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Papers by Carl LASKIN

Revue de Médecine Interne, Dec 1, 2015

Introduction L’evolution des anticorps antiphospholipides (aPL) et leur lien avec le pronostic ma... more Introduction L’evolution des anticorps antiphospholipides (aPL) et leur lien avec le pronostic materno-fœtal chez les femmes porteuses d’aPL ou d’un veritable syndrome des antiphospholipides (SAPL), sont mal connus. L’objectif de cette etude etait de determiner comment les aPL varient au cours de la grossesse et d’evaluer le lien entre ces eventuelles variations et les complications materno-fœtales, dans une cohorte prospective de femmes enceintes porteuses d’aPL, plus ou moins en association avec un lupus erythemateux systemique (LES). Patients et methodes Les donnees ont ete collectees au sein d’une cohorte de patientes porteuses d’aPL, inclues dans une large etude prospective multicentrique observationnelle, dont l’objectif etait d’identifier les phenotypes cliniques, les biomarqueurs et tests biologiques pertinents pour la prediction de la survenue d’une complication materno-fœtale apres le 1 er trimestre de grossesse, chez les patientes porteuses d’aPL et/ou d’un LES. Les aPL ont ete mesures de facon centralisee, aux 1 er , 2 nd et 3 e trimestres de grossesse ainsi qu’a 3 mois du post-partum, en suivant les recommandations internationales pour les criteres biologiques du SAPL. Les complications de la grossesse attribuees a la presence des aPL (CMF) etaient definies comme la survenue de : une mort fœtale apres 12 semaines de gestation, une mort neonatale, un accouchement premature avant 36 semaines de gestation du a une pre-eclampsie ou a une insuffisance placentaire, ou un retard de croissance inferieur au 5 e percentile. Resultats Cent cinquante-deux patientes ont ete incluses. L’âge moyen etait de 31,9 ± 4,6 ans, 57 % des patientes etaient atteintes d’un SAPL, avec dans 24 % des cas un antecedent de thrombose, et 36 % avaient un LES. En debut de grossesse, 90 (59 %) etaient IgG anticardiolipines (aCL) positives, 29 (19 %) IgM aCL positives, 59 (39 %) IgG anti-beta 2 Glycoproteine I (aβ2GPI) positives, 26 (17 %) IgM aβ2GPI positives et 79 (52 %) avaient un anticoagulant circulant (ACC). Pendant la grossesse, les aPL ont globalement persiste a titres eleves chez les patientes positives a l’inclusion. Neanmoins, une diminution des titres d’aPL d’isotype IgG a ete observee au cours de la grossesse, cette diminution etait statistiquement significative au cours des 2 e et 3 e trimestres en comparaison au 1 er trimestre ( p e trimestre de grossesse ( p nd trimestre. Parmi ces patientes, 30 (67 %) etaient IgG aCL positives, 5 (11 %) IgM aCL positives, 20 (45 %) IgG aβ2GPI positives, 8 (18 %) IgM aβ2GPI positives et 36 (80 %) avaient un ACC. La presence d’un ACC, quel que soit l’âge gestationnel, etait le seul facteur associe a la survenue d’une CMF (80 % versus 43 %, p p p Conclusion Dans notre large cohorte prospective de femmes enceintes porteuses d’aPL, une diminution modeste des aPL a ete observee au cours de la grossesse. Cette diminution n’etait pas associee a la survenue de complications materno-fœtales. Nos resultats suggerent donc que le suivi des aPL au cours de la grossesse ne semble pas necessaire.

Fertility and Sterility, Sep 1, 2005

The aim of the study is to evaluate the site-specific immunoregulatory mechanisms against bacteri... more The aim of the study is to evaluate the site-specific immunoregulatory mechanisms against bacterial infection in the human fallopian tubes. DESIGN: We investigated the effects of lipopolysaccharide (LPS) and proinflammatory cytokines on the production of CXC chemokines by cultured oviductal epithelial cells (OEC) and oviductal stromal fibroblasts (OSF) using enzyme-linked immunosorbent assays and western blot analysis. MATERIALS AND METHODS: Normal oviducts were obtained from premenopausal patients who had undergone sterilization or hysterectomies for leiomyoma.To study the production of granulocyte chemotactic protein-2 (GCP-2), growth-regulated oncogene ␣ (GRO␣), and epithelial neutrophil activating peptide-78 (ENA-78) by OEC and OSF. The supernatant was then replaced with recombinant human TNF-␣, recombinant human IL-1␤, and LPS. The expression of the toll-like receptor (TLR) 4 and others were observed by western blot analysis. RESULTS: LPS stimulated the secretion of GCP-2, GRO␣, and ENA-78 by OSF, but not by OEC. Tumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ (IL-1␤) also stimulated these chemokine secretions by both OEC and OSF. The expression of the TLR4 was detected only in OSF, but not in OEC. The CD14 expression was not detected in either OEC or OSF. A significant expression of the TNF-receptor (TNFR) I, TNFRII, the IL-1 receptor (IL-1R) I, and IL-1RII were detected in both OEC and OSF. The phosphorylation of the inhibitor kB-␣ (IB-␣) protein was not detected in OEC after stimulation by LPS, whereas IB-␣ phosphorylation was observed after stimulation by TNF-␣ or IL-1␤ in these cells. However, IB-␣ phosphorylation was observed in OSF after stimulation by either LPS, TNF-␣, or IL-1␤. CONCLUSION: These results suggest that epithelial cells and fibroblasts in the human fallopian tube have evolved aunique, site-specific mechanism for recognizing Gram-negative pathogens. The lack of TLR4 in OEC may be important for avoiding a state of unnecessary inflammation that could disrupt the epithelial barrier and cause irreversible tubal scarring.

Journal of Immunology, Sep 1, 1983

We report experiments designed to determine if the tolerance defect in NZB mice results from i) f... more We report experiments designed to determine if the tolerance defect in NZB mice results from i) failure of NZB cells to become tolerant, or ii) the ability of NZB cells to interfere actively with the development of tolerance. The results indicate that NZB cells are primed by the tolerogen itself and actively interfere with the expression of tolerance by DBA/2 cells, which normally can be rendered tolerant.

Arthritis Research & Therapy, Mar 19, 2020

Background: Lupus patients are at risk for pregnancy loss, and it has been generally accepted tha... more Background: Lupus patients are at risk for pregnancy loss, and it has been generally accepted that women with SLE should have low disease activity prior to conception. However, there are conflicting results regarding the effect of pregnancy on SLE flares. This study aims to identify predictors of flares during and after pregnancy in SLE patients with inactive or stable disease activity during the first trimester and to characterize and estimate the frequency of post-partum flares in these patients. Methods: SLE patients in the multicenter, prospective PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study were evaluated for flares during and after pregnancy using the SELENA-SLEDAI Flare Index. Flares during pregnancy were assessed in all 384 patients and post-partum flares in 234 patients with study visits 2-6 months post-partum. Logistic regression models were fit to the data to identify independent risk factors for flare. Results: During pregnancy, 20.8% of patients had mild/moderate flares and 6.25% had severe. Post-partum, 27.7% of patients had mild/moderate flares and 1.7% had severe. The mild flares rarely required treatment. Younger age, low C4 and higher PGA at baseline were independently associated with higher risk of having at least one mild/moderate or severe flare during pregnancy. Older patients were at decreased risk of flare, as well as those with quiescent disease at baseline. No variables evaluated at baseline or the visit most proximal to delivery was significantly associated with risk of flare post-partum. Medications were not associated with flare during or after pregnancy. Conclusion: In patients with inactive or stable mild disease activity at the time of conception, lupus disease flares during and after pregnancy are typically mild and occur at similar rates. Flares during pregnancy are predicted by the patients' age and clinical and serological activity at baseline.

Journal of Immunology, Nov 1, 1981

Annals of Internal Medicine, Aug 4, 2015

Background-Since systemic lupus erythematosus (SLE) affects women of reproductive age, pregnancy ... more Background-Since systemic lupus erythematosus (SLE) affects women of reproductive age, pregnancy is a major concern. Objective-To identify predictors of adverse pregnancy outcome (APO) in inactive or stable active SLE patients Design-Prospective Cohort Setting-Multicenter Patients-385 patients (49% non-Hispanic White; 31% prior nephritis) with SLE in PROMISSE. Exclusion criteria were: proteinuria >1000 mg/24 hour, creatinine >1.2 mg/dL, prednisone >20 mg/day, or multi-fetal pregnancy. Measurements-APO included: fetal/neonatal death; birth <36 weeks due to placental insufficiency, hypertension, or preeclampsia; and small for gestational age (SGA) <5%. Disease activity was assessed by SLEPDAI and physician's global assessment (PGA). Results-APO occurred in 19.0% (95% CI: 15.2%-23.2%) of pregnancies, fetal death (4%), neonatal death (1%), preterm delivery (9%), and SGA (10%). Severe flares in the second and third trimester occurred in 2.5% and 3.0%, respectively. Baseline predictors of APO included lupus anticoagulant positive (OR = 8.32, 95% CI: 3.59-19.26), antihypertensive use (OR = 7.05, 95% CI: 3.05-16.31), PGA>1 (OR = 4.02, 95% CI: 1.84-8.82) and platelets (OR = 1.33 per 50K decrease, 95% CI:1.09-1.63); non-Hispanic White was protective (OR = 0.45, 95% CI: 0.24-0.84). Maternal flares, higher disease activity, and smaller increase in C3 later in pregnancy also predicted APO. Among women without baseline risk factors, the APO rate was 7.8%. For those either LAC positive, or LAC negative but non-White or Hispanic and taking antihypertensives, APO rate was 58%; fetal/neonatal mortality 22%. Limitations-Excluded patients with high disease activity. Conclusions-In pregnant SLE patients with inactive or stable mild/moderate disease, severe flares are infrequent, and absent specific risk factors, outcomes are favorable.

The Journal of Rheumatology, Apr 1, 2021

To evaluate the association between ethnicity and neonatal lupus erythematosus (NLE), as well as ... more To evaluate the association between ethnicity and neonatal lupus erythematosus (NLE), as well as specific NLE manifestations in a large multiethnic population. Methods. We conducted a cohort study of the children (≤ 1 yr of age) seen in the NLE clinic at The Hospital for Sick Children (SickKids), between January 2011 and April 2019. The cohort was divided into European, non-European, and mixed European-non-European groups according to parent-reported child's ethnicity (Canada Census categories). Outcomes were NLE and specific NLE manifestations (cardiac, cutaneous, cytopenias, transaminitis, and macrocephaly). The frequency of NLE and specific manifestations were compared between ethnic groups (Fisher exact test). We tested the association between ethnicity and (1) NLE risk, and (2) specific NLE manifestations with logistic regression models, including covariates for child's sex, maternal rheumatic disease status during pregnancy, and maternal use of antimalarials during pregnancy (multiple comparisons threshold P < 0.008). Results. We included 324 children born to 270 anti-Ro antibody-positive mothers. Median age at first visit was 1.8 (IQR 1.4-2.3) months, and median follow-up time was 12 (IQR 2-24) months. The majority was non-European (48%), with 34% European, and 18% mixed European-non-European. There was no significant association between non-European ethnicity (OR 1.18, 95% CI 0.71-1.94, P = 0.51), mixed European-non-European ethnicity (OR 1.13, 95% CI 0.59-2.16, P = 0.70), and NLE risk compared with European ethnicity. We also did not find an association between ethnicity and specific NLE manifestations in univariate or multivariable-adjusted models. Conclusion. In a large multiethnic cohort, there was no association between a child's ethnicity and NLE risk or specific NLE manifestations.

Archives of Gynecology and Obstetrics, Jan 19, 2019

Purpose To determine if endometrial injury prior to the first or second in vitro fertilization (I... more Purpose To determine if endometrial injury prior to the first or second in vitro fertilization (IVF) cycle affects clinical pregnancy rates. Methods This study was a randomized, multicentre, controlled study performed at three Canadian outpatient fertility clinics. Patients undergoing their first or second IVF cycle were randomized to a single endometrial injury 5-10 days prior to the start of gonadotropins in an IVF cycle compared to no injury. The primary outcome was clinical pregnancy rate. Secondary outcomes were live birth rates, implantation rate, endometrial thickness, number of oocytes retrieved and the rate of embryo cryopreservation. Results Fifty-one women were randomized (25 in the endometrial injury group and 26 in the control group); however, the study was terminated prematurely due to slow recruitment (target 332 patients). Groups were similar at baseline for: age, duration of infertility, BMI, day 3 FSH, and the number having first IVF cycle. The groups were similar for gonadotropin dose, endometrial thickness, number of oocytes retrieved, and embryo cryopreservation rate. The clinical pregnancy rate in the endometrial injury group was 52% (13/25) and 46% (12/26) in the control group (p = 0.45). Live birth rate in the endometrial injury group was 52% (13/25) and 35% (9/26) in the control group (p = 0.17). The implantation rate was also similar (58% vs. 45%, p = 0.17). Conclusions This study did not detect a difference in implantation, clinical pregnancy or live birth rates; however, the lack of difference in this study may be because it was underpowered. Clinical trials registrations gov: NCT01983423

De Gruyter eBooks, Feb 7, 2022

American Journal of Obstetrics and Gynecology, 2019

OBJECTIVE: Perinatal Mood and Anxiety Disorders (PMADs) are the most common complication of the p... more OBJECTIVE: Perinatal Mood and Anxiety Disorders (PMADs) are the most common complication of the perinatal period and screening for PMADs is recommended by multiple societies and organizations for maternal and child benefit. The aim of this study was to establish the prevalence of anxiety symptoms in the obstetric population. The secondary aim was to evaluate the Edinburgh Postnatal Depression Screen's (EPDS) ability to screen for anxiety related symptoms as compared to the Generalized Anxiety Disorder-7 (GAD-7). STUDY DESIGN: Women receiving obstetric care at the University of Alabama at Birmingham were screened simultaneously using the EPDS and GAD-7 from 10/1/17 to 5/31/18. The screened population included English and Spanish speaking women from public and private offices at varied gestational ages and postpartum. Only the first screen was included if a woman was screened more than once. Along with demographics, the total score on both the EDPS and GAD-7, as well as the score on three anxiety-specific EPDS questions were collected. A positive score was set at 10 for both the GAD-7 and EPDS. The data were then analyzed using standard statistical modeling including logistic regression and Pearson correlation coefficients. RESULTS: 407 women were screened and included; 102 (25%) were postpartum, 13 (3%) were in Spanish, and 203 (49%) received care in a public office. The prevalence of a positive GAD-7 was 17% and of a positive EPDS was 11%. The correlation between a positive EPDS and GAD-7 screen was noted to be 0.83 while the correlation between the anxiety specific EPDS questions (#4, 5, and 6) and GAD-7 was 0.75. A score of 5 or greater on the anxiety specific EPDS questions had a sensitivity of 75% and a specificity of 90% for a positive GAD-7 score. Demographic information were analyzed and none were found to be significantly associated with a positive screen for either anxiety or depression. CONCLUSION: PMADs are prevalent in the obstetric population. Using a score of 5 or greater on the three anxiety specific EPDS questions may be helpful in identifying women who could benefit from more anxiety specific screening and treatment. With a rate of symptomatic anxiety three times the rate of the general population, further clinical evaluation and treatment of anxiety in the obstetric population is warranted as part of routine screening for PMADs.

Ultrasound in Obstetrics & Gynecology, Sep 1, 2015

BMC Pregnancy and Childbirth, Oct 6, 2021

Background: Improvement in the prediction and prevention of severe maternal morbidity (SMM)-a ran... more Background: Improvement in the prediction and prevention of severe maternal morbidity (SMM)-a range of lifethreatening conditions during pregnancy, at delivery or within 42 days postpartum-is a public health priority. Reduction of SMM at a population level would be facilitated by early identification and prediction. We sought to develop and internally validate a model to predict maternal end-organ injury or death using variables routinely collected during pre-pregnancy and the early pregnancy period. Methods: We performed a population-based cohort study using linked administrative health data in Ontario, Canada, from April 1, 2006 to March 31, 2014. We included women aged 18-60 years with a livebirth or stillbirth, of which one birth was randomly selected per woman. We constructed a clinical prediction model for the primary composite outcome of any maternal end-organ injury or death, arising between 20 weeks' gestation and 42 days after the birth hospital discharge date. Our model included variables collected from 12 months before estimated conception until 19 weeks' gestation. We developed a separate model for parous women to allow for the inclusion of factors from previous pregnancy(ies). Results: Of 634,290 women, 1969 experienced the primary composite outcome (3.1 per 1000). Predictive factors in the main model included maternal world region of origin, chronic medical conditions, parity, and obstetrical/perinatal issues-with moderate model discrimination (C-statistic 0.68, 95% CI 0.66-0.69). Among 333,435 parous women, the C-statistic was 0.71 (0.69-0.73) in the model using variables from the current (index) pregnancy as well as pre-pregnancy predictors and variables from any previous pregnancy. Conclusions: A combination of factors ascertained early in pregnancy through a basic medical history help to identify women at risk for severe morbidity, who may benefit from targeted preventive and surveillance strategies

Journal of Immunology, Sep 15, 1986

Murine lupus is characterized by the production of numerous autoantibodies and immune complex glo... more Murine lupus is characterized by the production of numerous autoantibodies and immune complex glomerulonephritis. Anti-DNA antibodies are the hallmark of this disorder and may be associated pathogenetically with the glomerulonephritis. The cellular mechanisms underlying the regulation of the production of anti-DNA antibodies may prove to be the fundamental abnormalities responsible for the lupus syndrome seen in these mice. By using a system of spontaneous anti-DNA antibody production in vitro, we have determined that such production is characteristic of autoimmune NZB and MRL-lpr/lpr mice but not of the nonautoimmune control strains. Additional examination of the cellular mechanisms involved in the regulation of this response in NZB mice revealed: 1) this response is markedly T cell dependent, 2) NZB T cells are essential for maximal production of this autoantibody, and 3) NZB T cells actively interfere with normal immune regulatory mechanisms that lead to the production of anti-DNA antibodies spontaneously in vitro by nonautoimmune syngeneic B lymphocytes. Although these studies of anti-DNA antibody production in vitro disagree with previous work by others they successfully reproduce the results obtained earlier in experiments performed in vivo.

Human Reproduction

Study question Is it possible to use NEQsi to determine the statistical contributions of embryo q... more Study question Is it possible to use NEQsi to determine the statistical contributions of embryo quality and endometrial thickness (ET) to IVF cycle outcome? Summary answer Yes. Analytics revealed that the likelihood of pregnancy is reliably predicted by the quality of the embryo at any endometrial thickness. What is known already ET is widely utilized to assess the quality of endometrial preparation in IVF cycles. The connection between endometrial thickness and cycle outcome is divided in the literature; studies report correlation between ET and cycle outcome while others find no link between the two. Regardless, the statistical interactions between ET and embryo quality remain understudied. NEQsi was recently developed as a method for converting Gardner embryo grades to interval variables for use in statistical modeling. The combination of NEQsi scores and endometrial thickness measurements provides an opportunity to assess the contributions of embryo quality and ET on IVF cycle o...

Reproduction

In brief Immune dysfunction may contribute to or cause recurrent implantation failure. This artic... more In brief Immune dysfunction may contribute to or cause recurrent implantation failure. This article summarizes normal and pathologic immune responses at implantation and critically appraises currently used immunomodulatory therapies. Recurrent implantation failure (RIF) may be defined as the absence of pregnancy despite the transfer of ≥3 good-quality blastocysts and is unexplained in up to 50% of cases. There are currently no effective treatments for patients with unexplained RIF. Since the maternal immune system is intricately involved in mediating endometrial receptivity and embryo implantation, both insufficient and excessive endometrial inflammatory responses during the window of implantation are proposed to lead to implantation failure. Recent strategies to improve conception rates in RIF patients have focused on modulating maternal immune responses at implantation, through either promoting or suppressing inflammation. Unfortunately, there are no validated, readily available d...

Journal of Immunology, Apr 1, 1982

We have evaluated hapten-specific hyporesponsiveness induced by in vivo administration of TNP-mod... more We have evaluated hapten-specific hyporesponsiveness induced by in vivo administration of TNP-modified syngeneic spleen cells (TNP-SC). Pretreatment of non-autoimmune mice led to hyporesponsiveness to challenge with either TNP or the closely related hapten DNP coupled to Ficoll. There was also a significant reduction of the direct PFC response after challenge with TNP-HGG. In tolerized mice challenged with TNP-HGG, the IgM portion of the serum response was similarly suppressed; however, the total serum antibody as well as the indirect PFC response was not suppressed. There was no tolerance at all when the mice were challenged with DNP-HGG. Thus, exposure to TNP-SC results in an incomplete form of hapten-specific B cell tolerance. This tolerance is selective for the IgM isotype and does not extend to the cross-reactive hapten DNP on a thymic-dependent carrier, although it does extend to a DNP on a thymic-independent carrier. Autoimmune NZB mice were defective with regard to tolerance after injection of hapten-modified syngeneic spleen cells. They did manifest a reduced direct PFC response to the challenge with TNP-Ficoll, but failed to demonstrate cross-tolerance to DNP-Ficoll challenge. Moreover, they did not have suppression of the hapten-specific IgM response after challenge with TNP on the thymic-dependent carrier. These abnormalities in tolerance induction in NZB mice to modified self may help to explain the loss of self-tolerance that occurs spontaneously and is expressed as autoimmune disease.

Systemic lupus erythematosus (SLE) is a complex multisystem disorder which is associated with spe... more Systemic lupus erythematosus (SLE) is a complex multisystem disorder which is associated with specific genetic, environmental, hormonal, and cellular events culminating in autoantibody production and clinical disease manifestations. The precise derangements and interactions of these various factors have been the focus for considerable research in humans and also in the murine lupus models. These lupus-prone mice spontaneoulsy develop an illness which resembles the human disorder [1–3]. Although they do not necessarily reflect a perfect correlate for human SLE, they do allow insights into the pathogenetic mechanisms of SLE. Like human SLE, which is a heterogeneous disease with much variation between individual patients [4], the murine models of SLE also have a wide spectrum of presentation. Although no single mouse model completely represents the human counterpart, the mice in their entirety do demonstrate a spectrum comparable to that of patients. In this paper, we will emphasize st...

Canadian Medical Association Journal, 2019

nfertility affects 1 in 6 Canadian couples, many of whom turn to infertility treatment. These inc... more nfertility affects 1 in 6 Canadian couples, many of whom turn to infertility treatment. These include pharmacologic ovulation induction, intrauterine insemination, and more invasive assisted reproductive technologies, such as in vitro fertilization. In vitro fertilization often follows intense rounds of ovarian hyperstimulation, oocyte retrieval and intracytoplasmic sperm injection. 1 Assisted reproductive technology accounts for about 18 000 pregnancies in Canada each year, with 1%-4% of births conceived using infertility treatment. 2,3 Although infertility treatment improves the chances of a pregnancy among infertile couples, it may have unintended consequences for mother and newborn, such as a higher risk of preterm birth, low birth weight and cesarean delivery that are independent of age and plurality. 1,4-6 Canadian public funding programs for in vitro fertilization launched in the provinces of Quebec (2010-2015) 7 and Ontario (started in 2015 and ongoing) 8 have increased in vitro fertilization access among ethnically and socially diverse groups of women. 9 However, the effect on maternal health of infertility treatment in general-and in vitro fertilization in particular-is understudied.