L'infertilité affecte 11-15 % des Canadiennes et 8-20 % des couples ont de la difficulté à concevoir spontanément. Par conséquent, le recours à la procréation médicalement assistée (PMA) ne cesse d'augmenter, cependant la controverse demeure quant à ses risques sur la santé maternelle et celle des enfants. La PMA comprend les techniques de procréation assistée (TRA) (fécondation in vitro [FIV], insémination intra-utérine [IIU]) et les stimulateurs ovariens (SO), avec plus de 5 millions d'enfants issu d’une FIV au monde. La PMA a précédemment été associée à un risque accru d’issues adverses de grossesse incluant l’hypertension gestationnelle, les saignements utérins ainsi que les issues adverses affectant la santé de l’enfant, notamment les grossesses multiples, la prématurité, et le faible poids à la naissance sur lesquelles nous allons nous concentrer dans cette thèse de doctorat. Entre 05/08/2010-15/11/2015, le Québec fut la 1ère province Canadienne à financer un programme de remboursement universel pour la PMA, visant à augmenter le taux de natalité au Québec et réduire les grossesses multiples et leurs dépenses de santé associées en implémentant le transfert d'embryon unique. Le programme a été interrompu en 2015 dû aux dépenses de santé plus élevées que prévu. Nous avons identifié plusieurs lacunes de connaissances, que nous avons cherché à combler dans ce programme doctoral. Premièrement, aucun registre n’a été mis en place pour évaluer l'impact du programme sur les mères et les enfants. Deuxièmement, les études se concentrent sur les TRA ou combinent toutes les méthodes non-FIV, ce qui a des implications cliniques limitées. Les SO sont sous-analysées mais ont des implications cliniques importantes car ils constituent un traitement de première ligne pour l'infertilité. Enfin, les grossesses singleton sont moins évaluées alors qu’il est devenu évident qu'elles comportent des risques périnataux cliniquement importants. Cette thèse de doctorat est composée d'une revue de la littérature publiée et de trois études épidémiologiques effectuées dans la Cohorte des Grossesses du Québec (CQG). L'étude 1 quantifie les variations des tendances trimestrielles des issues obstétricales et périnatales 5 ans avant et pendant le programme québécois, et quantifie le risque de multiplicité associé au programme et à la PMA dans l’ensemble et par sous-types (SO seuls, TRA seuls, SO/TRA combinés) pendant ses années actives. Nous avons aussi étudié le rôle des grossesses multiples comme modificateur d'effet dans l'association entre la PMA et la prématurité. Entre 2005-2015, nous avons observé une augmentation de la prévalence de multiplicité par un facteur de 10. Les grossesses multiples ont augmenté significativement pendant le programme (rapport de cotes ajusté [RCa] 6,09, intervalle de confiance à 95 % [IC95%] 5,23-7,09) par rapport aux 5 ans avant. La PMA a significativement augmenté le risque de multiplicité (RCa 4,65, IC95% 3,84-5,62) par rapport à la conception spontanée. Les SO seuls augmentaient le plus le risque de multiplicité (RCa 6,28, IC95 % 4,56-8,64) par rapport à la conception spontanée. L’étude 2 quantifie le risque de prématurité associé à la PMA dans l'ensemble et par sous-type parmi les grossesses singleton survenues pendant le programme et dans une cohorte restreinte de grossesses PMA pour évaluer l'impact d’un biais d'indication (l’infertilité ou la sous-fertilité) potentiel. La PMA dans l’ensemble (RCa 1,46, IC95 % 1,25-1,72) et par sous-types : OS seul (RCa 1,47, IC95% 1,04-2,07), TRA seul (RCa 1,76, IC95% 1,01-3,06) et SO/TRA combinés (RCa 1,43, IC95% 1,19-1,73) étaient associées à un risque accru de prématurité par rapport à la conception spontanée. Enfin, l’étude 3 quantifie le risque de naitre petit/très petit pour l'âge gestationnel associé à la PMA dans l’ensemble et par sous-types. Connaissant l'association PMA/prématurité, nous avons aussi évalué le rôle de la prématurité comme modificateur d'effet dans l'association entre PMA et le fait de naitre petit ou très petit pour l'âge gestationnel. Bien qu'aucune association n'ait été observée entre la PMA et le fait de naitre petit ou très petit pour l'âge gestationnel, la PMA était associée à un risque accru de naitre petit ou très petit pour l'âge gestationnel (RCa 1,69, IC95 % 1,08-2,66) chez les prématurés spécifiquement. Nos résultats démontrent une augmentation significative des grossesses multiples pendant le programme, au-delà des seuils visés. Les SO seuls augmentent particulièrement les grossesses multiples, une technique de PMA ne pouvant être contrôlée par le transfert d’embryon unique. La PMA augmente le risque de prématurité, en particulier chez les singletons. Nos résultats confirment en outre qu’elle augmente également le risque de naitre petit pour l’âge gestationnel, en particulier chez singletons prématurés. / Infertility affects 11-15% of Canadian women, while 8-20% of couples report having difficulties conceiving spontaneously. As such, the use of medically assisted reproduction (MAR) has steadily increased, however controversy remains with regards to its risks on the health of mothers and children. MAR includes assisted reproductive technology (ART) (i.e. in vitro fertilization [IVF], intrauterine insemination [IUI]) and ovarian stimulators (OS), with over 5 million children born through IVF alone worldwide. MARs have previously been associated with an increased risk of adverse pregnancy outcomes including gestational hypertension, uterine bleeding as well as adverse child health outcomes including multiplicity, prematurity, and low birth weight. Perinatal outcomes will be the focus in this doctoral thesis. Between 05/08/2010-15/11/2015, Quebec was the first Canadian province to fund a universal MAR reimbursement program, which aimed to reduce multiplicity and associated health expenditures with the practice of single embryo transfers in the context of IVF and increase Quebec’s birth rate. The program was halted in 2015 following a higher than expected healthcare expenditure. We identified several knowledge gaps, which we have aimed to fill through this doctoral program. First, no database exists to assess the impact of Quebec’s universal MAR program on mothers and children. Second, evidence focuses on ART or combine all non-IVF (e.g. OS) methods together, which has limited clinical implications. OS are under analysed but carry clinical implications as they are a first line therapy for infertility. Lastly, singleton pregnancies are not always evaluated when it has become evident that they carry clinically relevant perinatal risks. This doctoral thesis is composed of a published literature review as well as three epidemiological studies conducted within the Quebec Pregnancy Cohort (QPC). Study 1 aimed to quantify the changes in quarterly trends of obstetrical and perinatal outcomes 5 years before and during the universal program in Quebec through an interrupted time series analysis, as well as quantify the risk of multiplicity in association with the program itself and MAR conceptions specifically during the active program years. In this first study we also aimed to evaluate the role of multiplicity as an effect modifier in the association between MAR conception and prematurity. Between 2005-2015, we observed a 10-fold increase in multiplicity. Multiplicity increased by 6-fold during the program (adjusted odds ratio [aOR] 6.09, 95% confidence interval [CI] 5.23-7.09) compared to 5 years prior. MAR significantly increased the risk of multiplicity by 4.7-fold (aOR 4.65, 95%CI 3.84-5.62) compared to spontaneous conception. OS alone increased the risk of multiplicity the most (aOR 6.28, 95%CI 4.56-8.64) compared to spontaneous conception. In Study 2, we quantified the risk of prematurity associated with MAR conceptions overall and by subtype (eg. OS alone, ART alone, OS/ART combined) among singleton pregnancies occurring during the program as well as in a restricted cohort of MAR-exposed pregnancies to evaluate the impact of indication (infertility/subfertility) bias. MAR conception was associated with an increased prematurity risk (aOR 1.46, 95%CI 1.25-1.72). All MAR types were associated with increased prematurity risk when compared to spontaneous conception: OS alone (aOR 1.47, 95%CI 1.04-2.07), ART alone (aOR 1.76, 95%CI 1.01-3.06), and OS/ART combined (aOR 1.43, 95%CI 1.19-1.73). Lastly, in Study 3, we aimed to quantify the risk of being born small/very small for gestational age (SGA, VSGA) associated with MAR overall and by subtype. In this study, knowing the MAR/prematurity association, we assessed the role of prematurity as an effect modifier in the association between MAR and SGA/VSGA. While no association was observed between MAR and SGA/VSGA, MAR was associated with an increased SGA risk (aOR 1.69, 95%CI 1.08-2.66) among preterms. Our findings show a significant increase of multiplicity during the program years, well above the thresholds targeted by the program administrators. OS alone particularly increases multiplicity the most, an MAR technique that cannot be controlled through single embryo transfer. MARs increase the risk of preterm, particularly among singleton pregnancies. Our results further confirm that they also increase the risk of SGA, specifically among preterm singleton pregnancies.

Indiana University-Purdue University Indianapolis (IUPUI) / Methamphetamine (MA) is a widely abused psychostimulant that has been shown to evoke an array of neurobiological abnormalities and cognitive deficits in humans and in rodent models (Marshall & O'Dell, 2012). Alterations in cognitive function after repeated drug use may lead to impaired decision-making, a lack of behavioral control, and ultimately the inability to abstain from drug use. Human studies have shown that alterations in neurobiology resulting from prolonged MA use may lead to a number of cognitive deficits, including impairments in executive function, learning, memory, and impulsivity. These impairments, specifically those that engage the prefrontal cortex (PFC) or hippocampus (HC), may persist or recover based on the duration of abstinence. In rodents, repeated intermittent injections of MA yield protracted changes in neurobiology and behavior, which have been shown to effectively model a number of the biological and cognitive abnormalities observed in addiction. In order to assess the temporal evolution of impaired cognitive function throughout abstinence, sensitization was first induced in rats (7 x 5.0 mg/kg MA over 14 days). MA-treated rats initially exhibited a robust increase in locomotion that transitioned to stereotypy as the induction phase progressed. Then, the effects of MA sensitization on social interaction (SI), temporal order recognition (TOR) and novel object recognition (NOR) was assessed at one-day and 30-days post induction. No differences were observed in SI in either group or after a single injection of MA. However, an acute injection of 5.0 mg/kg of MA 30-minutes prior to testing dramatically reduced SI time. Impairments in TOR and NOR were observed in MA-treated rats after one day of abstinence, and impairments in TOR, but not NOR, were observed on day 30 of abstinence. No differences in TOR and NOR after a single injection of MA or saline were observed. These data establish that after 30 days of abstinence from a sensitizing regimen of MA, the ability to recall the temporal sequence that two stimuli were encountered was impaired and that was not attributable to impaired novelty detection. These data also suggest that at least some of the neurocognitive abnormalities caused by chronic MA administration may normalize after prolonged abstinence, since the ability to detect novelty recovered after 30 days of abstinence. These data provide compelling support that, since MA-sensitization caused temporal deficits in memory, PFC and HC function may be differentially impaired throughout the time course of abstinence.