ORIGINAL ARTICLE: Treatment with Tumor Necrosis Factor Inhibitors and Intravenous Immunoglobulin Improves Live Birth Rates in Women with Recurrent Spontaneous Abortion

Winger, Edward E.; Reed, Jane L.

doi:10.1111/j.1600-0897.2008.00585.x

Cited by 151 publications

(120 citation statements)

References 31 publications

(26 reference statements)

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“…Indeed, a recent study showed that treatment with TNF-a inhibitors and i.v. Ig may improve live birth rates in women who suffer recurrent pregnancy loss (57).…”

Section: Discussionmentioning

confidence: 99%

Spontaneous Pregnancy Loss Mediated by Abnormal Maternal Inflammation in Rats Is Linked to Deficient Uteroplacental Perfusion

Renaud

Cotechini

Quirt

et al. 2011

The Journal of Immunology

123

113

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Abnormal maternal inflammation during pregnancy is associated with spontaneous pregnancy loss and intrauterine fetal growth restriction. However, the mechanisms responsible for these pregnancy outcomes are not well understood. In this study, we used a rat model to demonstrate that pregnancy loss resulting from aberrant maternal inflammation is closely linked to deficient placental perfusion. Administration of LPS to pregnant Wistar rats on gestational day 14.5, to induce maternal inflammation, caused fetal loss in a dose-dependent manner 3–4 h later, and surviving fetuses were significantly growth restricted. Pregnancy loss was associated with coagulopathy, structural abnormalities in the uteroplacental vasculature, decreased placental blood flow, and placental and fetal hypoxia within 3 h of LPS administration. This impairment in uteroplacental hemodynamics in LPS-treated rats was linked to increased uterine artery resistance and reduced spiral arteriole flow velocity. Pregnancy loss induced by LPS was prevented by maternal administration of the immunoregulatory cytokine IL-10 or by blocking TNF-α activity after treatment with etanercept (Enbrel). These results indicate that alterations in placental perfusion are responsible for fetal morbidities associated with aberrant maternal inflammation and support a rationale for investigating a potential use of immunomodulatory agents in the prevention of spontaneous pregnancy loss.

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“…Indeed, a recent study showed that treatment with TNF-a inhibitors and i.v. Ig may improve live birth rates in women who suffer recurrent pregnancy loss (57).…”

Section: Discussionmentioning

confidence: 99%

Spontaneous Pregnancy Loss Mediated by Abnormal Maternal Inflammation in Rats Is Linked to Deficient Uteroplacental Perfusion

Renaud

Cotechini

Quirt

et al. 2011

The Journal of Immunology

123

113

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“…In women who suffer habitual abortion, there is no elevation of sTNF-R1 and sTNF-R2 levels during pregnancy [30]. Treatment with inhibitors of tumor necrosis factor and intravenous immunoglobulin was found to improve live birth rates in women with habitual abortion [31].…”

Section: Etanerceptmentioning

confidence: 99%

A pathway profile-based method for drug repositioning

et al. 2012

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Finding new applications for existing pharmaceuticals, known as drug repositioning, is a validated strategy for resolving the problem of high expenditure but low productivity in drug discovery. Currently, the prevalent computational methods for drug repositioning are focused mainly on the similarity or relevance between known drugs based on their "features", including chemical structure, side effects, gene expression profile, and/or chemical-protein interactome. However, such drug-oriented methods may constrain the newly predicted functions to the pharmacological functional space of the existing drugs. Clinically, many drugs have been found to bind "off-target" (i.e. to receptors other than their primary targets), which can lead to undesirable effects. In this study, which integrates known drug target information, we propose a disease-oriented strategy for evaluating the relationship between drugs and disease based on their pathway profile. The basic hypothesis of this method is that drugs exerting a therapeutic effect may not only directly target the disease-related proteins but also modulate the pathways involved in the pathological process. Upon testing eight of the global best-selling drugs in 2010 (each with more than three targets), the FDA (Food and Drug Administration, USA)-approved therapeutic function of each was included in the top 10 predicted indications. On average, 60% of predicted results made using our method are proved by literature. This approach could be used to complement existing methods and may provide a new perspective in drug repositioning and side effect evaluation. Drug discovery is a time-consuming and laborious process. To bring a single de novo drug to the market, an average of more than $800 million is spent in a time period of ~15 years [1]. Moreover, about 90% of drugs fail during development in phase I clinical trials [2], a rate caused mainly by findings of low therapeutic efficacy and/or unacceptable toxicity [3,4]. Others are discovered to have similar drawbacks, even after approval by drug regulatory authorities (e.g. the US Federal Drug Administration (FDA)), or postmarketing. In exceptional circumstances, it is necessary to either modify the drug or even withdraw it from the market. The "thalidomide affair", a highly recognizable example of a drug having tragic unintended effects, is a typical example. Thalidomide was withdrawn from the market in the early 1960s because of teratogenic effects. However, it has since been reborn as an FDA-approved treatment for cancers and lepriasis owing to the discovery of new indications, namely immunomodulatory and anti-angiogenic activities [5][6][7][8].Despite enormous increases in novel technologies over recent times, the productivity of drug discovery efforts has actually decreased since the mid-1990s [9]. The need to define a novel strategy and/or utilize new resources in drug discovery is urgent. Drug repositioning, which aims to discover new indications for existing drugs, can shorten the development cycle and reduce the risk of u...

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“…So far, the recommendations per observational studies are that women of childbearing age with autoimmune diseases should ideally plan to conceive when their disease is well controlled and while on no medication, and most pregnant patients can discontinue their anti-TNFα treatment early in pregnancy without increasing maternal and fetal risks. 197 Anti-TNFα treatment has been shown to increase live birth rates in women with recurrent spontaneous abortion 67 and in a subset of patients with a history of .2 failed in-vitro fertilization attempts, 200 with the latter study having an impressive 100% pregnancy and 88% take-home baby rate. In both of the cohort-controlled, non-randomized studies, treatment was generally started a month prior to starting a cycle of conception, and continued until a fetal heart was demonstrable by ultrasound.…”

Section: Tnfα-inhibitors and Their Role In Pregnancymentioning

confidence: 99%

“…Although the observational studies of Winger et al represent important new data in the field of reproductive immunology, 67,200,202,203 further prospective randomized controlled studies are needed. Studies in mice are showing that targeting placental TNFα using TNFα-antagonists such as etanercept prevents fetal hypoxia and neuroproliferative defects in the fetal brain.…”

Section: Tnfα-inhibitors and Their Role In Pregnancymentioning

confidence: 99%

“…66 Once treated with TNFα inhibitors, this group of women had an increase in the rate of live births. 67 TNFα is unlikely to be the only mediator and, in most cases of miscarriage, there are additional triggers. 9 Evidence shows that TNFα, IFNγ and NK cells cannot induce miscarriage separately, but a Th1-NK-macrophage triad may bring about miscarriage, which can in turn be suppressed by a Th2 cytokine response.…”

Section: Tnfα and Its Receptors In Miscarriagementioning

confidence: 99%

See 1 more Smart Citation

The role of tumor necrosis factor-receptors in pregnancy with normal and adverse outcome

Calleja‐Agius¹,

Muttukrishna²,

Jauniaux³

2012

IJICMR

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ORIGINAL ARTICLE: Treatment with Tumor Necrosis Factor Inhibitors and Intravenous Immunoglobulin Improves Live Birth Rates in Women with Recurrent Spontaneous Abortion

Cited by 151 publications

References 31 publications

Spontaneous Pregnancy Loss Mediated by Abnormal Maternal Inflammation in Rats Is Linked to Deficient Uteroplacental Perfusion

Spontaneous Pregnancy Loss Mediated by Abnormal Maternal Inflammation in Rats Is Linked to Deficient Uteroplacental Perfusion

A pathway profile-based method for drug repositioning

The role of tumor necrosis factor-receptors in pregnancy with normal and adverse outcome

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