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Pharmacokinetics of Interferon-Alpha in Pregnant Women and Fetoplacental Passage
Abstract
Interferon (IFN) therapy is currently not approved for use during pregnancy. Two HIV-seropositive pregnant women, who were due to undergo abortion in the second trimester of pregnancy, were given a single intramuscular dose of IFN-alpha, with their informed consent. Blood samples were taken simultaneously from the mothers and fetuses, together with amniotic fluid. IFN was undetectable in the fetal blood and amniotic fluid in both cases. Pharmacokinetic parameters were similar to those in nonpregnant women. We conclude that maternal IFN-alpha during pregnancy should be safe for the fetus. The indications for IFN therapy in pregnancy could therefore be the same as those in the non-pregnant state.
... Interferon alpha is a large molecule and is not expected to cross the placenta barrier in relevant concentrations. In 1995, Pons et al. demonstrated in two HIV-seropositive pregnant women given interferon alpha that it was undetectable both in the fetal blood and amniotic fluid [60]. It is not mutagenic in vitro or teratogenic in animal studies [6,13,18,60]. ...
... In 1995, Pons et al. demonstrated in two HIV-seropositive pregnant women given interferon alpha that it was undetectable both in the fetal blood and amniotic fluid [60]. It is not mutagenic in vitro or teratogenic in animal studies [6,13,18,60]. So far, over 90 MPN patients, mostly pregnant ET and PV women, received interferon alpha during pregnancy [17,19,20,27,29,55,61,62,63,64,65,66,67,68,69,70]. ...
Introduction: The management of pregnancy during the course of BCR-ABL1-negative myeloproliferative neoplasms (MPN) is an increasingly relevant problem. This is mostly due to earlier and better diagnosis of MPN together with the trend in modern society towards delaying pregnancy until later life.
Areas Covered: The present review aims to provide an overview of the available literature data concerning outcome of pregnancy in MPN. Possible therapeutic modalities are discussed and a management algorithm is suggested.
Expert Commentary: Most data are available for women with essential thrombocythemia and we present 793 published pregnancies. Live birth rate is 68.5% with 31.5% miscarriages. Spontaneous abortion is the most frequent complication with 26.5%, followed by stillbirth with 4.8%. Maternal complications are relatively low with 1.8% major thrombotic and 2.4% major bleeding events. In polycythemia vera the situation is clinically more complex and roughly 150 pregnancy reports are available. There is very limited information in primary myelofibrosis with less than 20 reported pregnancies. With active management including control of blood counts, aspirin, low molecular weight heparin and in higher risk cases interferon alpha pregnancy in MPN is manageable with a success rate not far below the normal situation with 80%.
... In humans, IFN-a does not cross the placental barrier in significant amounts [40,41]. No IFN-a was detectable in fetal blood and amniotic fluid in the two HIV-seropositive pregnant women reported by Pons and colleagues treated with IFN-a during the 2nd trimester of pregnancy [40]. ...
... In humans, IFN-a does not cross the placental barrier in significant amounts [40,41]. No IFN-a was detectable in fetal blood and amniotic fluid in the two HIV-seropositive pregnant women reported by Pons and colleagues treated with IFN-a during the 2nd trimester of pregnancy [40]. In the two cases reported by Haggstrom et al., IFN-a concentration in the babies were <1 U/ mL as compared to 21-58 U/mL in their treated mothers [41]. ...
The last decade has witnessed important advances in the field of managing cancer during pregnancy. However, still limited data is available on the safety of administering targeted agents in pregnant cancer patients. Given the increasing use of targeted agents in clinical practice, it is becoming vital to properly understand how far they can be used in a pregnant patient without compromising the outcome of the fetus. Unlike chemotherapy, monoclonal antibodies are large molecules that require active transport via the placenta to reach the fetus. On the other hand, similarly to chemotherapy, small molecules like tyrosine kinase inhibitors (TKIs) can cross the placenta throughout the pregnancy period. The majority of targeted agents have worrying preclinical data discouraging their use during pregnancy. Multi-TKIs are of particular concern given their potential interference with other vital physiological functions that could be necessary in fetal development. Yet this does not mean that all targeted agents should be avoided completely during pregnancy. The current review provides a critical evaluation on all targeted agents that are currently in clinical use and provides a guide in order to help clinicians counseling their pregnant cancer patients.
Copyright © 2015 Elsevier Ltd. All rights reserved.
... La transmission du virus au foetus aura donc lieu en l'absence d'anticorps spécifiques, avant même que le système immunitaire de la mère ait été sollicité. L'interféron produit par la mère en réponse au virus, dans son sang, ne franchit pas la barrière placentaire [30]. Il ne peut donc protéger le foetus. ...
Subacute sclerosing panencephalitis, a late complication of measles, is still present during epidemics of this disease due to insufficient vaccination. After a historical review, the importance of the diagnostic criteria and the pathophysiology of SSEP are discussed. Numerous studies on the parameters of innate immunity and interferon responses tend to show a decrease in the activity of cellular immunity. Several hypotheses are formulated based on the publications of the different forms of the disease: Congenital, perinatal, forms with short incubation similar to acute inclusion encephalitis (AIE), rapidly evolving forms, forms of the immunocompromised, or even adults. Familial forms have been identified, suggesting a genetic cause. Based on the duration of the latency period, two groups have been individualized, prompting a retrospective and prospective analysis of the exomes of these patients. The knowledge of the genes involved should be useful for the understanding of the pathophysiology of SSPE and other late neurological RNA virus infections.
... The pegylated IFN-α was commenced on her. IFN-α is a safe drug that can be used throughout gestation with no adverse effect on the fetus [2], [9], [10], [22], [23]. IFN-α inhibits cell proliferation through its effect on protein synthesis, RNA breakdown, and possibly by immunomodulation. ...
Hematological malignancy in pregnancy is a rare condition which leads to lack of prospective study and randomized control trial. Nevertheless, it has own challenge to the medical field in term of managing patient with the said condition. The dilemma is to decide among the necessities of continuation of pregnancy, the choice of diagnostic tools and chemotherapeutic drugs, and the timing of initiation treatment without disregarding the women's wish and preferences. The process often has a profound psychological burden on patients and family members. Furthermore, delays in diagnosis and intervention will adversely affect the outcomes of pregnancy and the disease itself. The effect of teratogenicity of chemotherapeutic drugs on the fetus and the progression of the disease during pregnancy are the main concern in treating this group of patients. This article will review the management and outcomes of 6 cases of hematological malignancy in pregnancy in one center (3 Hodgkin lymphoma, 1 chronic myeloid leukemia, 1 hairy cell leukemia, and 1 myeloproliferative neoplasms).The outcomes of the pregnancy cases in this article were five successful live births with one case of early neonatal death due to prematurity with a history of second-trimester loss. The treatment was initiated during the second trimester to reduce the risk of chemotherapy to the fetus.Even though a few cases had fetal growth compromise but the fetal outcomes seem to be good with early interventions and multidisciplinary approached.
Keywords:Leukemia, lymphoma, myeloproliferative neoplasm, pregnancy.
... 233 SYNTHÈSE REVUES d'interféron circulant, dont l'origine foetale peut être attestée par son absence du sang maternel. À noter que l'interféron alpha, injecté à des fins thérapeutiques à des femmes infectées par le virus de l'immunodéficience humaine (VIH), ne franchit pas la barrière placentaire [24]. L'hypothèse d'une stimulation des voies de la signalisation de l'interféron à l'origine de ces maladies congénitale sera confirmée quatre ans plus tard, lorsque Lebon et al. [29] rapportent la présence d'une activité interféron alpha dans le sérum et le liquide céphalorachidien (LCR) d'enfants atteints d'une encéphalopathie rare d'origine génétique [28][29][30]. ...
... Although interferons are a Category C drug, in which no controlled studies have been conducted in animals or humans, in general the literature has demonstrated safety of interferon for use in pregnancy [70,75]. Pharmacologic studies have not detected interferon in fetal blood or amniotic fluid [76]. Of 78 pregnancies treated with interferon reported in the literature, the live birth rate was 94%, with no fetal malformations [70]. ...
Interferon alfa was first used in the treatment of myeloproliferative neoplasms (MPNs) over 30 years ago. However, its initial use was hampered by its side effect profile and lack of official regulatory approval for MPN treatment. Recently, there has been renewed interest in the use of interferon in MPNs, given its potential disease-modifying effects, with associated molecular and histopathological responses. The development of pegylated formulations and, more recently, ropeginterferon alfa-2b has resulted in improved tolerability and further expansion of interferon’s use. We review the evolving clinical use of interferon in essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). We discuss interferon’s place in MPN treatment in the context of the most recent clinical trial results evaluating interferon and its pegylated formulations, and its role in special populations such as young and pregnant MPN patients. Interferon has re-emerged as an important option in MPN patients, with future studies seeking to re-establish its place in the existing treatment algorithm for MPN, and potentially expanding its use for novel indications and combination therapies.
... We did not find any study on the transplacental passage of interferon beta. However, inter-322 ferons have high molecular weights and it has been shown that interferon alpha does not 323 cross the placenta in humans, according to data in the ex vivo cotyledon perfusion model 324 (136,137) as well as neonatal cord blood samples (138). By analogy, we can assume that be-325 ta interferon does not cross the placental barrier. ...
Background
Treatment of COVID-19 is mostly symptomatic, but a wide range of medications are under investigation against SARS-CoV-2. Although pregnant women are excluded from clinical trials, they will inevitably receive therapies whenever they appear effective in non-pregnant patients and even under compassionate use.
Method
We conducted a review of the literature on placental transfer and pregnancy safety data of drugs under current investigation for COVID-19.
Results
Regarding remdesivir, there are no data in pregnant women. Several other candidates already have safety data in pregnant women, since they are repurposed drugs already used for their established indications. They may thus be used in pregnancy, although their safety in the context of COVID-19 may differ from conventional use. These include the HIV protease inhibitors such as lopinavir/ritonavir which have low placental transfer; interferon which does not cross the placental barrier, and (hydroxy) chloroquine, which have high placental transfer. There are also pregnancy safety and placental transfer data for colchicine, steroids, oseltamivir and azithromycin, as well as some monoclonals. However, some drugs are strictly prohibited in pregnancy due to known teratogenicity (thalidomide) or fetal toxicities (renin-angiotensin system blockers). Other candidates including tocilizumab and other IL-6 inhibitors, umifenovir and favipiravir have insufficient data on pregnancy outcomes.
Conclusion
In life-threatening cases of COVID-19, the potential risks of therapy to the fetus may be more than offset by the benefit of curing the mother. While preclinical and placental transfer studies are required for a number of potential anti-SARS CoV2 drugs, several medications can already be used in pregnant women.
... SYNTHÈSE REVUES d'interféron circulant, dont l'origine foetale peut être attestée par son absence du sang maternel. À noter que l'interféron alpha, injecté à des fins thérapeutiques à des femmes infectées par le virus de l'immunodéficience humaine (VIH), ne franchit pas la barrière placentaire [24]. L'hypothèse d'une stimulation des voies de la signalisation de l'interféron à l'origine de ces maladies congénitale sera confirmée quatre ans plus tard, lorsque Lebon et al. [29] rapportent la présence d'une activité interféron alpha dans le sérum et le liquide céphalorachidien (LCR) d'enfants atteints d'une encéphalopathie rare d'origine génétique [28][29][30]. ...
In this brief review, the authors present a history of the different aspects of the scientific puzzle leading from pioneer animal studies and astute clinical experimental observations to a mature appreciation of the deleterious role of excess of a type I interferon in human pathology.
© 2019 médecine/sciences – Inserm.
... Although interferon was detectable at the feto-placental interface in the non-diseased state, it was not recorded in the blood of fetuses of women free from infection. Furthermore, it was shown that interferon alpha administered to pregnant women infected with human immunodeficiency virus did not cross the placenta [33]. In contrast, an acid labile alpha interferon activity was present in the sera of fetuses and children with congenital rubella [34], at as early as 20 weeks of gestation, raising the question as to whether this interferon might play an active role in the sequelae of such infection. ...
... The use of IFN-α could be an option when stopping TKI therapy in women with a suboptimal response. The maternal IFN-α concentration during pregnancy should be safe for the fetus, and IFN therapy during pregnancy could have the same outcomes as in nonpregnant women (Pons et al. 1995). IFN-α treatment does not significantly increase the risk of major malformations, miscarriage, stillbirth, or preterm delivery above that in the general population (Brojeni et al. 2012). ...
IntroductionComplications associated with chronic myeloid leukemia (CML) during pregnancy are rare, and management is challenging because very limited data are available on this patient group. Case descriptionWe herein report a successful pregnancy and delivery in a patient diagnosed with CML. The patient was treated with imatinib (400 mg/day) as a first-line therapy. However, she became pregnant while she was in complete hematological remission and had a complete cytogenetic response. Because she elected to continue the pregnancy to term, imatinib treatment was stopped after 5 months of gestation and the patient was then treated with interferon-alpha for the remainder of her pregnancy. However, the CML did not relapse. She successfully gave birth to a male infant at 39 weeks by cesarean section with no adverse sequelae or malformations. Discussion and EvaluationThe treatment of pregnant women with CML is difficult because of few available therapeutic options and limited data regarding the potential harm to the fetus. Conception should be planned and TKI therapy discontinued in female patients during pregnancy, and individual risks need to be considered when an unplanned pregnancy occurs. Conclusions
Our experience will be useful for counseling patients inadvertently exposed to tyrosine kinase inhibitors such as imatinib during pregnancy.
... In 1995, Pons et al. (25) reported two HIV-seropositive pregnant women given a single intramuscular dose of IFN-alpha, just before the abortion in the second trimester. They found undetectable IFN levels in the fetal blood and amniotic fluid in both cases. ...
... IFNa was used intramuscularly in two women with HIV who were going to have curettage. Blood and amniotic fluid samples did not demonstrate any detectable IFN levels in both cases [5]. Single case report has shown that IFN use in pregnant women with HCV and thrombocytopenia has resulted in healthy deliveries [6]. ...
In general, interferon (IFN) is avoided during pregnancy due to the possibility of fetal side effects. We, herein, reported two childbearing women with chronic hepatitis B (HB) infection who used pegylated interferon alfa 2b (PEG IFNα 2b) in first trimester unintentionally. We compared hepatitis B contracting rates of gestations in which IFN was used and not used. The cases are unique in that they could highlight the importance of interferon use in early gestation for preventing vertical transmission particularly if combined with antiviral therapy for the rest of pregnancy.
... In case of hematologic or cytogenetic relapse, restarting treatment can be considered. Interferon (IFN) can be used safely throughout gestation [27]. Hydroxyurea may be considered to treat leukocytosis after fetal organogenesis [28]. ...
Malignancy is the second most common cause of mortality in the reproductive period and it complicates up to one out of every 1,000 pregnancies. When cancer is diagnosed during pregnancy, the management approach must take into consideration both the mother and her fetus. Hematologic cancers diagnosed in pregnancy are not common, resulting in paucity of randomized controlled trials. Diagnosis of such malignancies may be missed or delayed, as their symptoms are similar to those encountered during normal pregnancy. Also, many imaging studies may be hazardous during pregnancy. Management of these malignancies during pregnancy induces many treatment-related risks for mother and baby and should consider patient’s preferences for pregnancy continuation. In this article, hematologic malignancies diagnosed in pregnant patients including acute leukemias, chronic myeloid leukemia, lymphomas, multiple myeloma and myeloproliferative neoplasms, will be reviewed, including diagnostic and management strategies and their impact on the pregnant patient and the developing fetus.
... Császármetszés utáni komplikációk 21,4%-ban fordultak elő egy norvégiai kohorszvizsgálatban, ahol 2751 volt a császármetszések száma a teljes populációban. A komplikációk előfordulása is gyakoribb volt általános anaesthesia mellett mint regionális anaesthesia esetén [46]. ...
... Interferon can be considered safe throughout pregnancy 34 and hydroxyurea can be used to control leucocytosis after organogenesis. 35 When necessary, TKIs therapy with Imatinib or Nilotinib could be considered after placenta has been formed and organogenesis completed, 36 although high Nilotinib concentration has been found in fetal liver, in animal models. ...
The management of patients with chronic myeloid leukemia (CML) during pregnancy has become recently a matter of continuous debate. The introduction of the Tyrosine Kinase Inhibitors (TKIs) in clinical practice has dramatically changed the prognosis of CML patients; in fact, patients diagnosed in chronic phase can reasonably expect many years of excellent disease control and good quality of life, as well as a normal life expectancy, including the necessity to address issues relating to fertility and pregnancy. Physicians are frequently being asked for advice regarding the need for, and/or the appropriateness of, stopping treatment in order to conceive. In this report, we will review the data published in terms of fertility, conception, pregnancy, pregnancy outcome and illness control for TKI treated CML patients, as well as how to manage a planned and/or unplanned pregnancy.
... Other modalities of therapy that have been used include hydroxyurea, interferon-α, and leukapheresis [10][11][12], each of which is potentially problematic during pregnancy, although interferon may be a safer option though less efficacious than imatinib [13,14]. We described 2 CML patients that gave birth following different approaches to the management of their pregnancies. ...
The outcome in patients with chronic myeloid leukemia (CML) has dramatically improved over the last decade due to the widespread use of novel tyrosine kinase inhibitors such as imatinib. As overall survival has improved, the number of women with CML that wish to become pregnant has increased. As such, attending physicians are faced with a dilemma - continue life-prolonging medication to treat the cancer, or interrupt its use due to its potential teratogenicity. Herein we describe 2 CML patients that gave birth. Case 1 was managed via substitution of imatinib with interferon. The patient’s child underwent genetic evaluation at age 3 years, achieved normal developmental milestones, and despite being shorter than his peers was proportional. In terms of morphology, the child had clinodactyly, short fifth fingers, and slightly downward slanting palpebral fissures, but otherwise appeared normal. In case 2 imatinib was continued throughout the pregnancy. This patient’s child underwent postpartum evaluation by a geneticist and was observed to be morphologically normal, except for clinodactyly and low-set ears.
Conflict of interest:None declared.
... They are expressed for a short period in high concentrations, and have antiluteolytic, antiviral, Antiproliferative, and immunomodulator effects through receptors on the endometrial epithelium [19]. Pons et al. studied the pharmacokinetics of -IFN in pregnant women in 1995 and demonstrated that -IFN was undetectable both in the amniotic fluid and in fetal blood, and that the pharmacokinetic parameters did not differ from that in non-pregnant women [20]. Thus, at the doses used, -IFN does not seem to cross the placenta and cannot cause any damage to embryogenesis or to the development of the immunologic system in the fetus [13]. ...
... Data on the pharmacokinetics of interferons in pregnancy are limited. A study of two women given a single intramuscular dose prior to termination of pregnancy [10] reported that interferon was undetectable in fetal blood and amniotic fluid. Animal studies have reported a similar finding with no placental transfer demonstrated unless the interferon was coadministered with a chemical inducer [11]. ...
It is estimated there are 350-400 million people worldwide chronically infected with HBV. Many of these are women and of reproductive age. As such, they may face therapeutic decisions regarding antiviral therapy and the implication this may have on future or current pregnancies. This article reviews the data of all antivirals licensed for use against hepatitis B infection regarding teratogenicity, carcinogenicity, clinical experience during pregnancy, placental transfer and excretion in breast milk.
... Several case reports exist of successful pregnancies in women receiving IFN-α at all stages of pregnancy and for various conditions, including CML. [58][59][60][61] Because of its large size (19,300 da), IFN-α probably does not cross the placental barrier significantly. 62 Thus, the drug is probably safe in pregnancy, although avoiding its use if not essential would seem prudent. No data are available on the safety of IFN during breastfeeding, and whether any components of the drug are excreted in breast milk is unknown. ...
The introduction of tyrosine kinase inhibitors into clinical practice now offers most patients with chronic myelogenous leukemia lengthy remissions and the possibility of normal life expectancies. These improved survivals have resulted in the need to address issues relating to quality of life, including fertility and procreation. Treatment may require lifelong daily therapy with drugs that might inhibit proteins essential to gonadal function, implantation, and embryogenesis. Animal data suggest that imatinib at standard dosages is unlikely to impair fertility in either adult male or female animals. However, human data remain limited, particularly in children and adolescents. Children born to men who are actively taking imatinib at conception seem healthy, and current advice is not to discontinue treatment. In contrast, data are less encouraging for children born to women exposed to imatinib during pregnancy. Although numbers are small, a disturbing cluster of rare congenital malformations has prevented imatinib from being recommended safely, particularly during the period of organogenesis. Alternative strategies for managing pregnancy in chronic myelogenous leukemia include one or both of regular leukapheresis and interferon-alpha. Pregnancy in advanced-phase disease presents particular problems.
... 35 The degree to which the large molecule IFN crosses the placental barrier is not known, although it was not detectable in the fetal blood from two women taking IFN. 36 In the end, it might be argued that the advice to stop IFN use in pregnancy is strengthened by the knowledge that the risk of relapse on stopping DMTs may well be mitigated by the natural reduction in relapse rate associated with pregnancy itself. ...
At any one time, there are around 20 000 women of childbearing age with multiple sclerosis (MS) in the UK who may be considering having children. Neurologists can be asked for information from both patients and obstetric colleagues on a range of topics related to pregnancy and MS that extend beyond the well-known implications for relapse risk. This article aims to provide a brief overview for the general neurologist of the most commonly encountered issues and questions including those occasionally related to pregnancy management. The take-home message is that pregnancy does not hold adverse risks for the majority of patients with MS, or vice versa.
... Although six cases were also exposed to interferon (IFN-α-2b), it is not considered dangerous for the fetus. Interferon belongs to Class C according to the FDA; it is able to inhibit testicular function but does not cross the placenta [11,12]. ...
We report seven cases of newborns conceived within 6 months from the end or during paternal ribavirin exposure.
The management of cancer during pregnancy requires a patient-centered, multidisciplinary approach to balance maternal and fetal well-being given the rarity of this clinical scenario and lack of substantial data. Involvement of oncology and nononcology medical specialists and ethical, legal, and psychosocial supports, as needed, is instrumental in navigating the complexities of care for this patient population. Critical periods of fetal development and physiological changes in pregnancy must be considered when planning diagnostic and therapeutic approaches during pregnancy. The complexity of symptom recognition and interventional approaches contributes to diagnostic delays of cancers during pregnancy. Ultrasound and whole-body diffusion-weighted magnetic resonance imaging are safe throughout pregnancy. Surgery can be safely performed throughout pregnancy, with the early second trimester preferred for intra-abdominal surgery. Chemotherapy can be safely administered after 12-14 weeks of gestation until 1-3 weeks before the anticipated delivery. Most targeted and immunotherapeutic agents are contraindicated during pregnancy because of limited data. Pelvic radiation during pregnancy is absolutely contraindicated, while if radiation to the upper body is needed, administration should only be considered early in pregnancy. To ensure that the total cumulative fetal exposure to ionizing radiation does not exceed 100 mGy, early inclusion of the radiology team in the care plan is required. Closer prenatal monitoring is recommended for maternal and fetal treatment-related toxicities. Delivery before 37 weeks of gestation should be avoided if possible, and vaginal delivery is preferred unless obstetrically indicated or specific clinical scenarios. Postpartum, breastfeeding should be discussed, and the neonate should receive blood work to assess for acute toxicities with follow-up arranged for long-term monitoring.
The SARS–CoV-2 infection has caused both acute and chronic COVID–19 disease during the recent pandemic with emerging more transmissible SARS–CoV–2 Omicron variants (BQ1 and XBB1) that have increased demands for more effective immunogens and therapeutic approaches to protect the lives of numerous SARS–CoV-2 affected individuals and reduce overall disease burden that could be affected by concurrent other pathogens causing diseases. Following a worldwide campaign of mass vaccination, there is still a significant demand to quell the harmful effects of novel SARS–CoV–2 infections due to higher mutation rates within specific areas of the SARS–CoV-2 domain, leading to enhanced viral entry, especially within individuals with one or more significant comorbidities, and there is still a dilemma of how prevention of future pandemics will occur as within host animal mutations and cross species transfer naturally occurs. Concerns intersect at a specific point; a gained evolutionary ability of several viruses over the previous centuries to remain undetected during the first stages of infection by means of capping the 5' end of their DNA and RNA genes respectively. This may occur by reducing the rate of host Type I and Type III Interferons (IFN) cellular synthesis, that would usually occur and affect both apoptotic pathways, that facilitate viral replication and clearance, as well as immune cells, that process and present pathogenic antigen epitopes. Furthermore, although methods of vaccination exist, other methods in clinical development remain that could evoke an immune response in different cellular, serum or mucosal compartments being cellular, serum and mucosal that evoke differential antibody responses. Antibodies are classed as natural and synthetic. Natural antibodies are further classified into neutralizing and non-neutralizing, whilst synthetic antibodies are also further classified into monoclonal and polyclonal. As a result of single cell study transcriptome research, viruses do utilize an array of protein receptors for receptor-mediated cellular entry. This, therefore suggests that potential differential production of antibody immunoglobulins (Ig) within serum and mucosal areas remains affected by cytokines, adhesion molecules and chemokines that can be upregulated or downregulated upon host viral infection. Serum plasma antibodies can be multimeric that may not efficiently cross the nasal epithelium cell layer, therefore offering less protection against mucosal inflammation due to mucin proteins. On the other hand, antibodies produced by mucosal plasma cells at epithelial surfaces are known to provide effective immune responses in some viral infections. The existence of developments that stimulate mucosal immune responses has so far only been seen with influenza nasal immunogens. Nevertheless, scientists developed ways of immunization and early treatment worldwide that generally showed good success rates and fewer risks of adverse events, and the still early present stages of COVID-19 research should also be taken into consideration. For example, the administration of human interferons I and III into the nasal mucosa cellular layer, as key mediators of anti–viral activity, can stimulate cellular activity to train the innate and adaptive immune system cells to develop and appropriately stimulate an adequate immune response through B and T cells. Recently, it was discovered that specific plants secrete proteins that also stimulate the production of Type I Interferons. It might be that focusing on directly offering the immune system the information about the genetics and protein structure of the pathogen, rather than training its first-line mechanisms to develop faster, excessively increases its specificity, making it reach a level that brings the virus the opportunity to evolve and escape previously-developed host immune mechanisms. Naturally-selected polymorphic viruses through genetic recombination pose challenges to traditional concepts of cellular and molecular immune system neutralization of these viruses during the first stages of cellular infection. It is until the scientific community realizes this potentially crucial aspect that we will probably continue to face serious epidemics and pandemics of respiratory diseases over the coming several decades, evidenced with dengue fever and more recently monkeypox. Type I IFNs tend to be produced faster than Type III IFNs, and the first induce slightly more abundant pro-inflammatory signals than the latter, meaning that type III IFNs, if produced early, may further decrease the extent of excessive proinflammatory signals. Hence, we believe that nasal sprays containing a low dosage of Type I and Type III IFNs not only represent a relevant COVID-19 therapeutic, but also a potential unknown modulatory therapy of the future. Of note, it has been indicated that IFN I and / or III display significant immunizing and early therapeutic effects for other viral evoked diseases like Influenza (Influenza (A)H1N1), rabies (Rabies lyssavirus), measles (Measles virus), rubella (Rubivirus rubellae), Hepatitis B, HIV-induced AIDS, Ebola, Marburg, as well as bacterial diseases, such as lower respiratory tract infectious diseases induced by Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus, and a number of oncological diseases, like hepatic melanoma.
Maternal infectious disease may pose considerable challenges to the fetal health due to the distribution of important elements of the sanguine and lymphatic system from the mother via the umbilical cord. The mother and the fetus have a degree of interdependence that is similar to the one between the eukaryotic cell and the mitochondrion, particularly during the first half term of the pregnancy, which explains the increased appetite of the expecting mother during the first stages of the fetal development. There is a solid bridge between the adaptive immune system and the encephalon that was only discovered a few decades ago. As a result, scientists may still be in the introductory stages of research, and there might be a significant and profound degree of association between the immune system and a healthy neurological development. There is a significant link between the onset of significant maternal infectious disease and the onset of neurodevelopmental disease in the fetus, and virtually all immune cells play major roles in the promotion and inhibition of neurogenesis alike. Likewise, there is a probability that maternal infectious diseases during pregnancy represent a risk factor of fetal neurodevelopmental disease, as a pressurised development of the adaptive immune memory could result in a pressurised or inhibited neurological development, which both can result in a delayed development of certain sub-regions of the brain. For example, the fetus may display poorer social abilities and sharp analytical skills later in life, which is an important sign of neurodevelopmental disease. A pressurised development of the adaptive immune memory could not require the development of a significant form of disease, but rather just a sharp rate of immune preparation against several important pathogenic agents during the introductory stages of life, when the encephalon experiences the sharpest increase rate in development. The problem per se is not the process of immunisation, but a much sharper process of immunisation over the first stages of life in case of an exposure to one dangerous pathogen or more numerous kinds of pathogens and antigens that normally cause moderate disease morbidity. The more dangerous the microbe is, the sharper the development of the adaptive immune memory will be, and the same happens in the case of an increased number of infectious microbes and antigens that infected the cells of the mothers and the fetuses in cause, and this may, in the majority of the situations, still be the case even if the pathogens are already significantly weakened or lifeless, given that the gain of adaptive immune memory alone constitutes an important factor of neurogenesis and an increased rate of neurological development, and that the infant will become almost or fully protected against the pathogens in cause, despite not having had experienced the disease beforehand. In this case, neurodevelopmental delays are possibly not caused by an impaired neurogenesis, but by an excessive one, whilst maternal infection-associated neurodevelopmental delays may be caused by an impaired neurogenesis. Nevertheless, the aetiology of immunity-related neurodevelopmental delays may be more complex in nature and implicate a chronological and spatial sequence of induced excedentary and deficitary rates of neurogenesis, hence reflecting the incredibly complex nature and various forms of neurodevelopmental disease. It is important to mention that a single dose of infant immunisation brings significantly lower risks of adverse neurological events than the onset of a significant maternal infectious disease during pregnancy. The objective of paediatric neuro-immunological studies may be to improve the understanding of the association between a healthy immune developmental rate and a balanced ratio of the developmental rates of important brain regions and sub-regions.
The COVID-19 pandemic and the recently-emerged highly transmissible SARS-CoV-2 Omicron variants have increased the demands for novel immunising and therapeutic approaches to protect the lives of patients with significant co-morbidities. Following a worldwide campaign of mass vaccination, there is still a significant demand to quell the harmful effects of the novel SARS-CoV-2 variants on people with serious co-morbidities, and there is still a dilemma of how we could prevent potentially catastrophic effects of future pandemics upon the human race. And the concerns intersect at a specific point; a gained evolutionary ability of several viruses over the previous centuries to go undetected during the first stages of infection by means of capping the 5' end of their genetic material, reducing the synthetic rate of Type I and Type III Interferons, temporarily inhibiting the apoptotic pathways of infected cells to facilitate a rapid viral replication, and inhibiting antigenic presentation. Type I and III Interferon-based viral immune evasion may be primarily associated with a delayed clearance of the viral load. Past clinical data also suggests that the SARS-CoV-2 spike glycoprotein is capable of inhibiting the V(D)J antibody gene rearrangement in developing B-lymphocytes, as well as diverse important cellular processes of DNA repair by downregulating the BRCA1 and 53BP1 genes. Furthermore, most traditional methods of vaccination do not particularly boost mucosal immunity and as a result, there is a visible gap that viruses can easily fill in, which implicates a reduced stimulation of a mucosal plasma cell production. Serum plasma antibodies do not cross the nasal epithelium and hence, offer little protection against mucosal inflammation, unlike the antibodies produced by mucosal plasma cells. We acknowledge the existence of a significant challenge to stimulate mucosal immune responses due to the high complexity of its structure-function axis. Nevertheless, over the past half century, numerous scientists developed ways of immunisation and early treatment worldwide that generally showed outstanding levels of success and insignificant risks of adverse events. An important example implicates the administration of human interferons I and III into the nasal mucosa to simulate local infection and train the innate immune system to robustly become activated and transmit essential signals before viruses silence it. Recently, it was discovered that specific plants secrete proteins that also stimulate the production of Type I Interferons. It might be that focusing on directly offering the immune system the information about the genetics and protein structure of the pathogen, rather than training its first-line mechanisms to develop faster, excessively increases its specificity, making it reach a level that brings the virus the opportunity to evolve and escape previously-developed host immune mechanisms. Naturally-selected polymorphic viruses had generated long-term evolutionary responses to deeply tackle the ability of the complex human immune system to neutralise viruses during the first stages of cellular infection. It is until the scientific community realises this that we will probably continue to face serious epidemics and pandemics of respiratory diseases over the coming several decades.
Maternal infectious disease may pose considerable challenges to the fetal health due to the distribution of important elements of the sanguine and lymphatic system from the mother via the umbilical cord. The mother and the fetus have a degree of interdependence that is similar to the one between the eukaryotic cell and the mitochondrion, particularly during the first half term of the pregnancy, which explains the increased appetite of the expecting mother during the first stages of the fetal development. There is a clear bridge between the adaptive immune system and the encephalon that was only discovered a few decades ago, and this bridge may be stronger than the scientific community previously determined. As a result, scientists may still be in the introductory stages of research, and there might be a significant and profound degree of association between the immune system and a healthy neurological development, which means that pathogenic immune evasion may also represent a primary factor for the onset of fetal neurodevelopmental delays. Virtually all immune cells and numerous immune pathways have associations with neuronal production and maintenance, and innovative research broadly used this fact to explore the efficacy rates of various drugs to treat immunological and oncological diseases. Anti-inflammatory chemokines and cytokines generally play a role in neuroprotection, whilst pro-inflammatory chemokines and cytokines, as well as antibody activation and the recruitment of the vast majority of immune cells, have a bi-directional influence upon neurogenesis rates; a restricted extent of immune activation stimulates neurogenesis whilst exaggerated immune responses inhibit it. Ultimately, it is both exaggerated neurogenesis and inhibited neurogenesis that may affect healthy rates of neurodevelopment in fetuses and babies, given their critical stages of neurological development. A further apprehension of the relationship between developmental immunity and neurology is essential for innovative research in both immunology and neurology, and it may even be that some specific areas of traditional vaccinology may be implicated in this association that requires further scientific analysis.
The COVID-19 pandemic and the recently-emerged highly transmissible SARS-CoV-2 Omicron variants have increased the demands for novel immunising and therapeutic approaches to protect the lives of patients with significant co-morbidities. Following a worldwide campaign of mass vaccination, there is still a significant demand to quell the harmful effects of the novel SARS-CoV-2 variants on people with serious co-morbidities, and there is still a dilemma of how we could prevent potentially catastrophic effects of future pandemics upon the human race. And the concerns intersect at a specific point; a gained evolutionary ability of several viruses over the previous centuries to go undetected during the first stages of infection by means of capping the 5' end of their genetic material, reducing the synthetic rate of Type I and Type III Interferons, temporarily inhibiting the apoptotic pathways of infected cells to facilitate a rapid viral replication, and inhibiting antigenic presentation. Type I and III Interferon-based viral immune evasion may be primarily associated with a delayed clearance of the viral load. Past clinical data also suggests that the SARS-CoV-2 spike glycoprotein is capable of inhibiting the V(D)J antibody gene rearrangement in developing B-lymphocytes, as well as diverse important cellular processes of DNA repair by downregulating the BRCA1 and 53BP1 genes. Furthermore, most traditional methods of vaccination do not particularly boost mucosal immunity and as a result, there is a visible gap that viruses can easily fill in, which implicates a reduced stimulation of a mucosal plasma cell production. Serum plasma antibodies do not cross the nasal epithelium and hence, offer little protection against mucosal inflammation, unlike the antibodies produced by mucosal plasma cells. We acknowledge the existence of a significant challenge to stimulate mucosal immune responses due to the high complexity of its structure-function axis. Nevertheless, over the past half century, numerous scientists developed ways of immunisation and early treatment worldwide that generally showed outstanding levels of success and insignificant risks of adverse events. An important example implicates the administration of human interferons I and III into the nasal mucosa to simulate local infection and train the innate immune system to robustly become activated and transmit essential signals before viruses silence it. Recently, it was discovered that specific plants secrete proteins that also stimulate the production of Type I Interferons. It might be that focusing on directly offering the immune system the information about the genetics and protein structure of the pathogen, rather than training its first-line mechanisms to develop faster, excessively increases its specificity, making it reach a level that brings the virus the opportunity to evolve and escape previously-developed host immune mechanisms. Naturally-selected polymorphic viruses had generated long-term evolutionary responses to deeply tackle the ability of the complex human immune system to neutralise viruses during the first stages of cellular infection. It is until the scientific community realises this that we will probably continue to face serious epidemics and pandemics of respiratory diseases over the coming several decades.
Immunotherapy has greatly improved outcomes for subgroups of patients with cancer. As indications keep expanding, there is an unmet need to gain a better understanding of the effect of these therapies on pregnancy and fertility. During pregnancy, substantial adaptations occur in the maternal immune system to maintain protection against pathogens while avoiding detrimental reactions to the semi-allogeneic fetus. The pathways involved in the establishment of this fetomaternal tolerance can be hijacked by cancers. Immunotherapies that target these inhibitory pathways, or that directly interact with the regulatory immune cells involved in tolerance mechanisms, might therefore result in complications during pregnancy. Similarly, by activating the patient's immune system with immunotherapy, a broad range of immune-related adverse events can occur that could negatively affect the fetus or impede a future desired pregnancy. This Review summarises preclinical and clinical data related to the use of immunotherapy during pregnancy, including all approved immune checkpoint inhibitors, recombinant cytokines, cell therapies, vaccines, and immunomodulatory drugs.
Background:
Subacute sclerosing panencephalitis (SSPE) is a rare, non-treatable and fatal neurological complication of measles, still present due to the return of the epidemic linked to the loosening of vaccination policies. Its mechanism remains unexplained.
Objective:
The main objective was to investigate explanatory variables relating to the risk of developing SSPE and its pathophysiology.
Methods:
Literature analysis was focused on different varieties of SSPE: perinatal forms, short-incubation forms similar to acute measles inclusion body encephalitis (MIBE), rapidly evolving forms, forms occurring in the immunosuppressed, adult forms, and family forms. In addition, several studies on the parameters of innate immunity and interferon responses of patients were analyzed.
Results:
Two main data were highlighted: a relationship between the so-called fulminant forms and the prescription of corticosteroids was established. In familial SSPE, two groups were individualized according to the duration of the latency period, prompting an analysis of patient exomes.
Conclusion:
Treatment with corticosteroids should be banned. Knowledge of the genes involved and epigenetics should be useful for understanding the pathophysiology of SSPE and other late-onset neurological infections with RNA viruses.
Background
Management of pregnant patients with BCR‐ABL‐positive leukemia is challenging. Managing a patient who has been diagnosed while pregnant requires a different approach as compared with a patient who plans to become pregnant while on the treatment with tyrosine kinase inhibitor (TKI). Interferon (IFN)‐alpha is a useful option in both situations due to teratogenic potential of TKIs.
Methods
We presented a series of 12 successful pregnancies in 11 women with BCR‐ABL‐positive leukemia, whose leukemia was managed with IFN‐alpha throughout their pregnancy.
Results
All children have normal growth and development. All patients remained at least in hematological response and could start or resume TKI after delivery or breastfeeding.
Conclusion
Because of the increased risk of teratogenicity and spontaneous abortion in female patient with pregnancy, when receiving TKI, IFN‐alpha can be considered a safe drug to be administered throughout pregnancy and could represent the drug of choice in this situation during the era of TKI therapy.
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This chapter provides an overview of immunomodulators, which include immunosuppressive and immunostimulatory agents. Chemically defined immunosuppressants, such as azathioprine, cyclosporine A, mycophenolate mofetil, and tacrolimus and, sirolimus are distinguished from monoclonal antibodies. Most clinical experience involves pregnancies after kidney and liver transplantation. Long-term therapies include azathioprine, cyclosporine, and tacrolimus in combination with glucocorticoids (usually prednisolone). If no rejection has occurred and if the transplantation has been performed more than 2 years before conception, the outcome of the pregnancy is likely to be good. Women with immunosuppressant therapy are more frequently delivered by cesarean section. The immunomodulator drugs discussed in the chapter are azathioprine, cyclosporine A, selective immunosuppressants, interferons, thalidomide, immunomodulatory therapy, and other immunomodulators, such as glatiramer acetate, lenograstim, molgramostim, nartograstim, and pegfilgrastim.
Primary bone cancer is rarely associated with pregnancy [1,2]. The available information regarding its evaluation and management is very limited. A delay in diagnosis due to misinterpretation of tumor-related symptoms as those of normal pregnancy has been suggested [3]. Although magnetic resonance imaging is the diagnostic method of choice [4] and can be repeated many times in pregnancy [5], ultrasound, biopsy to stage the tumor, and clinical examination remain equally safe and important in arriving at the diagnosis. Tests applying X-rays or gamma-rays (isotope scans) should be avoided [6]. Independence of bone tumors from hormonal regulation was shown [3]. The association of bone neoplasm with pregnancy may be fortuitous [7]. Rare cases of recurrent bone tumors diagnosed during pregnancy might be due to increased medical surveillance [8]. Therapeutic considerations are complex, and a combined modality approach including surgery, radiation, and chemotherapy is often used and should be tailored to the individual patient. While surgical resections are generally regarded as safe during pregnancy, chemotherapy and radiation treatment are likely to be deferred until after delivery [6,9]. The decision-making analysis should include the type and site of the primary tumor, its growth rate and associated symptoms, the use of specific diagnostic tests, and appropriate treatment options [10]. Vaginal deliveries are possible [6,9]. In cases of bone malignancies involving the pelvis, cesarean section delivery might be considered to increase fetal safety [11]. Nevertheless, spontaneous vaginal deliveries after hemipelvectomy due to malignant tumors of the pelvis have been reported [12].
Malignant melanoma is a serious health problem worldwide and is increasing at a rate that exceeds all other solid tumors [1]. The increasing incidence is accompanied by an associated decrease in age at presentation. It is the most common cancer in women ages 25–29 years and approximately 35% of women with melanoma are of child-bearing age [2]. Malignant melanoma during pregnancy has an estimated incidence between 0.14 and 2.8 cases per 1,000 births [3] and represents 8% of malignancies diagnosed during pregnancy [4]. The signs and symptoms of melanoma are similar to the nonpregnant population and the anatomic location of the primary tumor does not differ between pregnant and nonpregnant women [5]. Changes in size, color, and configuration of any pigmented lesion suggest a malignant change and the need for further investigation [6]. Two-thirds of melanomas occur in pre-existing nevi [7]. However, some degree of hyperpigmentation during pregnancy is experienced by most women [8]. It has been suggested that this hyperpigmentation may lead to a delay in diagnosis of the disease [9]. A growing number of reports suggest minimal changes in size occur during pregnancy [10–12]. Bleeding and ulceration are more ominous signs and require immediate attention. Excisional biopsy is the recommended procedure for any suspicious lesions. Staging Clinical staging traditionally has included assessment of the local tumor site and adjacent skin, regional lymph node areas, and distant organs that are frequently the site of metastatic disease. The decision to perform radiological investigations in the pregnant patient should be based on the presence of symptoms, the stage of the pregnancy, the specific test needed, and the estimated dose of ionizing radiation and risks associated with that dose. In most cases, the doses involved in diagnostic radiology, including computed tomography scan of abdomen and pelvis, are lower than the threshold dose that may place the fetus at risk [13].
The deleterious effects of maternal drug administration on the unborn child are usually considered in terms of teratogenicity. However, few prescribers are aware of the effects that some drugs passively received at the end of pregnancy can have on neonatal adaptation. In addition to analgesics administered during labor, some 15 % of pregnant women take chronic treatments. The aim of this report is to examine the possible risks of such " inherited " drug substances, in order to improve neonatal safety. Gestational modifications of drug metabolism are briefly discussed, along with the timing of embryonic and/or fetal drug exposure and the characteristics of placental drug transfer. Vital threats include effects on the central nervous system, respiration, and hemodynamics. The fetal and neonatal impacts of the main pharmacological categories are summarized, distinguishing those that are strongly contraindicated from those that can be used safely, with caution, during pregnancy. The French National Academy of Medicine stresses the need for specific warnings for healthcare professionals on neonatal hazards of intrauterine drug exposure. This information must be part of the curriculum for medical students of all specialties, and must be underlined by drug companies and regulatory authorities. It should notably be provided through websites such as the Paris Teratogenicity Reference Center (Centre de référence sur les agents tératogènes, CRAT).
We report a case of a young patient with chronic viral hepatitis HBV infection, diagnosed with CML in March 2006 and treated with imatinib 400mg/die as first line therapy with concomitant Lamivudine. Patient obtained a complete hematologic response (CHR) in 2 months, complete cytogenetic response (CCyR) in six months and major molecular response (MMR) at 24 months. After three years of treatment, she became imatinib intolerant and resistant. In November 2009 patient started nilotinib 400mg/BID. Patient tolerated well the new molecule never experiencing hepatic impairment. After switching to nilotinib, she reached in 12 months transcript reduction more than 3 log (MMR). Even if patient had been informed of the need of continuous therapy and to use effective methods of contraception during tyrosine kinase inhibitor (TKI) treatment, in 2012 she decided to plan a pregnancy. In August 2012 a MR4 was documented, and treatment discontinued before starting pregnancy. She was placed on interferon and observed throughout her pregnancy. The disease remained stable achieving an undetectable transcript level; she delivered a healthy boy in September 2013. Treatment with nilotinib was re-started three months after delivery, and she is still in molecular remission (MR5). A complete discussion of the case and the available literature is presented.
Background:
Most ocular changes in pregnancy are harmless. For example, 14% of pregnant women need a new eyeglass prescription. Some changes, however, are serious, such as retinal effects of hypertension, which can be a sign of pre-eclampsia. Ocular changes may give rise to uncertainty about the administration of ophthalmological drugs or the optimal method of childbirth.
Method:
This review is based on pertinent literature retrieved by a selective search in Medline and on guidelines from Germany and abroad. Recommendations about drugs were taken from the Embryotox and Reprotox databases, the German Red List, and the United States Food and Drug Administration (FDA).
Results:
40% to 100% of pregnant women with high blood pressure have retinal changes whose severity is correlated with the severity of pre-eclampsia or eclampsia. Diabetic women should undergo ocular examination before and during pregnancy. Pre-existing retinal changes worsen during pregnancy in 55% of cases. Most ocular diseases can be treated with the usual drugs in pregnant women and nursing mothers, although the evidence for drug safety is derived from case series and the treatment is usually provided off label. Ocular conditions that are present before pregnancy are irrelevant to the choice of a method of childbirth.
Conclusion:
Pregnant women and nursing mothers can undergo most types of ophthalmological examination and treatment. Recommendations about drug treatment should be checked against current information that can be found on the embryotox.de and reprotox.de websites.
Augenerkrankungen müssen auch während der Schwangerschaft und Stillzeit behandelt werden. Der Einsatz von Medikamenten birgt ein Risiko für Mutter und Kind. Der Beitrag gibt den Kenntnisstand zur Anwendung der wichtigsten Ophthalmika in der Schwangerschaft und Stillzeit wieder. Erörtert werden die Diagnostik am Auge (Tonometrie, Mydriasis, Angiographie) und die Behandlung von Infektionen am Auge, Glaukom, Allergien, diabetische Retinopathie, Schmerzen oder Entzündungen.
Essential thrombocythaemia is a rare myeloproliferative disorder that often presents with haemorrhagic or thrombotic complications. It may be detected incidentally in an asymptomatic younger adult and there are only a few case reports of essential thrombocythaemia in pregnant women. The risks posed by essential thrombocythaemia during pregnancy and its optimal management are uncertain. To determine if there is increased incidence of obstetric complications seen in women who have essential thrombocythaemia, we collected a large case series from a number of tertiary obstetric units in Australia and New Zealand.
There were 30 pregnancies in 12 women who had essential thrombocythaemia. There were 17 live births (57%). 7 stillbirths (23%), 5 miscarriages (17%) and 1 ectopic (3%). Five pregnancies were complicated by placental abruption. When the outcomes of those women who received treatment with aspirin or interferon were compared to those that did not receive any treatment, there was a trend towards a higher livebirth rate (79% v 38%, p = 0.06). Seven women were treated with aspirin and 5 had successful outcomes with no fetal complications. Four women were treated with α-interferon which reduced their platelet counts and all had successful outcomes with no fetal complication. These findings suggest that there is a high incidence of miscarriage, stillbirth and abruption in women with essential thrombocythaemia. Their pregnancies should be carefully monitored. Treatment with low dose aspirin and/or the use of α-interferon may be associated with an improved pregnancy outcome.
Ocular therapy is necessary even during pregnancy but the use of pharmaceutical substances bears the risk of side effects on mother and child. The article reflects current knowledge on how to treat the most important eye diseases during pregnancy and breastfeeding. The review covers the diagnostics (tonometry, mydriasis, angiography) as well as treatment of infections of the eyes, glaucoma, allergies, diabetic retinopathy, pain and inflammation.
Women with multiple sclerosis (MS) are advised to discontinue interferon-beta therapy before trying to conceive. Unplanned pregnancies occur and risks related to exposure remain unclear.
To determine pregnancy outcomes following interferon-beta therapy, we examined pregnancies from a global drug safety database containing individual case safety reports received in the post-marketing setting and safety data from clinical trials of subcutaneous interferon beta-1a in MS.
One thousand and twenty-two cases of exposure to subcutaneous interferon beta-1a during pregnancy were retrieved; 679 had a documented outcome. In cases for which exposure duration was available (n = 231), mean time of foetal exposure to subcutaneous interferon beta-1a before treatment discontinuation was 28 days; most pregnancies (199/231; 86.1%) were exposed for ≤ 45 days. To avoid bias, only outcomes for prospective data (n = 425) in pregnancies exposed to interferon beta-1a in utero were analysed further. Of these, 324 (76.2%) resulted in normal live births and four (0.9%) in live births with congenital anomalies (3 [0.7%] were 'major'). Four (0.9%) pregnancies resulted in stillbirths (1 [0.2%] with foetal defects). There were 5 (1.2%) ectopic pregnancies, 49 (11.5%) spontaneous abortions and 39 (9.2%) elective terminations. Most pregnancies exposed to subcutaneous interferon beta-1a in utero were associated with normal live births. The rates of spontaneous abortion and major congenital anomalies in live births were in line with those observed in the general population.
These data should be taken into account when considering options for women with MS who become pregnant or who are planning pregnancy while on treatment with subcutaneous interferon beta-1a.
The Philadelphia-negative chronic myeloproliferative neoplasms encompass essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). A major break-through in the understanding of the pathogenesis of these neoplasms occurred in 2005 by the discovery of the JAK2 V617F mutation in the large majority of patients with PV and in half of those with ET and PMF. A number of studies have shown that the "tumor burden" may be monitored at the molecular level in JAK2-positive patients using highly sensitive real-time quantitative PCR. During the last 25 years several studies have shown that interferon-alpha (IFN-alpha) induces complete haematological remissions in a large proportion of the patients. However, its use in clinical practice has unfortunately been limited due to side effects with high drop-out rates in most studies. Recently, IFN-alpha2 has been shown to induce deep molecular remissions and also normalization of the bone marrow in PV, which may be sustained even after discontinuation of IFN-alpha2 therapy. Accordingly, in the coming years we are most likely facing a new era of increasing interest for using IFN-alpha2 in the treatment of patients with PV, ET and the hyperproliferative phase of PMF. This paper reviews the history of IFN - in principle IFN-alpha2 - and its present status in the treatment of PV and related diseases. The role of IFN-alpha2 as immune therapy in the future treatment of CMPNs is highlighted and the rationale for the concept of minimal residual disease and potentially cure after long-term immune therapy with IFN-alpha2 is discussed and foreseen as an achievable goal in the future.
With the improved survivals offered by the tyrosine kinase inhibitors has come the necessity to address issues relating to quality of life and one such area is that of fertility and parenting. Animal data suggest that imatinib at standard dosages is unlikely to impair fertility in either adult males or females but human data remain limited. Children born to men who are actively taking imatinib at the time of conception appear healthy and current advice is not to discontinue treatment. In contrast the data relating to children born to women exposed to imatinib during pregnancy are less encouraging. Although numbers are small there has been a disturbing cluster of rare congenital malformations such that imatinib cannot be safely recommended, particularly during the period of organogenesis. The appropriate management of children with CML has also been radically changed by the advent of imatinib. The features of the disease at presentation, the natural history and the response to therapy seem to be identical in children to that seen in adults. Now that imatinib has been in clinical use for almost ten years without severe long-term side effects, most physicians are now comfortable advising a trial of imatinib prior to consideration of transplant. Data relating to the efficacy and safety of second generation tyrosine kinase inhibitors in childhood is entirely absent and transplant remains the first choice for patients failing imatinib and perhaps also for young patients with sub-optimal responses.
Pregnancy is a high-risk event in women with essential thrombocythemia (ET). This observational study evaluated pregnancy outcome in ET patients focusing on the potential impact of aspirin (ASA) or interferon alpha (IFN) treatment during pregnancy. We retrospectively analyzed 122 pregnancies in 92 women consecutively observed in the last 10 years in 17 centers of the Italian thrombocythemia registry (RIT). The live birth rate was 75.4% (92/122 pregnancies). The risk of spontaneous abortion was 2.5-fold higher than in the control population (P < 0.01). ASA did not affect the live birth rate (71/93, 76.3% vs. 21/29, 72.4%, P = 0.67). However, IFN treatment during pregnancy was associated with a better outcome than was management without IFN (live births 19/20, 95% vs. 73/102, 71.6%, P = 0.025), and this finding was supported by multivariate analysis (OR: 0.10; 95% CI: 0.013-0.846, P = 0.034). The JAK2 V617F mutation was associated with a poorer outcome (fetal losses JAK2 V617F positive 9/25, 36% vs. wild type 2/24, 8.3%, P = 0.037), and this association was still significant after multivariate analysis (OR: 6.19; 95% CI: 1.17-32.61; P = 0.038). No outcome concordance between first and second pregnancies was found (P = 0.30). Maternal complications occurred in 8% of cases. In this retrospective study, in consecutively observed pregnant ET patients, IFN treatment was associated with a higher live birth rate, while ASA treatment was not. In addition, the JAK2 V617F mutation was confirmed to be an adverse prognostic factor.
Described as a myeloproliferative disorder mainly affecting elderly women, recent reports now confirm the occurrence of essential thrombocythemia at younger ages, which questions treatment during pregnancy. We report a further case of uneventful full term pregnancy with the use of interferon-alpha for maternal essential thrombocythemia which suggests that interferon-alpha could be considered as an effective and safe treatment during pregnancy for women with essential thrombocythemia. Further studies are warranted to determine whether interferon-alpha is the optimal therapeutic option during pregnancy for this patient population.
We assayed fetal serum interferon-alpha (IFNA), a cytokine produced by leukocytes as a response to viral infection, in a series of 59 consecutive cases of ventriculomegaly diagnosed in utero and in 89 controls. Results were correlated with other findings including karyotype, maternal-fetal screening for serum antibodies to specific infectious pathogens, viral cultures of amniotic fluid, and neuropathological examination or postnatal follow-up. Fetal serum IFNA assay was negative in the five ventriculomegalies associated with a genetic anomaly and positive in the three cases with documented cytomegalovirus infections. In addition, fetal serum IFNA was detected significantly more often in the cases of ventriculomegaly with unexplained pathogenesis (15/51, 29.4 per cent) than in controls (1/89, 1.1 per cent). Detection of IFNA suggestive of viral infection in fetuses with otherwise unexplained ventriculomegaly underscores the need for more extensive viral screening in such cases.
A 34-year-old woman on interferon for CML for 7 years, experienced problems with conception. Full work-up revealed a short luteal phase and therapy with clomiphene was initiated. Pregnancy occurred and a normal infant was delivered by C-section. The detailed infertility evaluation is described and the impact of interferon therapy on pregnancy is reviewed. Successful pregnancy appears possible in woman taking interferon on a chronic basis.
To report treatment of a patient with acute retinal necrosis during pregnancy.
A 24-year-old woman in her twenty-third week of gestation was diagnosed with acute retinal necrosis. A combination of acyclovir and interferon therapy was started at 25 weeks. Pars plana vitrectomy was performed during the 26th week of gestation.
The necrotizing retina became gliotic within 3 weeks of surgery. The patient's visual acuity improved to LE, 20/40. A healthy baby was delivered at 39 weeks of gestation.
Combination therapy of acyclovir and interferon followed by surgery partially restored the patient's vision without affecting fetal development.
We report a case of a patient who became pregnant while on interferon-alpha therapy for chronic hepatitis C. To date, there have been 23 reported cases of interferon administration during pregnancy; only one was in a patient with hepatitis C. We report our case and review the literature regarding the effects of interferon on pregnancy.
Bovine interferon-alpha I1 (bIFN-alpha) may be useful for enhancing fertility in sheep and cattle because it has extensive sequence homology with ovine and bovine trophoblast protein-1 and, like those proteins, extends corpus luteum lifespan. To test the effectiveness of bIFN-alpha to enhance fertility, several experiments were performed in which inseminated heifers were given i.m. injections of bIFN-alpha approximately at the time of embryo-mediated signals that result in maintenance of the corpus luteum. In Exp. 1, heifers given 20 mg of bIFN-alpha daily from d 14 to 17 tended (P less than .07) to have lower pregnancy rates at d 110 to 112 of gestation (36/75; 48% vs 43/72; 60%). Similar results were obtained in Exp. 2 when heifers received a single injection of 40 mg of bIFN-alpha or placebo at d 13 after estrus; pregnancy rates at d 42 were 39/104 (38%) for bIFN-alpha and 47/98 (48%) for placebo. In Exp. 3, heifers were given gradually increasing doses of bIFN-alpha or placebo from d 11 to 19, because such a regimen had been shown to reduce the number of heifers experiencing hyperthermia after bIFN-alpha injection. Pregnancy rates were 42/95 (44%) for bIFN-alpha and 62/111 (56%) for placebo. Across all three experiments, pregnancy rates were lower (P less than .01) for heifers treated with bIFN-alpha (117/274; 43%) than for heifers treated with placebo (152/281; 54%). In conclusion, these results demonstrate that, under the administration systems used, bIFN-alpha does not increase pregnancy rate, but rather tends to reduce it.
The cells of the immune system exchange information by a complex network of molecules referred to as lymphokines: these include the interferons. The physiology of the interferons, both in terms of control and function, is poorly understood. However, there is ample evidence that production of alpha-interferon is characteristic of the fetoplacental unit in both the human and other species. Indeed, the major trophoblast protein in early pregnancy in the sheep is alpha-interferon and in this species the molecule appears to have an important anti-luteolytic effect. The function of the interferons in human pregnancy is not known but, by analogy with information from other experimental systems, it might reflect aspects of the immune relationship between the mother and the fetus.
The kinetics of maternal-fetal interferon and a chemical interferon inducer were studied in Swiss-Webster white mice at 8, 15, and 19 days of gestation. Crude interferon was administered by maternal tail vein injection to one group. There was no transfer of interferon to the fetus despite high maternal levels. A chemical interferon inducer (10-carboxymethyl-9-acridanone) was given intramuscularly to a second group. Both maternal and fetal interferon responses rapidly reached significant levels, although the fetal response was less than that of the mother. Presence of the inducer was demonstrated in both maternal and fetal samples, indicating placental transport of the chemical to the fetus. The implications of these findings for the fetal immune response are discussed.
Tubuloreticular inclusions were observed in placental chorionic villi of rhesus monkeys after pregnant female monkeys were injected intramuscularly with recombinant leukocyte A interferon (25 X 10(6) units/kg). They were identified in endothelial cells, fibroblasts, and Hofbauer cells of the chorionic villi, providing evidence that interferon crossed at least part of the maternal-fetal partition. Induction of tubuloreticular inclusions in these cells by exogenous interferon has not been previously reported. Tightly packed regular tubular arrangements appeared in endothelial and Hofbauer cells and loosely organized tubular arrays in fibroblasts. The maximum dimension of the tubuloreticular inclusions measured 3 micron and the diameter of the tubules was 20 nm. The tubuloreticular inclusions were continuous with, and surrounded by, smooth endoplasmic reticulum that was often connected to rough endoplasmic reticulum. The tubuloreticular inclusions were not detected in placental chorionic villi from monkeys not treated with interferon or from interferon-treated monkeys 30 days after cessation of treatment. These results indicate that the formation of tubuloreticular inclusions in rhesus monkey placentas was a transient response associated with elevated serum levels of interferon.