The Affordability and Accessibility of Ontario's Publicly Funded IVF Program: A Survey of Patients.

OBJECTIVE: On December 21, 2015, the Province of Ontario created the Ontario Fertility Program to fund one cycle of in vitro fertilization (IVF) to improve IVF affordability and access for Ontarians below age 43. The objective of this study was to determine whether the Program was meeting this goal, based on the experiences of participating patients. METHODS: Participation in an electronic survey was invited through posters and brochures placed within the waiting rooms of all 25 IVF clinics providing funded IVF in Ontario and by a survey link placed on websites focused on fertility issues. RESULTS: The survey was carried out at the end of the second year of the Program (September to December 2017), with 514 participants completing >75% of it. Program strengths were noted as follows: decreases in financial inequities of family building for the infertile; lowering of the opportunity cost of accessing IVF; and destigmatizing and raising public awareness of infertility as a legitimate medical condition. Weaknesses were as follows: lack transparency and consistency in clinics' patient prioritization schemes; clinic concentration in cities leading to geographic inequities in access; and high ancillary costs being financially burdensome. The following opportunities were suggested: funding of more than one IVF cycle and its supporting medications; standardization of prioritization schemes; and tying Program access to means testing. CONCLUSION: Patients strongly support the Program and noted improved IVF affordability, but the Program's reliance on existing private clinics for treatment provision has meant unresolved geographic inequities and inconsistent prioritization schemes. Because this is the first Program study of patients' experience, the results will help policymakers determine areas to re-evaluate for continued or increased funding and opportunities to collaborate with health care providers and clinic owners to improve provision and access.

Outcome of pregnancy in women with psoriatic arthritis compared to healthy controls.

OBJECTIVES: The mean age at onset of psoriatic arthritis (PsA) ranges between the 4th-6th decades of life. However, little is known about fertility and pregnancy outcome in PsA patients. The aim of this study was to examine whether fertility and pregnancy outcome of PsA patients are different from healthy controls and to evaluate PsA and psoriasis disease activity perception during pregnancy and the year postpartum. METHODS: A questionnaire-based study, including demographic, fertility, pregnancy outcome, and disease activity questions, was conducted in PsA patients and healthy controls. The inclusion criterion was diagnosis of PsA before at least 1 pregnancy. Descriptive statistics are provided. T tests and Pearson chi-square tests were used to analyze the differences between continuous and categorical variables, respectively. RESULTS: The 74 PsA patients and 74 healthy controls were not significantly different in most of the demographic variables. The mean number of pregnancies, children, and infertility diagnosis were not significantly different between the groups. The pregnancy outcomes in the PsA group (n = 151) and in the control group (n = 189) were similar in: live birth (76% vs. 76%, P = 0.3), vaginal delivery (48% vs. 51%, P = 0.6), gestation age (38.5 vs. 38.3, P = 0.3), weight at birth (3.4 kg vs. 3.4 kg, P = 0.5), low rate of maternal and fetal complications, and the duration and rate of breastfeeding. Most (58%) patients reported favorable joint activity during pregnancy and 50% reported worsening during the 1st postpartum year. CONCLUSIONS: PsA patients do not have more infertility or worse pregnancy outcomes compared to healthy controls.

Maternal and Fetal Outcomes in a Cohort of Patients Exposed to Tumor Necrosis Factor Inhibitors throughout Pregnancy.

OBJECTIVE: Tumor necrosis factor inhibitors (TNFi) are increasingly used in pregnancy but are frequently withheld in the second or third trimesters. We evaluated the maternal and fetal outcomes of women who continued their TNFi throughout pregnancy compared to women who interrupted TNFi during pregnancy. METHODS: We retrospectively analyzed the outcomes of women seen in clinic with rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis (JIA), or ankylosing spondylitis, who were exposed to TNFi during pregnancy. We separated pregnancies into 2 groups based on the level of TNFi exposure and compared outcomes. RESULTS: In Group 1 (TNFi exposure in first trimester only), 11 women had 14 pregnancies and 12 live births. There were 2 first-trimester losses (2/14, 14%), one in the setting of active RA. Five pregnancies (5/14, 35.7%) were complicated by a disease flare. Eight patients (8/12, 66%) flared postpartum. In Group 2 (TNFi exposure throughout pregnancy), 29 women had 32 pregnancies and 34 live births. Three (3/28, 10.7%) adverse pregnancy outcomes were reported in 2 patients. One patient had a twin pregnancy and delivered at 33 weeks after developing preterm premature rupture of membranes at 32 weeks in the setting of a JIA flare. Her second pregnancy was complicated by active JIA before and throughout gestation, and hemolysis, elevated liver enzyme levels, and low platelet levels (HELLP) syndrome at 39 weeks. Another patient with comorbid antiphospholipid syndrome underwent a cesarean birth at 36 weeks for suspicion of HELLP syndrome. Six (6/32, 18.7%) postpartum flares occurred. CONCLUSION: Women who discontinued their TNFi during pregnancy had a higher risk of peri- or postpartum flare compared to those who continued their TNFi throughout pregnancy.

Effect of chronic hypertension on assisted pregnancy outcomes: a population-based study in Ontario, Canada.

OBJECTIVE: To evaluate maternal and neonatal outcomes in women with chronic hypertension who conceive using assisted reproductive technologies (ART). DESIGN: Population-based retrospective cohort study. SETTING: Obstetric hospitals. PATIENT(S): Singleton pregnancies of at least 20 weeks' gestational age to women 18 years and older who delivered a live or stillborn infant between April 1, 2006, and March 31, 2012, categorized as exposed based on a diagnosis of chronic hypertension in the mother predating the index pregnancy. INTERVENTION(S): Medically assisted pregnancy including in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI), intrauterine insemination, and ovulation induction. PRIMARY OUTCOME: placental-mediated complications of pregnancy (preeclampsia/eclampsia, stillbirth, fetal growth restriction/low birthweight [<10th percentile], or clinically significant placental abruption); secondary outcomes: cesarean delivery (planned/unplanned), prematurity (<37 or <32 weeks), and neonatal death. RESULT(S): Our cohort included 807,765 singleton pregnancies. We used log binomial regression to compute the adjusted relative risks of the various outcomes in women with hypertension as compared with healthy women in ART and unassisted pregnancies. When we tested an interaction term between hypertension and ART in multivariate models, women with ART pregnancies were at higher risk of placental-mediated complications than were those with unassisted pregnancies (adjusted risk ratio 1.48; 95% confidence interval, 1.35, 1.56). The risk was even greater in hypertensive women who used ART (adjusted risk ratio 6.77; 95% confidence interval, 4.72, 9.72). Our findings persisted when assessing IVF only and when evaluating nulliparas. CONCLUSION(S): Hypertension is more frequent in ART-treated women. Hypertension increases the risk of placental complications, which appear to be compounded in ART versus unassisted pregnancies.

A Focus on Maternal Health Before Assisted Reproduction: Results From a Pilot Survey of Canadian IVF Medical Directors.

OBJECTIVE: To describe current physician practice patterns in Canada with regard to performing in vitro fertilization in high-risk patients. METHODS: All medical directors of IVF clinics registered with the Canadian Fertility and Andrology Society (n=35) were invited to participate in an online survey between January and May 2014. We carried out descriptive analyses of participants' responses regarding implementation of local restrictive policies for access to IVF. Whether practice patterns differed in hospital versus community-based clinics was assessed using chi-square testing with significance set at alpha<0.05. RESULTS: The response rate was 77.1%. More than one half of clinics (55.6%) were university-affiliated, and 29.6% were hospital-based. The majority of respondents (70.4%) used an upper age limit for permitting IVF (median 50 years, IQR 44 to 50), mostly because of lower pregnancy and live birth rates. Approximately one half of respondents limited treatment according to BMI (median upper permitted BMI 38 kg/m2, IQR 35 to 40 kg/m2) to minimize complications during pregnancy. Most respondents (77.8%) believed that routine pre-IVF medical assessment would be useful in their daily practice. There was a non-significant trend towards more restrictive policies in hospital-based clinics compared with community-based clinics. CONCLUSION: Our findings confirm that Canadian reproductive medicine physicians are taking maternal health factors into consideration when assessing patients' suitability for IVF. Nevertheless, there is between-clinic variability in the parameters used to assess eligibility for treatment. In light of the changing maternal demographic, more research is needed on assisted reproductive technology and perinatal outcomes in women who are at risk for pregnancy complications.

Objectif : Décrire les profils de pratique actuels des médecins canadiens en ce qui a trait à la tenue d'une fécondation in vitro chez des patientes exposées à des risques élevés. Méthodes : Tous les directeurs médicaux des cliniques de FIV inscrites à la Société canadienne de fertilité et d'andrologie (n = 35) ont été conviés à participer à un sondage en ligne entre janvier et mai 2014. Nous avons mené des analyses descriptives des réponses des participants en ce qui concerne la mise en œuvre de politiques locales de restriction de l'accès à la FIV. La présence de différences entre les milieux hospitaliers et les cliniques communautaires en ce qui a trait aux profils de pratique a été évaluée au moyen d'un test de chi carré (seuil de signification : alpha < 0,05). Résultats : Le taux de réponse a été de 77,1 %. Plus de la moitié des cliniques (55,6 %) étaient affiliées à une université et 29,6 % des cliniques opéraient en milieu hospitalier. La majorité des répondants (70,4 %) utilisaient une limite supérieure en matière d'âge pour la tenue d'une FIV (médiane : 50 ans, intervalle interquartile : de 44 à 50 ans), principalement en raison des taux moindres de grossesse et de naissance vivante. Près de la moitié des répondants limitaient l'accès au traitement en fonction de l'IMC (IMC supérieur médian permis : 38 kg/m2, intervalle interquartile : de 35 à 40 kg/m2), et ce, afin de minimiser les complications au cours de la grossesse. La plupart des répondants (77,8 %) estimaient que la tenue systématique d'une évaluation médicale pré-FIV serait utile dans le cadre de leur pratique quotidienne. Une tendance non significative envers l'adoption de politiques plus restrictives a été constatée au sein des cliniques hospitalières, par comparaison avec les cliniques communautaires. Conclusion : Nos constatations confirment que les médecins canadiens œuvrant dans le domaine de la médecine génésique prennent en considération des facteurs de santé maternelle dans le cadre de leur évaluation du caractère adéquat de la FIV pour leurs patientes. Quoi qu'il en soit, les paramètres utilisés pour évaluer l'admissibilité au traitement varient d'une clinique à l'autre. Compte tenu de l'évolution des caractéristiques démographiques maternelles, la tenue d'autres recherches s'avère requise sur le recours à la procréation assistée et les issues périnatales chez les femmes qui sont exposées à des risques de connaître des complications de grossesse.

The lupus anticoagulant: results from 2257 patients attending a high-risk pregnancy clinic.

Routine investigation for recurrent pregnancy loss includes measurement of antiphospholipid antibodies under the perception that the lupus anticoagulant (LAC) is prevalent in this population. Our tertiary clinic sees ~250 new patients with recurrent pregnancy loss annually, in addition to those with systemic lupus erythematosus and/or antiphospholipid syndrome. We measure LAC using a 4-assay panel that expands on the 2 assays recommended by the International Society on Thrombosis and Haemostatis (ISTH) guidelines. Of 2257 patients tested for LAC during a 6-year period, 62 (2.7%) repeatedly tested positive. Only 5 patients (0.2%) had both a history of early recurrent miscarriage and LAC positivity. Patients with LAC had a significantly more frequent history of thrombosis (35.5% vs 2.4%). LAC was absent in an overwhelming majority of women with exclusively early recurrent pregnancy loss but was associated with sporadic stillbirth. Among our panel of assays, none was predominant, and an increasing number of positive assays was associated with an increased history of morbidity. Therefore, our results do not support the ISTH contention that 2 assays are sufficient to identify and describe patients with LAC. We found that a confirmed, repeated LAC was very infrequent even in a high-risk setting.

Anticardiolipin antibodies and recurrent early pregnancy loss: a century of equivocal evidence.

In 1987, Nigel Harris cautioned against over-diagnosing the antiphospholipid syndrome (APS). In what was a rather prophetic editorial titled 'The Syndrome of the Black Swan', he suggested that while patients with APS do indeed exist, they are probably much more unusual than many medical professionals might like to believe. He expressed concern that the value of studying antiphospholipid antibodies (aPLs) as interesting non-organ specific autoantibodies, would become lost in a 'sea of over-interpreted and over-reported laboratory and clinical findings'. It is our contention that 25 years later, this prediction has come to pass, particularly with respect to one type of aPL and its relation to a clinical event, namely anticardiolipin antibodies and early recurrent pregnancy loss. In this commentary, we trace the evolution of the current dogma and propose that reevaluation of available data from an alternative perspective results in quite a different understanding, the acceptance of which would necessitate not only a revision of the classification criteria for APS but also the subsequent revision of many diagnoses.

Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial.

OBJECTIVE: To compare live birth rates in women with recurrent pregnancy loss (RPL) and either autoantibodies or a coagulation abnormality, treated with low molecular weight heparin plus aspirin (LMWH/ASA) or ASA alone, and to place our results in context with other randomized clinical trials (RCT) with similar cohorts. METHODS: The HepASA Trial was an RCT including patients with a history of RPL and at least 1 of the following: antiphospholipid antibody (aPL), an inherited thrombophilia, or antinuclear antibody. Treatment groups were stratified by aPL status and history of early versus late pregnancy losses. Patients received either LMWH/ASA or ASA alone. The primary outcome was live birth; secondary outcomes included adverse events and bone loss at the spine and femoral neck. Literature over the past 20 years was reviewed to identify comparable RCT. RESULTS: Over 4 years, 859 women with RPL were screened: 88 (10.2%) fulfilled inclusion criteria, became pregnant and were randomized to receive either LMWH/ASA or ASA alone. aPL were present in 42 (47.7%) patients in each group. The trial was stopped after 4 years when an interim analysis showed no difference in live birth rates in the 2 groups, and a lower rate of pregnancy loss in the ASA only group than expected. In the LMWH/ASA group, 35/45 (77.8%) had a live birth versus 34/43 (79.1%) in the ASA only group (p = 0.71). Neither number of prior losses nor aPL status was correlated with pregnancy outcome. There were no cases of pregnancy related thrombosis in either group. Mean change in BMD did not differ by treatment group at either the lumbar spine (p = 0.57) or femoral neck (p = 0.15). RCT since 2000 for aPL positive women with RPL and similar inclusion criteria report a mean live birth rate of 75% with either LMWH or ASA. CONCLUSION: LMWH/ASA did not confer incremental benefit compared to ASA alone for this population. Regardless of treatment regimen, number of prior losses, or aPL positivity, almost 80% of women in our RPL cohort had a successful pregnancy outcome. These findings contribute to a growing body of literature that contests the emerging standard of care comprising LMWH/ASA for this population.

Incidence of postpartum thrombosis and preterm delivery in women with antiphospholipid antibodies and recurrent pregnancy loss.

OBJECTIVE: To determine the frequency of preterm deliveries and postpartum thrombotic events (TE) in pregnancies resulting in live birth in women with antiphospholipid antibodies (aPL) and a history of recurrent pregnancy loss (RPL) but without prior TE. METHODS: We reviewed the pregnancy outcomes of women referred to our clinic with a history of RPL. Prepregnancy investigation of RPL included history of TE and aPL positivity (anticardiolipin IgG and lupus anticoagulant). We recorded use of anticoagulation therapy during and after pregnancy, obstetric outcome, gestational age at delivery, and postpartum course. Included in our study were women with unexplained RPL with no history of TE attending our clinic who subsequently had pregnancies that resulted in a live birth. RESULTS: Over a 5-year period, 260 women with RPL and no history of TE had a live birth at our clinic. Eighty-seven (33.5%) were positive for aPL and 173 (66.5%) were negative for aPL. Twenty-four percent of deliveries in the aPL-positive group occurred before 37 weeks' gestation compared to 9.8% of deliveries in the aPL-negative group (p = 0.004; 95% CI 0.052-0.234). There were no antepartum TE in either group. One woman in the aPL-positive group (1.1%) had a deep vein thrombosis 3.5 weeks postpartum while receiving prophylactic anticoagulant therapy, compared to none in the aPL-negative group. CONCLUSION: A significantly higher proportion of aPL-positive patients had preterm deliveries compared to aPL-negative patients, but pregnancy-related TE was infrequent: 99.0% of aPL-positive women with a history of RPL and no prior TE who had a live birth at our clinic had an uneventful pregnancy, delivery, and postpartum course.

Postpartum management of women at increased risk of thrombosis--results of a Canadian pilot survey.

OBJECTIVE: To determine current practice patterns in the postpartum management of women at increased risk of thrombosis. METHODS: Physicians affiliated with the University of Toronto departments of Obstetrics and Gynecology, Rheumatology, Hematology, and Obstetric Medicine who provide care to pregnant women were mailed a questionnaire that presented 6 clinical scenarios involving postpartum management of a woman at risk for thrombosis, with (1) recurrent pregnancy loss and antiphospholipid antibody syndrome (APS) treated with aspirin (ASA) in the pregnancy; (2) 2 pregnancy losses and a low titer antiphospholipid antibody (aPL) treated with ASA and low molecular weight (LMW) heparin with placental insufficiency; (3) known APS and pregnancy loss treated with LMW heparin and delivered by cesarean section; (4) a previous 17 week fetal death and aPL; (5) a previous deep vein thrombosis while on oral contraception; and (6) systemic lupus erythematosus and secondary APS with a history of a stillbirth. Physicians were asked whether they would recommend postpartum coagulation, and if so to choose from a list of treatment options. RESULTS: Of the 71 questionnaires mailed, 44 were returned (62%). Three physicians replied that their practices do not include patients similar to those presented in the cases and chose not to respond to the clinical scenarios. Percentages of responders recommending treatment in each scenario were 29% for Case 1, 49% for Case 2, 63% for Case 3, 41% for Case 4, 51% for Case 5, and 58% for Case 6. Recommendation for treatment differed among medical specialties, with rheumatologists being less likely to treat in all cases. Prophylactic heparin was selected as the treatment of choice most frequently by those recommending anticoagulation 70% (84/120). CONCLUSION: Postpartum treatment recommendations for women at increased risk of thrombosis are variable across different practitioner specializations demonstrating clinical equipoise regarding therapy. More definitive research is needed and broader study of physicians involved in the care of these patients is planned to more accurately describe and understand the decision to treat these patients.

Decrease in pregnancy loss rates in patients with systemic lupus erythematosus over a 40-year period.

OBJECTIVE: To determine if there has been a statistically significant change in pregnancy loss and preterm delivery rates in patients with systemic lupus erythematosus (SLE). METHODS: We analyzed the pregnancy outcomes of our SLE patients over the past 3 years and reviewed the literature over the past 40 years. We extracted pregnancy loss and preterm delivery data from reports of postdiagnosis SLE pregnancies. Studies were grouped into 5-year periods and weighted according to sample size. Group means, calculated for each study period, were plotted using linear regression to determine significance, and compared with population norms for the same periods. RESULTS: The rate of loss in SLE pregnancies over the past 40 years decreased from a mean of 43% in 1960-1965 to 17% in 2000-2003 (r2 = 0.648). This approximates the pregnancy loss rate in the general US population. Preterm deliveries were not uniformly reported and were rarely stratified into spontaneous or physician-initiated. Prior to 1980, it was not possible to derive group means for each time period. From 1980 to 2002, however, there was a trend toward a decrease in preterm births in SLE pregnancies, although they continue to be more frequent in SLE than in the general population. CONCLUSION: Improvements in disease management and perinatal monitoring have resulted in a significant decrease in pregnancy loss in SLE over the last 40 years and a trend toward decreased preterm deliveries over the last 20 years in comparison to the general population. These advances highlight the importance of collaboration between rheumatologists and perinatologists. Given these data, the description of SLE-associated pregnancy could be revised to reflect a more positive prognosis for mother and fetus.

Antiphospholipid syndrome in systemic lupus erythematosus: is the whole greater than the sum of its parts?

This article compares the manifestations of systemic lupus erythematosus (SLE) in the presence and absence of antiphospholipid antibodies (aPLs), the hallmark autoantibodies of antiphospholipid syndrome (APS). The combination of SLE and APS appears to be of greater concern than either entity alone. APS complicates SLE by adding a vaso-occlusive factor to the inflammatory component that adversely affects the prognosis of those who have lupus and aPLs. The increase in both morbidity and mortality when both are present has significant therapeutic implications. Anticoagulation may be a safer and more appropriate therapeutic option than instituting a regimen of corticosteroids and immunosuppressive agents with all their attendant adverse effects. It falls upon the physician to clearly define the disease entity and fully evaluate the disease process.

Preterm deliveries in women with systemic lupus erythematosus.

OBJECTIVE: To compare the clinical, laboratory, and demographic variables of women in our clinic with systemic lupus erythematosus (SLE) who have had a pregnancy resulting in a live birth and identify any correlations with either term or preterm delivery. METHODS: Pregnancies in women with SLE from 1999 to 2001 were retrospectively reviewed. We recorded demographic data, disease activity (SLE Disease Activity Index, SLEDAI), obstetric history, prednisone dosage, other medications taken during pregnancy, history of renal disease, and autoantibody status [including antinuclear antibody, anti-DNA, anticardiolipin IgG (aCL), and lupus anticoagulant (LAC)]. Preterm delivery was defined as gestational age at delivery < 37 weeks. We performed a literature survey using PubMed and the key words SLE, pregnancy, and outcome. RESULTS: Of the 72 pregnancies, 28 (38.9%) resulted in preterm deliveries. There were no significant differences in any demographic or disease variables measured comparing term versus preterm delivery groups. More women in the preterm group were taking > or = 10 mg/day prednisone during their pregnancy (50.0% vs 22.2%; p = 0.028), and the mean dose was significantly higher than the term group taking > or = 10 mg/day (24.8 vs 16.7 mg/day; p = 0.047). There was a higher prevalence of women with aCL IgG in the preterm group (p = 0.023). The mean weeks gestation was shorter for women positive for aCL IgG compared to the group negative for aCL (34.9 +/- 4.4 vs 37.5 +/- 3.2 weeks, respectively; p = 0.032). There was no difference in second trimester disease activity between the term and preterm groups (33.3% and 36.4% of each group had a SLEDAI of 0). However, significantly more women in the term group received no medication during their pregnancies compared to women in the preterm group (20.0% vs 0.0%; p = 0.031). CONCLUSION: The rates of preterm deliveries, premature rupture of membranes, intrauterine growth restriction, and aPL in SLE pregnancies vary considerably in published reports, most of which are retrospective analyses. Our rates closely approximate the median values for all measures. We found preterm deliveries to be associated with disease activity (as determined by the use of any medication throughout pregnancy vs no medication, and prednisone dose > or = 10 mg/day) and the presence of aCL IgG but not LAC. Our results suggest that inactive disease rather than controlled disease at the onset of pregnancy may be the determining factor in extending SLE pregnancies to full term, thereby decreasing maternal and fetal morbidity.