A case-based narrative review of pregnancy-associated atypical hemolytic uremic syndrome/complement-mediated thrombotic microangiopathy.

Atypical hemolytic uremic syndrome is a complement-mediated thrombotic microangiopathy caused by uncontrolled activation of the alternative complement pathway in the setting of autoantibodies to or rare pathogenic genetic variants in complement proteins. Pregnancy may serve as a trigger and unmask atypical hemolytic uremic syndrome/complement-mediated thrombotic microangiopathy (aHUS/CM-TMA), which has severe, life-threatening consequences. It can be difficult to diagnose aHUS/CM-TMA in pregnancy due to overlapping clinical features with other thrombotic microangiopathy syndromes including hypertensive disorders of pregnancy. However, the distinction among thrombotic microangiopathy etiologies in pregnancy is important because each syndrome has specific disease management and treatment. In this narrative review, we discuss 2 cases to illustrate the diagnostic challenges and evolving approach in the management of pregnancy-associated aHUS/CM-TMA. The first case involves a 30-year-old woman presenting in the first trimester who was diagnosed with aHUS/CM-TMA and treated with eculizumab from 19 weeks' gestation. Genetic testing revealed a likely pathogenic variant in CFI. She successfully delivered a healthy infant at 30 weeks' gestation. In the second case, a 22-year-old woman developed severe postpartum HELLP syndrome, requiring hemodialysis. Her condition improved with supportive management, yet investigations assessing for aHUS/CM-TMA remained abnormal 6 months postpartum consistent with persistent complement activation but negative genetic testing. Through detailed case discussion describing tests assessing for placental health, fetal anatomy, complement activation, autoantibodies to complement regulatory proteins, and genetic testing for aHUS/CM-TMA, we describe how these results aided in the clinical diagnosis of pregnancy-associated aHUS/CM-TMA and assisted in guiding patient management, including the use of anticomplement therapy.

Pregnancy and Reproductive Risk Factors for Cardiovascular Disease in Women.

Beyond conventional risk factors for cardiovascular disease, women face an additional burden of sex-specific risk factors. Key stages of a woman's reproductive history may influence or reveal short- and long-term cardiometabolic and cardiovascular trajectories. Early and late menarche, polycystic ovary syndrome, infertility, adverse pregnancy outcomes (eg, hypertensive disorders of pregnancy, gestational diabetes, preterm delivery, and intrauterine growth restriction), and absence of breastfeeding are all associated with increased future cardiovascular disease risk. The menopause transition additionally represents a period of accelerated cardiovascular disease risk, with timing (eg, premature menopause), mechanism, and symptoms of menopause, as well as treatment of menopause symptoms, each contributing to this risk. Differences in conventional cardiovascular disease risk factors appear to explain some, but not all, of the observed associations between reproductive history and later-life cardiovascular disease; further research is needed to elucidate hormonal effects and unique sex-specific disease mechanisms. A history of reproductive risk factors represents an opportunity for comprehensive risk factor screening, refinement of cardiovascular disease risk assessment, and implementation of primordial and primary prevention to optimize long-term cardiometabolic health in women.

Assessing cardiovascular disease risk in women with a history of hypertensive disorders of pregnancy: A guidance paper for studies using administrative data.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) are a major cause of maternal morbidity and mortality, and their association with increased cardiovascular disease (CVD) risk represents a major public health concern. However, assessing CVD risk in women with a history of these conditions presents unique challenges, especially when studies are carried out using routinely collected data. OBJECTIVES: To summarise and describe key challenges related to the design and conduct of administrative studies assessing CVD risk in women with a history of HDP and provide concrete recommendations for addressing them in future research. METHODS: This is a methodological guidance paper. RESULTS: Several conceptual and methodological factors related to the data-generating mechanism and study conceptualisation, design/data management and analysis, as well as the interpretation and reporting of study findings should be considered and addressed when designing and carrying out administrative studies on this topic. Researchers should develop an a priori conceptual framework within which the research question is articulated, important study variables are identified and their interrelationships are carefully considered. CONCLUSIONS: To advance our understanding of CVD risk in women with a history of HDP, future studies should carefully consider and address the conceptual and methodological considerations outlined in this guidance paper. In highlighting these challenges, and providing specific recommendations for how to address them, our goal is to improve the quality of research carried out on this topic.

Antenatal glycemic management and postpartum cardiovascular disease risk screening.

OBJECTIVE: This study aims to evaluate the cardiovascular disease (CVD) risk profiles of patients referred to the maternal health clinic (MHC) with a history of gestational diabetes (GDM). METHODS: Eligible patients had their MHC appointment at 6 months postpartum between November 2011 and May 2022 and experienced GDM in their most recent pregnancy. Included participants were then divided into subgroups comparing methods of glycemic control: diet-controlled GDM and insulin-controlled GDM. Additionally, the MHC recruited 47 patients who have not experienced a complication in pregnancy to act as a comparator group in research studies. Demographics, medical and pregnancy history, and CVD risk scores were compared between the three groups. RESULTS: 344 patients with GDM were included in the analysis; 165 insulin-controlled and 179 diet-controlled. When measuring the median 30 year Framingham risk score based on both BMI and lipids, there was a significant stepwise increase seen from the unexposed group, the diet-controlled GDM, and the insulin-controlled groups, respectively (all P < 0.05). The presence of metabolic syndrome showed a stepwise increase in prevalence when comparing the unexposed group, diet exposure group, and the insulin exposure group, respectively (16.7%, 21.5%, 44.8%; P < 0.05). CONCLUSION: Our findings reinforce the prevalence of maternal CVD risk among GDM-diagnosed patients in the postpartum period and the necessity for screening. More specifically, our findings show how CVD risk may differ based on required interventions for glycemic control throughout pregnancy. Future research should aim to compare a more diverse patient population to optimize the generalizability of glycemic control-specific CVD outcomes.

Before and After Legalization: Cannabis Use Among Pregnant Patients at a Tertiary Care Centre in Ontario.

We compared levels of cannabis and other substance use before and after the legalization of cannabis in the obstetric population of the Kingston General Hospital (KGH). Urine samples were collected from patients admitted to KGH labour and delivery in September/October 2018 and September/October 2019. Urine was anonymously screened for cannabis and other substances. Approximately 9.5%-10% of patients screened positive for cannabis. We found no difference in the prevalence of cannabis use in our sample after legalization. Health care providers should discuss cannabis with patients who are pregnant or planning a pregnancy.

Knowledge and Use of Cannabis in Pregnancy: An Ontario Public Health Needs Assessment in Partnership with the Society of Obstetricians and Gynaecologists of Canada.

Studies show poor maternal and fetal outcomes associated with prenatal cannabis use. With the legalization of cannabis in Canada, it is of timely importance to increase awareness of the effects of its use in pregnancy. An anonymous, online questionnaire was used to assess the pregnant population's knowledge, beliefs, and risk perceptions concerning cannabis. Additionally, educational materials on the effects of prenatal cannabis use were evaluated. A potential knowledge gap was found among 9%-19% of participants, who reported that cannabis posed no risk of harm to the pregnant person or fetus. Moreover, minor changes could improve the effectiveness of educational resources.

Evaluation of a Postpartum Cardiovascular Risk Screening Clinic: An Analysis of Interpregnancy and Subsequent Pregnancy Outcomes.

OBJECTIVE: At the Maternal Health Clinic (MHC), women with certain pregnancy complications are seen for appointments focusing on lifestyle modification and future pregnancy counselling. This study's objective is to determine whether women who attended the MHC following a pregnancy complicated by gestational diabetes mellitus (GDM) or a hypertensive disorder of pregnancy (HDP) have improved interpregnancy and subsequent pregnancy outcomes, compared with non-attendees. METHODS: A retrospective cohort study was conducted including all pregnancies ≥20 weeks gestation at Kingston Health Sciences Centre (KHSC) from April 2010 to Dec 2019. Women with ≥2 deliveries were eligible for inclusion, with 2 pregnancies per woman included. These criteria identified 178 patients who attended the MHC and 133 who did not. Continuous variables with normal distribution were assessed with independent sample t tests. Continuous variables without normal distribution and ordinal variables were assessed with Mann-Whitney U tests. Categorical variables were assessed with Pearson's χ2 tests. Preterm delivery, HDP and GDM recurrence, HDP and GDM progression, and change in first-trimester blood pressure and pre-pregnancy weight were examined using multivariate regression modelling. Probability values <0.05 determined significance. RESULTS: MHC attendance was associated with improvements in interpregnancy weight reduction (P = 0.002), fewer interpregnancy type II diabetes diagnoses (P < 0.001), and a later gestational age at delivery (P < 0.001). There were no differences in subsequent pregnancy complication recurrence rates of GDM (P = 0.731) or an HDP (P = 0.139) between cohorts. CONCLUSION: In our examination of MHC outcomes, we found improvements in certain interpregnancy and subsequent pregnancy outcomes. These results support the continued development and funding of these clinics.

Guideline No. 426: Hypertensive Disorders of Pregnancy: Diagnosis, Prediction, Prevention, and Management.

OBJECTIVE: This guideline was developed by maternity care providers from obstetrics and internal medicine. It reviews the diagnosis, evaluation, and management of the hypertensive disorders of pregnancy (HDPs), the prediction and prevention of preeclampsia, and the postpartum care of women with a previous HDP. TARGET POPULATION: Pregnant women. BENEFITS, HARMS, AND COSTS: Implementation of the recommendations in these guidelines may reduce the incidence of the HDPs, particularly preeclampsia, and associated adverse outcomes. EVIDENCE: A comprehensive literature review was updated to December 2020, following the same methods as for previous Society of Obstetricians and Gynaecologists of Canada (SOGC) HDP guidelines, and references were restricted to English or French. To support recommendations for therapies, we prioritized randomized controlled trials and systematic reviews (if available), and evaluated substantive clinical outcomes for mothers and babies. VALIDATION METHODS: The authors agreed on the content and recommendations through consensus and responded to peer review by the SOGC Maternal Fetal Medicine Committee. The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, along with the option of designating a recommendation as a "good practice point." See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and conditional [weak] recommendations).The Board of the SOGC approved the final draft for publication. INTENDED USERS: All health care providers (obstetricians, family doctors, midwives, nurses, and anesthesiologists) who provide care to women before, during, or after pregnancy.

Directive clinique no 426 : Troubles hypertensifs de la grossesse : Diagnostic, prédiction, prévention et prise en charge.

OBJECTIF: La présente directive a été élaborée par des fournisseurs de soins de maternité en obstétrique et en médecine interne. Elle aborde le diagnostic, l'évaluation et la prise en charge des troubles hypertensifs de la grossesse, la prédiction et la prévention de la prééclampsie ainsi que les soins post-partum des femmes avec antécédent de trouble hypertensif de la grossesse. POPULATION CIBLE: Femmes enceintes. BéNéFICES, RISQUES ET COûTS: La mise en œuvre des recommandations de la présente directive devrait réduire l'incidence des troubles hypertensifs de la grossesse, en particulier la prééclampsie, et des issues défavorables associées. DONNéES PROBANTES: La revue exhaustive de la littérature a été mise à jour en tenant compte des nouvelles données probantes jusqu'en décembre 2020 et en suivant la même méthodologie que pour la précédente directive de la Société des obstétriciens et gynécologues du Canada (SOGC) sur les troubles hypertensifs de la grossesse. La recherche s'est limitée aux articles publiés en anglais ou en français. Les recommandations relatives aux traitements s'appuient d'abord sur les essais cliniques randomisés et les revues systématiques (lorsque disponibles), ainsi que sur l'évaluation des résultats cliniques substantiels chez les mères et les bébés. MéTHODES DE VALIDATION: Les auteurs se sont entendus sur le contenu et les recommandations par consensus et ont répondu à l'examen par les pairs du comité de médecine fœto-maternelle de la SOGC. Les auteurs ont évalué la qualité des données probantes et la force des recommandations en utilisant le cadre méthodologique d'évaluation, de développement et d'évaluation (GRADE) et se sont gardé l'option de désigner certaines recommandations par la mention « bonne pratique ¼. Voir l'annexe A en ligne (tableau A1 pour les définitions et tableau A2 pour l'interprétation des recommandations fortes et conditionnelles [faibles]). Le conseil d'administration de la SOGC a approuvé la version définitive aux fins de publication. PROFESSIONNELS CIBLES: Tous les fournisseurs de soins de santé (obstétriciens, médecins de famille, sages-femmes, infirmières et anesthésistes) qui prodiguent des soins aux femmes avant, pendant ou après la grossesse.

Maternal Cardiovascular Function Following a Pregnancy Complicated by Preeclampsia.

Preeclampsia is a hypertensive pregnancy complication with an unknown etiology and high maternal burden worldwide. Burgeoning research has linked preeclampsia to adverse maternal health outcomes remote from pregnancy; however, the intermediary mechanisms responsible for this association have not been sufficiently established. In the present narrative review, we summarize leading evidence of structural and functional cardiovascular changes associated with prior preeclampsia, and how these changes may be linked to future maternal disease. KEY POINTS: · Prior preeclampsia is associated with subclinical structural and functional vascular changes remote from pregnancy.. · Maternal cardiac adaptations to preeclampsia may have long-term implications on cardiovascular health.. · Clinicians have an opportunity to minimize maternal disease risk following preeclampsia..

Postpartum microvascular functional alterations following severe preeclampsia.

Preeclampsia is associated with adverse maternal health outcomes later in life. Vascular endothelial dysfunction has been previously described following preeclampsia. We hypothesized that microvascular endothelial dysfunction associated with preeclampsia persists postpartum and may identify those at greatest risk of future cardiovascular disease. The objective of this study was to examine postpartum microvascular endothelial function in women after a pregnancy complicated by preeclampsia. Women with previous preeclampsia (n = 30) and normotensive controls (n = 30) between 6 mo and 5 yr postpartum were recruited. Severity of preeclampsia [severe (n = 16) and mild (n = 14)] was determined by standardized chart review. Microvascular reactivity in the forearm was measured with laser speckle contrast imaging, coupled with iontophoresis; endothelium-dependent and endothelium-independent vasodilation was induced with 1% acetylcholine and sodium nitroprusside solutions, respectively. A postocclusive reactive hyperemia test assessed vasodilatory response following three minutes of suprasystolic (200 mmHg) occlusion with a mechanized cuff. Women with prior severe preeclampsia exhibited significantly higher vasodilation to acetylcholine and sodium nitroprusside compared to controls (P < 0.01; P = 0.03) and prior mild preeclampsia (P = 0.03; P < 0.01). Neither the degree of postocclusive reactive hyperemia (P = 0.98), nor time to return halfway to baseline [OR = 1.026 (0.612, 1.72); P = 0.92], differed between preeclampsia and controls. In conclusion, severe preeclampsia is associated with heightened postpartum microvascular endothelium-dependent and endothelium-independent vasoreactivity. These changes, or a common antecedent, may be linked to postpartum alterations in vascular function that predispose women to disease after preeclampsia. Further investigation should identify the contributing mechanism and the degree to which it could be amenable to medical intervention.NEW & NOTEWORTHY We examine maternal microvascular function after preeclampsia, identifying heightened endothelium-dependent and endothelium-independent microvascular reactivity following severe disease. Our study represents a noteworthy addition to the existing literature with the use of a novel imaging modality, vascular perturbation, postpartum time point, and patient population with differentiation of preeclampsia into severe and nonsevere subtypes. These results represent a novel addition to the growing clinical and academic understanding of maternal health outcomes following preeclampsia.

Caesarean section in pregnancies conceived by assisted reproductive technology: a systematic review and meta-analysis.

BACKGROUND: Caesarean section rates are higher among pregnancies conceived by assisted reproductive technology (ART) compared to spontaneous conceptions (SC), implying an increase in neonatal and maternal morbidity. We aimed to compare caesarean section rates in ART pregnancies versus SC, overall, by indication (elective versus emergent), and by type of ART treatment (in-vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), fresh embryo transfer, frozen embryo transfer) in a systematic review and meta-analysis. METHODS: We searched Medline, EMBASE and CINAHL databases using the OVID Platform from 1993 to 2019, and the search was completed in January 2020. The eligibility criteria were cohort studies with singleton conceptions after in-vitro fertilization and/or intracytoplasmic sperm injection using autologous oocytes versus spontaneous conceptions. The study quality was assessed using the Newcastle Ottawa Scale and GRADE approach. Meta-analyses were performed using odds ratios (OR) with a 95% confidence interval (CI) using random effect models in RevMan 5.3, and I-squared (I2) test > 75% was considered as high heterogeneity. RESULTS: One thousand seven hundred fifty studies were identified from the search of which 34 met the inclusion criteria. Compared to spontaneous conceptions, IVF/ICSI pregnancies were associated with a 1.90-fold increase of odds of caesarean section (95% CI 1.76, 2.06). When stratified by indication, IVF/ICSI pregnancies were associated with a 1.91-fold increase of odds of elective caesarean section (95% CI 1.37, 2.67) and 1.38-fold increase of odds of emergent caesarean section (95% CI 1.09, 1.75). The heterogeneity of the studies was high and the GRADE assessment moderate to low, which can be explained by the observational design of the included studies. CONCLUSIONS: The odds of delivering by caesarean section are greater for ART singleton pregnancies compared to spontaneous conceptions. Preconception and pregnancy care plans should focus on minimizing the risks that may lead to emergency caesarean sections and finding strategies to understand and decrease the rate of elective caesarean sections.

Family History of Hypertension, Cardiovascular Disease, or Diabetes and Risk of Developing Preeclampsia: A Systematic Review.

Preeclampsia is a severe pregnancy complication with high potential for adverse effects on maternal and fetal health during the perinatal period. It is also associated with an increased risk of maternal cardiovascular disease later in life. Development of preeclampsia can be decreased by prescribing low-dose aspirin to high-risk women. At present, maternal and pregnancy factors are used to assess the risk of preeclampsia. One additional factor that could add to the assessment of risk is a family history of hypertension, cardiovascular disease, or diabetes, especially for nulliparous women who do not have a pregnancy history to inform treatment decisions. Therefore, we conducted a systematic review to assess the association between family history of the aforementioned conditions and preeclampsia. Four databases including MEDLINE, EMBASE, the Cochrane Library, and CINAHL/pre-CINAHL were searched for observational studies that examined a family history of hypertension, cardiovascular disease, or diabetes in women with preeclampsia and in a control population. Studies were evaluated for quality using the Newcastle-Ottawa Scale. A total of 84 relevant studies were identified. A meta-analysis was not conducted due to suspected heterogeneity in the included studies. Most studies reported a positive association between a family history of hypertension or cardiovascular disease and the development of preeclampsia. The majority of studies examining family history of diabetes reported non-significant associations. Overall, family history of hypertension or cardiovascular disease is associated with a higher risk for developing preeclampsia and should be considered when assessing women in the first trimester for low-dose aspirin.

Standardized Postpartum Follow-Up for Women with Pregnancy Complications: Barriers to Access and Perceptions of Maternal Cardiovascular Risk.

OBJECTIVE: Certain obstetrical complications are known to increase a woman's risk of future cardiovascular disease (CVD). The Maternal Health Clinic (MHC) provides postpartum cardiovascular risk counselling and follow-up; however, half of women referred do not attend. This study aimed to identify barriers to access, as well as whether attendance at the MHC improved the accuracy of patients' CVD risk perception. METHODS: MHC patients completed a CVD risk perception questionnaire prior to being assessed and 3 months after their appointment ("attendees"). Calculated lifetime CVD risk scores were compared with perceived risk to assess accuracy of risk perception. Patients who did not attend their MHC appointment ("non-attendees") were administered the questionnaire by phone and asked about perceived barriers to access. RESULTS: Sixty-seven of 137 eligible attendees (48.9%) completed both the pre- and post-MHC questionnaires. Significantly more participants accurately estimated their absolute CVD risk after their MHC appointment, although the majority continued to underestimate their risk. Among non-attendees, 81 of 130 women (62.3%) completed the questionnaire. The most common barriers to access cited were being too busy with childcare, accessing follow-up with the patient's family doctor instead, and difficulty attending their appointment. CONCLUSION: Lack of time and inconvenience were two common barriers to accessing the MHC. Improved collaboration with primary care providers and use of telemedicine may help to mitigate these issues. Both attendees and non-attendees appeared to have an inadequate perception of CVD risk. Standardized postpartum CVD risk screening and counselling may be an effective method of providing these women with risk education and improving the accuracy of their risk perception.

Cardiovascular Risk Screening and Pregnancy Complications: A Comparison of Two Canadian Maternal Health Clinic Populations.

OBJECTIVE: This study compared pregnancy-related cardiovascular disease risk indicators between women who attended 2 different postpartum screening and education clinics: 1 at an urban tertiary care centre and 1 at a northern, rural community hospital. Risk differences associated with ethnicity were also examined. METHODS: We conducted a retrospective record review that compared data from an urban clinic in Kingston, Ontario (n = 675) with those from a rural clinic in Prince Rupert, British Columbia (n = 65). Patients who had a hypertensive disorder of pregnancy, gestational diabetes, intrauterine growth restriction, idiopathic preterm birth, or placental abruption attended the clinics at 6 months postpartum. Demographic information, personal and family history, physical examination findings, and laboratory results were collected and used to generate cardiovascular risk estimates using validated scoring systems. These estimates were compared between clinic populations and between ethnic subsets. RESULTS: Fifty-five percent of the Prince Rupert cohort were Indigenous, while 87% of the Kingston cohort were White (P < 0.001). A greater proportion of the Kingston cohort had experienced hypertensive disorders of pregnancy (P = 0.002), while a greater proportion of the Prince Rupert cohort had developed gestational diabetes (P=0.010). The Prince Rupert population had higher lifetime and 30-year cardiovascular disease risk scores (P = 0.008 and P = 0.005, respectively). Indigenous patients had more major cardiovascular risk factors as well as higher lifetime and 30-year cardiovascular risk scores (P = 0.001 and P = 0.008, respectively) than White and Asian patients. CONCLUSION: The increased cardiovascular disease risk in both rural and Indigenous women supports the need for better postpartum care, long-term follow-up, and early promotion of cardiovascular health in these populations.

Cardiovascular Disease-Related Morbidity and Mortality in Women With a History of Pregnancy Complications.

BACKGROUND: Women with a history of certain pregnancy complications are at higher risk for cardiovascular (CVD) disease. However, most clinical guidelines only recommend postpartum follow-up of those with a history of preeclampsia, gestational diabetes mellitus, or preterm birth. This systematic review was undertaken to determine if there is an association between a broader array of pregnancy complications and the future risk of CVD. METHODS: We systematically searched PubMed, MEDLINE and EMBASE (via Ovid), CINAHL, and the Cochrane Library from inception to September 22, 2017, for observational studies of the association between the hypertensive disorders of pregnancy, placental abruption, preterm birth, gestational diabetes mellitus, low birth weight, small-for-gestational-age birth, stillbirth, and miscarriage and subsequent CVD. Likelihood ratio meta-analyses were performed to generate pooled odds ratios (OR) and 95% intrinsic confidence intervals (ICI). RESULTS: Our systematic review included 84 studies (28 993 438 patients). Sample sizes varied from 250 to 2 000 000, with a median follow-up of 7.5 years postpartum. The risk of CVD was highest in women with gestational hypertension (OR 1.7; 95% ICI, 1.3-2.2), preeclampsia (OR 2.7; 95% ICI, 2.5-3.0), placental abruption (OR 1.8; 95% ICI, 1.4-2.3), preterm birth (OR 1.6; 95% ICI, 1.4-1.9), gestational diabetes mellitus (OR 1.7; 95% ICI, 1.1-2.5), and stillbirth (OR 1.5; 95% ICI, 1.1-2.1). A consistent trend was seen for low birth weight and small-for-gestational-age birth weight but not for miscarriage. CONCLUSIONS: Women with a broader array of pregnancy complications, including placental abruption and stillbirth, are at increased risk of future CVD. The findings support the need for assessment and risk factor management beyond the postpartum period.

Carbon monoxide increases utero-placental angiogenesis without impacting pregnancy specific adaptations in mice.

BACKGROUND: Cigarette smokers have a reduced risk of developing preeclampsia, possibly attributed to an increase in carbon monoxide (CO) levels. Carbon monoxide is a gasotransmitter that has been implicated in maintaining vascular tone, increasing angiogenesis, and reducing inflammation and apoptosis at physiological concentrations. Moderately increasing CO concentrations may have therapeutic potential to prevent or treat preeclampsia; however, the effects of CO on pregnancy are under studied. Our objective was to investigate the effect of CO on major angiogenic and inflammatory markers in pregnancy, and to evaluate the effect of CO on indicators of placental health. FINDINGS: Pregnant CD-1 mice were constantly exposed to either ambient air or 250 ppm CO from conception until gestation day (GD)10.5 or GD16.5. Using a qRT-PCR array, we identified that CO increased expression of major angiogenic genes at the implantation site on GD10.5, but not GD16.5. Pro-inflammatory cytokines in the plasma and tissue lysates from implantation sites in treated mice were not significantly different compared to controls. Additionally, CO did not alter the implantation site phenotype, in terms of proliferative capacity, invasiveness of trophoblasts, or abundance of uterine natural killer cells. CONCLUSIONS: This study suggests that CO exposure is pro-angiogenic at the maternal-fetal interface, and is not associated with demonstrable concerns during murine pregnancy. Future studies are required to validate safety and efficacy of CO as a potential therapeutic for vascular insufficiency diseases such as preeclampsia and intrauterine growth restriction.

Riboflavin and pyrroloquinoline quinone generate carbon monoxide in the presence of tissue microsomes or recombinant human cytochrome P-450 oxidoreductase: implications for possible roles in gasotransmission.

Carbon monoxide (CO), an endogenously produced gasotransmitter, regulates inflammation and vascular tone, suggesting that delivery of CO may be therapeutically useful for pathologies like preeclampsia where CO insufficiency is implicated. Our strategy is to identify chemicals that increase the activity of endogenous CO-producing enzymes, including cytochrome P-450 oxidoreductase (CPR). Realizing that both riboflavin and pyrroloquinoline quinone (PQQ) are relatively nontoxic, even at high doses, and that they share chemical properties with toxic CO activators that we previously identified, our goal was to determine whether riboflavin or PQQ could stimulate CO production. Riboflavin and PQQ were incubated in sealed vessels with rat and human tissue extracts and CO generation was measured with headspace-gas chromatography. Riboflavin and PQQ increased CO production ∼60% in rat spleen microsomes. In rat brain microsomes, riboflavin and PQQ increased respective CO production approximately fourfold and twofold compared to baseline. CO production by human placenta microsomes increased fourfold with riboflavin and fivefold with PQQ. In the presence of recombinant human CPR, CO production was threefold greater with PQQ than with riboflavin. These observations demonstrate for the first time that riboflavin and PQQ facilitate tissue-specific CO production with significant contributions from CPR. We propose a novel biochemical role for these nutrients in gastransmission.

The determinants of maternal homocysteine in pregnancy: findings from the Ottawa and Kingston Birth Cohort.

OBJECTIVE: Observational studies have linked elevated homocysteine to vascular conditions. Folate intake has been associated with lower homocysteine concentration, although randomised controlled trials of folic acid supplementation to decrease the incidence of vascular conditions have been inconclusive. We investigated determinants of maternal homocysteine during pregnancy, particularly in a folic acid-fortified population. DESIGN: Data were from the Ottawa and Kingston Birth Cohort of 8085 participants. We used multivariable regression analyses to identify factors associated with maternal homocysteine, adjusted for gestational age at bloodwork. Continuous factors were modelled using restricted cubic splines. A subgroup analysis examined the modifying effect of MTHFR 677C>T genotype on folate, in determining homocysteine concentration. SETTING: Participants were recruited in Ottawa and Kingston, Canada, from 2002 to 2009. PARTICIPANTS: Women were recruited when presenting for prenatal care in the early second trimester. RESULTS: In 7587 participants, factors significantly associated with higher homocysteine concentration were nulliparous, smoking and chronic hypertension, while factors significantly associated with lower homocysteine concentration were non-Caucasian race, history of a placenta-mediated complication and folic acid supplementation. Maternal age and BMI demonstrated U-shaped associations. Folic acid supplementation of >1 mg/d during pregnancy did not substantially increase folate concentration. In the subgroup analysis, MTHFR 677C>T modified the effect of folate status on homocysteine concentration. CONCLUSIONS: We identified determinants of maternal homocysteine relevant to the lowering of homocysteine in the post-folic acid fortification era, characterised by folate-replete populations. A focus on periconceptional folic acid supplementation and improving health status may form an effective approach to lower homocysteine.

Committee Opinion No. 399: Management of Tick Bites and Lyme Disease During Pregnancy.

OBJECTIVE: Lyme disease is an emerging infection in Canada caused by the bacterium belonging to the Borrelia burgdorferi sensu lato species complex, which is transmitted via the bite of an infected blacklegged tick. Populations of blacklegged ticks continue to expand and are now established in different regions in Canada. It usually takes more than 24 hours of tick attachment to transfer B. burgdorferi to a human. The diagnosis of early localized Lyme disease is made by clinical assessment, as laboratory tests are not reliable at this stage. Most patients with early localized Lyme disease will present with a skin lesion (i.e., erythema migrans) expanding from the tick bite site and/or non-specific "influenza-like" symptoms (e.g., arthralgia, myalgia, and fever). Signs and symptoms may occur from between 3 and 30 days following the tick bite. The care of pregnant patients with a tick bite or suspected Lyme disease should be managed similarly to non-pregnant adults, including the consideration of antibiotics for prophylaxis and treatment. The primary objective of this committee opinion is to inform practitioners about Lyme disease and provide an approach to managing the care of pregnant women who may have been infected via a blacklegged tick bite. INTENDED USERS: Health care providers who care for pregnant women or women of reproductive age. TARGET POPULATION: Women of reproductive age. EVIDENCE: In November 2018, Medline, EMBASE, PubMed, and CENTRAL databases were searched for 2 main categories: (1) Lyme disease and (2) other tick-borne diseases. Because the main focus was Lyme disease, and considering the limited number of the articles, no further filters were applied for publication time or type of study. For other tick-borne diseases, the results were restricted to a publication date within the last 10 years (2008-2018). The search terms were developed using MeSH terms and keywords including Lyme Disease, Pregnancy, Pregnant Women, Pregnancy Complications, Ehrlichiosis, Anaplasmosis, Rocky Mountain Spotted Fever, Babesiosis, Tularemia, Powassan Virus, Encephalitis Viruses, Tick-Borne, Tick-Borne Diseases, Colorado Tick Fever, Q Fever, Relapsing Fever, and Southern Tick-Associated Rash Illness. All articles on Lyme disease and other tick-borne diseases with a target population of pregnant women were included; other groups and populations were excluded. VALIDATION METHODS: The content and recommendations of this committee opinion were drafted and agreed upon by the authors. The Board of Directors of the Society of Obstetricians and Gynaecologists of Canada approved the final draft for publication.