy. The risk is more than 30% if treatment continues beyond the 20th week of pregnancy. Oligo-/anhydramnios was reversible after AT1-antagonist withdrawal. Among 16 retrospective case reports, three infants presented with a thrombosis of the inferior vena cava in the vicinity of the renal veins. Four out of 13 live births did not survive. CONCLUSIONS: Our survey suggests that the risk increases with duration of AT1-antagonist treatment into late pregnancy and oligo-/anhydramnios may be reversible after AT1-antagonist discontinuation. Thrombosis of inferior vena cava may be a new feature of AT1-antagonist fetopathy. AT1-antagonist medication during pregnancy constitutes a considerable risk and must be discontinued immediately. In case of indicative diagnostic findings in either the fetus or newborn, previous maternal AT1-antagonist exposure should be considered.

Regulation of vascular guanylyl cyclase by endothelial nitric oxide-dependent posttranslational modification.

In isolated cells, soluble guanylyl cyclase (sGC) activity is regulated by exogenous nitric oxide (NO) via downregulation of expression and posttranslational S-nitrosylation. The aim of this study was to investigate whether such regulatory mechanism impact on endothelium-dependent vasodilation in a newly developed mouse strain carrying an endothelial-specific overexpression of eNOS (eNOS(++)). When compared with transgene negative controls (eNOS(n)), eNOS(++)-mice showed a 3.3-fold higher endothelial-specific aortic eNOS expression, increased vascular cGMP and VASP phosphorylation, a L-nitroarginine (L-NA)-inhibitable decrease in systolic blood pressure, but normal levels of peroxynitrite and nitrotyrosine formation, endothelium-dependent aortic vasodilation and vasodilation to NO donors. Western blot analysis for sGC showed similar protein levels of sGC-α1 and sGC-ß1 subunits in eNOS(n) and eNOS(++). In striking contrast, the activity of isolated sGC was strongly decreased in lungs of eNOS(++). Semiquantitative evaluation of sGC-ß1-S-nitrosylation demonstrated that this loss of sGC activity is associated with increased nitrosylation of the enzyme in eNOS(++), a difference that disappeared after L-NA-treatment. Our data suggest the existence of a physiologic NO-dependent posttranslational regulation of vascular sGC in mammals involving S-nitrosylation as a key mechanism. Because this mechanism can compensate for reduction in vascular NO bioavailability, it may mask the development of endothelial dysfunction.

Proatherogenic effects of estradiol in a model of accelerated atherosclerosis in ovariectomized ApoE-deficient mice.

Clinical studies revealed unfavorable effects of hormone replacement therapy in postmenopausal women despite strong evidence for vasoprotective effects of estrogen in animal models. Therefore, an attempt was made to address adverse effects of estradiol on atherosclerosis, endothelial function, and thrombosis in a murine model of atherosclerosis. ApoE(-/-) mice were bilaterally ovariectomized (OVX) and substituted with placebo or 17-beta-Estradiol (E(2), 1.1 and 6.6 microg/day) on Western diet for 90 days. Low-dose E(2) (1.1 microg/day) treatment significantly increased atherosclerotic plaque score, whereas high-dose E(2) (6.6 microg/day) reduced aortic plaque burden. The proatherosclerotic effects of low-dose E(2) were associated with decreased total collagen in aortic root lesions and impaired acetylcholine (ACh)-induced vasorelaxation of aortic rings. On the contrary, OVX compared with control reduced atherosclerosis, increased fibrillar collagen and improved endothelial function. The thrombotic response as measured in a photothrombosis model was not significantly altered by E(2) or OVX. Taken together, differential effects on atherosclerosis of the clinical relevant low-dose E(2) compared with high-dose E(2) were demonstrated. Importantly, the presented experimental conditions provide a model to study the untoward vascular effects of E(2) in the context of accelerated and advanced atherosclerosis.

Pharmacological induction of vascular extracellular superoxide dismutase expression in vivo.

Pentaerythritol tetranitrate (PETN) treatment reduces progression of atherosclerosis and endothelial dysfunction and decreases oxidation of low-density lipoprotein (LDL) in rabbits. These effects are associated with decreased vascular superoxide production, but the underlying molecular mechanisms remain unknown. Previous studies demonstrated that endogenous nitric oxide could regulate the expression of extracellular superoxide dismutase (ecSOD) in conductance vessels in vivo. We investigated the effect of PETN and overexpression of endothelial nitric oxide synthase (eNOS(++)) on the expression and activity of ecSOD. C57BL/6 mice were randomized to receive placebo or increasing doses of PETN for 4 weeks and eNOS(++) mice with a several fold higher endothelial-specific eNOS expression were generated. The expression of ecSOD was determined in the lung and aortic tissue by real-time PCR and Western blot. The ecSOD activity was measured using inhibition of cytochrome C reduction. There was no effect of PETN treatment or eNOS overexpression on ecSOD mRNA in the lung tissue, whereas ecSOD protein expression increased from 2.5-fold to 3.6-fold (P < 0.05) by 6 mg PETN/kg body weight (BW)/day and 60 mg PETN/kg BW/day, respectively. A similar increase was found in aortic homogenates. eNOS(++) lung cytosols showed an increase of ecSOD protein level of 142 +/- 10.5% as compared with transgene-negative littermates (P < 0.05), which was abolished by N(omega)-nitro-L-arginine treatment. In each animal group, the increase of ecSOD expression was paralleled by an increase of ecSOD activity. Increased expression and activity of microvascular ecSOD are likely induced by increased bioavailability of vascular nitric oxide. Up-regulation of vascular ecSOD may contribute to the reported antioxidative and anti-atherosclerotic effects of PETN.

Potential role of vasomotor effects of fibrinogen in bradykinin-induced angioedema.

BACKGROUND: Although bradykinin is known to play a major role in the pathophysiology of hereditary and angiotensin-converting enzyme inhibitor (ACEi)-induced angioedema, other factors acting as triggers or enhancers are likely important as well. OBJECTIVE: We hypothesized that fibrinogen might contribute to ACEi-induced angioedema (eg, through direct actions on vascular tone). METHODS: Plasma levels of fibrinogen were determined in 59 patients with acute angioedema. Vascular activity of human and bovine fibrinogen and its effects on bradykinin-induced vasodilation and phosphorylation of vasodilator-stimulated phosphoprotein were investigated in small (0.8-1.4 mm in diameter) porcine coronary artery and human internal thoracic artery (ITA) segments. RESULTS: In patients with ACEi-induced angioedema, fibrinogen levels (481 +/- 22 mg/dL, n = 39) were significantly higher than in patients with idiopathic angioedema (302 +/- 15 mg/dL, P < .001). Fibrinogen (1-15 mumol/L) induced a concentration-dependent vasodilation in preconstricted small porcine coronary arteries (n = 13), reaching a maximum vasodilator effect of 70% +/- 4.7%. Likewise, fibrinogen induced a 52.1% +/- 9.1% (n = 7) vasodilation in ITA rings. Fibrinogen vasorelaxations were completely inhibited by abciximab and diminished by endothelial denudation and treatment with the nitric oxide synthase inhibitor L-nitroargininemethylester and glibenclamide (P < .01). Importantly, fibrinogen increased the vasodilator potency of bradykinin by 10-fold (P < .0001) and increased bradykinin-induced vasodilator-stimulated phosphoprotein phosphorylation (P < .01). CONCLUSION: The increase of plasma fibrinogen levels, its vasodilator activity in human ITAs, and the potentiation of bradykinin-induced vasodilation suggest that fibrinogen might contribute to the pathophysiology of ACEi-induced angioedema. Thus acute-phase proteins, such as fibrinogen, might be viewed as risk factors for bradykinin-induced angioedema.

Hip arthroplasty with high chromium and cobalt blood levels--Case report of a patient followed during pregnancy and lactation period.

Metal-on-metal arthroplasty may lead to elevated blood chromium (Cr) and cobalt (Co) levels (>7 µg/l). Since carcinogenic, mutagenic, and teratogenic effects have been suggested, there is concern of pregnancy hazards for women with this condition. The 34-year-old patient has had a unilateral hip replacement for seven years. Before her pregnancy high Cr (47 µg/l) and Co (103 µg/l) blood concentrations were measured, but she did not develop any symptoms. A male infant was delivered after 41 weeks with first degree hypospadias. His levels were increased at 3 weeks of age: 14 µg/l (Cr) and 20 µg/l (Co), but decreased by 9 weeks to 6.7 µg/l (Cr) and 10.0 µg/l (Co). Maternal levels at delivery were 25 µg/l (Cr) and 51 µg/l (Co). The child was fully breast-fed and developed normally. An association between hypospadias and Cr/Co has to be considered speculative. The otherwise favorable outcome of this case may be reassuring for pregnant and breast-feeding patients with metal-on-metal hip replacements.

[Drug safety in pregnancy - the Embryotox project]. / Arzneimitteltherapiesicherheit in der Schwangerschaft - das Embryotox-Projekt.

In many countries drug risk classifications tend to create the impression of a high level of risk, leading healthcare professionals and consumers to overestimate the actual risk when seeking a drug of choice or estimating the risk of a past exposure during pregnancy. In addition, there are insufficient human data for the majority of drugs used by women of reproductive age to precisely assess their prenatal risk or safety. The Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy provides pertinent information in this field to healthcare professionals and pregnant women. After the initiation of a risk inquiry exposed pregnancies are followed through as to birth outcome and beyond. These follow-up data allow the detection of signals and the quantification of safety or risks for the unborn through evaluation in prospective cohort studies. Both a detailed risk characterisation and/or quantification of safety are essential to risk management after inadvertent drug exposure or when looking for a drug of choice. Individual consultations are available drawing on the results from the institute's own database and other working groups, and regularly updated information is also available via the open access database www.embryotox.de.

A(H1N1)v2009: a controlled observational prospective cohort study on vaccine safety in pregnancy.

BACKGROUND: A(H1N1)v2009 influenza vaccination of pregnant women was a challenge for health care providers, as little safety data were available. METHODS: We prospectively followed the pregnancies of women who were vaccinated at any time during pregnancy or ≤ 4 weeks prior to conception and compared these outcomes to a control cohort matched by the estimated date of birth. Primary endpoints: rate of spontaneous abortion and major malformations. Secondary endpoints: preeclampsia, gestational age at birth, and birth weight. RESULTS: Pregnancy outcome of 323 women immunized with adjuvanted or non-adjuvanted A(H1N1)v2009 influenza vaccines from 2009-09-28 to 2010-03-31 were compared to 1329 control subjects. The risk for spontaneous abortions (HR 0.89; 95% CI 0.36-2.19) and the rate of major malformations (all trimesters: OR 0.87; 95% CI 0.38-1.77; preconception and first trimester exposure: OR 0.79; 95% CI 0.13-2.64) did not vary between the two cohorts. Furthermore, there was no increase in preeclampsia, prematurity, and intrauterine growth retardation in the vaccinated cohort. CONCLUSION: The results of our study do not indicate a risk for the pregnant woman and the developing embryo/fetus after H1N1 vaccination. We provide and apply methods novel in observational studies on pregnancy outcome, especially if a single dose exposure is investigated.

Differential effects of medroxyprogesterone acetate on thrombosis and atherosclerosis in mice.

BACKGROUND AND PURPOSE: The risk for cardiovascular events including venous and arterial disease and stroke is elevated after treatment with estrogen and medroxyprogesterone acetate (MPA) in postmenopausal women. Here, we have investigated the effect of MPA on arterial thrombosis and atherosclerosis in a murine model of atherosclerosis. EXPERIMENTAL APPROACH: Apolipoprotein E (ApoE)-/- mice were bilaterally ovariectomized and treated with placebo, MPA (27.7 microg day(-1)) and MPA + 17-beta-oestradiol (E2; 1.1 microg day(-1)) for 90 days, on a Western-type diet. Thrombotic response was measured in a photothrombosis model, platelet activation by fluorescence activated cell sorting (FACS) analysis (CD62P) and thrombin generation by the endogenous thrombin potential (ETP). Furthermore, aortic plaque burden and aortic root plaque composition were determined. KEY RESULTS: MPA and MPA + E2-treated animals showed an aggravated thrombotic response shown by significantly reduced time to stable occlusion. The pro-thrombotic effect of MPA was paralleled by increased ETP whereas platelet activation was not affected. Furthermore, MPA + E2 reduced the number of cells positive for alpha-smooth muscle actin and increased hyaluronan in the plaque matrix. Interestingly, total plaque burden was reduced by MPA but unchanged by MPA + E2. CONCLUSION AND IMPLICATIONS: Long-term treatment with MPA and MPA + E2 increased arterial thrombosis despite inhibitory effects of MPA on atherosclerosis in ApoE-deficient mice. Increased thrombin formation, reduced smooth muscle content and remodelling of non-collagenous plaque matrix may be involved in the pro-thrombotic effects. Thus, MPA exhibits differential effects on arterial thrombosis and on atherosclerosis.