Positive Airway Pressure Treatment of Obstructive Sleep Apnea-Hypopnea in Hypertensive Disorders of Pregnancy: A Pilot Randomized Proof-of-Concept Clinical Trial.

Rationale: Maternal obstructive sleep apnea-hypopnea (OSAH) is associated with hypertensive disorders of pregnancy (HDP). OSAH treatment with positive airway pressure (PAP) in the general population lowers blood pressure (BP). However, there are limited data on the effects of PAP therapy in maternal OSAH. Objectives: Our primary objective was to assess the feasibility of recruitment to a pilot randomized trial and adherence to PAP therapy for OSAH in women with HDP. Secondary objectives included assessment of PAP effects on 24-h BP, arterial stiffness, and maternal and fetal outcomes. Methods: Women with singleton pregnancies at ⩾12 weeks' gestation and hypertension underwent home level 2 polysomnography; those with mild to moderate OSAH (apnea-hypopnea index ⩾ 5 events/h; women with severe OSAH with apnea-hypopnea index > 30 events/h and oxygen desaturation index > 30 were excluded) were randomized to either PAP or nasal dilator strip (NDS; control) therapy. After PAP education, adherence was monitored online with episodic phone or in-person support by research personnel. Twenty-four-hour BP and arterial stiffness were assessed at baseline and before delivery. Maternal and fetal outcomes were also recorded. Results: Of 105 potentially eligible participants, 67 agreed to undergo screening for OSAH over 38 months; 48 women meeting OSAH inclusion criteria were randomized to PAP (n = 27) or NDS (n = 21) therapy. Of these, 14 PAP (52%) and 13 NDS (62%) participants completed all predelivery measurements, with lack of completion due to urgent delivery (19% in the PAP group, 14% in the NDS group), PAP intolerance at initiation (19%), or other factors. Mean PAP use was 3.1 ± 2.5 h/night, with use ⩾4 h/night on 38.4 ± 33.7% of nights during 9.6 ± 4.0 weeks of treatment. BP was controlled within the target range in most participants. There were no differences in mean change in 24-hour BP or arterial stiffness measurements or in adverse maternal and fetal outcomes between the PAP and NDS groups in either intention-to-treat or per-protocol analyses. Conclusions: PAP adherence was suboptimal in this HDP cohort despite education and troubleshooting. Further work is required to identify optimal OSAH treatment strategies during pregnancy. Clinical trial registered with www.clinicaltrials.gov (NCT03309826).

A retrospective study comparing postoperative opioid prescribing practices in an academic medical centre.

Background: In the midst of the North American opioid crisis, identifying and intervening on drivers of high-risk opioid prescriptions is an important step towards reducing iatrogenic harm. Objectives: We aimed to identify factors associated with variations in high-risk opioid discharge prescriptions, following select surgical procedures, to guide future quality improvement initiatives. Methods: This retrospective cohort study analyzed 1322 patients who underwent select open pelvic and open abdominal surgeries between January 1 and December 31, 2017, in a tertiary health care centre in Montreal. Results: Patients who underwent open abdominal surgeries were prescribed significantly higher daily doses of morphine milligram equivalents (MME) (45 mg; interquartile range, 30-60), than patients who underwent either a caesarean delivery (20 mg, 20-20) or a hysterectomy (30 mg, 22-30). After adjustment for multiple potential confounders, abdominal surgery was associated with 4 times the odds of receiving more than 50 MME at hospital discharge compared with pelvic surgeries (odds ratio, 3.96; 95% confidence interval, 1.31-11.97). The availability of postoperative preprinted order sets with fixed high doses of opioids was also highly associated with the outcome. Conclusion: In our institution, some surgeries were more likely to receive high-risk opioid prescriptions at discharge. Efforts to optimize safer prescribing practices should address the creation and/or updating of preprinted order sets to reflect current best practice guidelines. This initiative could be overseen by hospital pharmacy and therapeutics committees.

Attention-deficit hyperactivity disorder in children born to mothers with infertility: a population-based cohort study.

STUDY QUESTION: Is the risk of attention-deficit hyperactivity disorder (ADHD) increased in children born to mothers with infertility, or after receipt of fertility treatment, compared to mothers with unassisted conception? SUMMARY ANSWER: Infertility itself may be associated with ADHD in the offspring, which is not amplified by the use of fertility treatment. WHAT IS KNOWN ALREADY: Infertility, and use of fertility treatment, is common. The long-term neurodevelopmental outcome of a child born to a mother with infertility, including the risk of ADHD, remains unclear. STUDY DESIGN, SIZE, DURATION: This population-based cohort study comprised all singleton and multiple hospital births in Ontario, Canada, 2006-2014. Outcomes were assessed up to June 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Linked administrative datasets were used to capture all hospital births in Ontario, maternal health and pregnancy measures, fertility treatment and child outcomes. Included were all children born at ≥24 weeks gestation between 2006 and 2014, and who were alive at age 4 years. The main exposure was mode of conception, namely (i) unassisted conception (reference group), (ii) infertility without fertility treatment (history of an infertility consultation with a physician within 2 years prior to conception but no fertility treatment), (iii) ovulation induction (OI) or intrauterine insemination (IUI) and (iv) IVF or intracytoplasmic sperm injection (ICSI). The main outcome was a diagnosis of ADHD after age 4 years and assessed up to June 2020. Hazard ratios (HRs) were adjusted for maternal age, income quintile, rurality, immigration status, smoking, obesity, parity, any drug or alcohol use, maternal history of mental illness including ADHD, pre-pregnancy diabetes mellitus or chronic hypertension and infant sex. In addition, we performed pre-planned stratified analyses by mode of delivery (vaginal or caesarean delivery), infant sex, multiplicity (singleton or multiple), timing of birth (term or preterm <37 weeks) and neonatal adverse morbidity (absent or present). MAIN RESULTS AND THE ROLE OF CHANCE: The study included 925 488 children born to 663 144 mothers, of whom 805 748 (87%) were from an unassisted conception, 94 206 (10.2%) followed infertility but no fertility treatment, 11 777 (1.3%) followed OI/IUI and 13 757 (1.5%) followed IVF/ICSI. Starting at age 4 years, children were followed for a median (interquartile range) of 6 (4-8) years. ADHD occurred among 7.0% of offspring in the unassisted conception group, 7.5% in the infertility without fertility treatment group, 6.8% in the OI/IUI group and 6.3% in the IVF/ICSI group. The incidence rate (per 1000 person-years) of ADHD was 12.0 among children in the unassisted conception group, 12.8 in the infertility without fertility treatment group, 12.9 in the OI/IUI group and 12.2 in the IVF/ICSI group. Relative to the unassisted conception group, the adjusted HR for ADHD was 1.19 (95% CI 1.16-1.22) in the infertility without fertility treatment group, 1.09 (95% CI 1.01-1.17) in the OI/IUI group and 1.12 (95% CI 1.04-1.20) in the IVF/ICSI group. In the stratified analyses, these patterns of risk for ADHD were largely preserved. An exception was seen in the sex-stratified analyses, wherein females had lower absolute rates of ADHD but relatively higher HRs compared with that seen among males. LIMITATIONS, REASONS FOR CAUTION: Some mothers in the isolated infertility group may have received undocumented OI oral therapy, thereby leading to possible misclassification of their exposure status. Parenting behaviour, schooling and paternal mental health measures were not known, leading to potential residual confounding. WIDER IMPLICATIONS OF THE FINDINGS: Infertility, even without treatment, is a modest risk factor for the development of ADHD in childhood. The reason underlying this finding warrants further study. STUDY FUNDING/COMPETING INTEREST(S): This study was made possible with funding from the Canadian Institutes of Health Research, Grant number PJT 165840. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Risk of Severe Maternal Morbidity After Bariatric Surgery: Retrospective Cohort Study.

OBJECTIVE: We assessed whether bariatric surgery before pregnancy lowers the risk of severe maternal morbidity to a level comparable to no obesity. SUMMARY OF BACKGROUND DATA: Obesity is a risk factor for severe maternal morbidity, but the potential for bariatric surgery to reduce the risk has not been studied. METHODS: We analyzed a retrospective cohort of 2,412,075 deliveries between 1989 and 2019 in Quebec, Canada. The main exposure measures were bariatric surgery before pregnancy and obesity without bariatric surgery, compared with no obesity. The outcome was severe maternal morbidity, a composite of life-threatening pregnancy complications. We estimated risk ratios (RR) and 95% confidence intervals (CI) for the association between bariatric surgery and severe maternal morbidity, adjusted for maternal characteristics. RESULTS: A total of 2654 deliveries (0.1%) were in women who had bariatric surgery, and 70,041 (29.0 per 1000) were in women who had severe maternal morbidity. Risk of severe maternal morbidity was not significantly elevated for bariatric surgery (RR 1.20; 95% CI 0.98-1.46), but was greater for obesity compared with no obesity (RR 1.60; 95% CI 1.55-1.64). Bariatric surgery was not associated with morbidities such as severe preeclampsia, sepsis, and cardiac complications compared with no obesity, but obesity was associated with elevated risks of these and other severe morbidities. Bariatric surgery was associated, however, with intensive care unit admission, compared with no obesity. CONCLUSIONS: Pregnant women with prior bariatric surgery have similar risks as nonobese women for most types of severe maternal morbidity, except for intensive care unit admission.

Pregnancy-associated pelvic vein thrombosis: Insights from a multicenter case series.

BACKGROUND: Pelvic vein thrombosis (PVT) is a rare complication of pregnancy that can lead to life-threatening complications, such as pulmonary embolism (PE). OBJECTIVE: To describe characteristics of PVT and its treatment in pregnancy in the province of Quebec, Canada. PATIENTS/METHODS: We developed a province-wide case series of PVT in pregnancy including four tertiary care centers and the Registry of Rare Diseases of the Groupe d'Étude en Médecine Obstétricale du Québec. Using diagnostic codes, we included cases with confirmed PVT on imaging during pregnancy or within 6 weeks postpartum from July 2003 to June 2018. RESULTS: A total of 47 cases were identified. PVT diagnosis was generally made in the early postpartum period (median of 9 [interquartile range (IQR) 4.5-12] days postpartum). Most PVT (94%) included in this series were symptomatic. Women presented primarily with abdominal pain (77%) and fever (55%), often prolonged despite antibiotics (mean 4.45 ± 2.39 days, with 39% having fever for more than 5 days). The most common risk factor was surgery (57%) and peripartum infections (54%). Thirty-eight (83%) women received antibiotics and 41 (89%) were anticoagulated. Three cases of PE (7%) occurred concomitantly, 11% of women required intensive care, and 19% had inferior vena cava (IVC) clot extension. The episode resulted in prolonged hospitalization (median 6 [IQR 3-10.75] days), with 48% being hospitalized more than 7 days. CONCLUSION: Symptomatic PVT has significant clinical implications with prolonged fever and risks of extension in the IVC and PE, leading to prolonged hospitalization including in the intensive care unit. Therapeutic anticoagulation and antibiotics, when infection is documented, should be considered for management.

Diagnosing Pulmonary Embolism in Pregnancy: Synthesis of Current Guidelines and New Evidence.

Pulmonary embolism (PE) complicates 5.4 per 10 000 pregnancies and remains a significant cause of maternal mortality. Prompt diagnosis and treatment of PE are key to ensuring optimal outcomes, but are not without risks associated with over-testing. Given the paucity of evidence informing PE diagnosis in pregnancy, marked heterogeneity exists among different societies in their recommendations. Here we provide an overview of existing recommendations and novel evidence informing the diagnosis of PE in pregnancy, including the use of d-dimers, the choice of diagnostic imaging modality, and the potential for breast cancer risk among women exposed to ionizing radiation from computed tomography pulmonary angiography (CTPA).

Circulating MicroRNAs Implicate Multiple Atherogenic Abnormalities in the Long-Term Cardiovascular Sequelae of Preeclampsia.

BACKGROUND: Women who have had preeclampsia (PE) are at increased risk for premature cardiovascular disease (CVD). The underlying pathophysiology of this risk remains unclear, but potentially involves subclinical vascular damage or dysfunction. Alterations in the levels of circulating microRNAs may be implicated, as they are known to play pervasive roles in vascular biology. We investigated whether levels of circulating microRNAs are altered between women with premature acute coronary syndrome (ACS), with and without a history of PE. METHODS: Women with premature ACS (age ≤ 55 years) were categorized based on a prior history of PE or normotensive pregnancy. Relative plasma levels of 372 microRNAs were initially assessed by polymerase chain reaction array in a subset of subjects (n = 12-13/group) matched for age, chronic hypertension, dyslipidemia, and smoking status. Candidate microRNAs were then validated in a larger cohort of ACS patients (n = 176). RESULTS: MicroRNAs previously linked to angiogenesis (miR-126-3p), inflammation (miR-146a-5p), and cholesterol metabolism (miR-122-5p) were significantly decreased in women with prior PE compared to women with prior normotensive pregnancy (P = 0.002, 0.017, and 0.009, respectively), even after adjustment for chronic hypertension. CONCLUSIONS: Circulating levels of miR-126-3p, -146a-5p, and -122-5p were significantly decreased in women with premature ACS who reported prior PE compared to those with prior normotensive pregnancy. These data provide novel insight into potential pathways that may contribute to the increased risk of CVD following PE.

Prevalence of Severe Maternal Morbidity and Factors Associated With Maternal Mortality in Ontario, Canada.

Importance: Severe maternal morbidity is defined by potentially life-threatening conditions. The association between the number of severe maternal morbidity (SMM) indicators and maternal death is not known. Objective: To quantify the association between the number of SMM indicators and maternal mortality. Design, Setting, and Participants: This population-based cohort study used provincial databases for data on all live birth and stillbirth hospital deliveries among women in Ontario, Canada, from April 1, 2002, to February 18, 2017. Excluded from this cohort were those with invalid identification number, non-Ontario residency, maternal age younger than 10 years or older than 55 years or unknown, or gestational age fewer than 20 weeks or unknown as well as any out-of-hospital births, ectopic pregnancies, or spontaneous or induced abortions. Exposures: Number of SMM indicators identified between 20 weeks' gestation and 42 days after the index delivery. Main Outcomes and Measures: Maternal death occurring from delivery to 42 days after the index delivery. Results: Of the 1 953 943 total births among 1 211 396 women, 181 maternal deaths occurred within 42 days after birth, a rate of 9.3 per 100 000 births. Of the 181 women who died, 123 (68.0%) had at least 1 SMM indicator compared with 1.7% (33 152) of women who survived. Standardized differences suggested that women who died, compared with the women who lived, were older (mean [SD] age, 31.0 [6.2] years vs 30.1 [5.5] years; standardized difference, 0.15) and more likely to reside in a lower-income area (99 [54.7%] vs 832 231 [42.6%]; standardized difference, 0.24), be nulliparous (93 [51.4%] vs 880 386 [45.1%]; standardized difference, 0.13), and be of Afro-Caribbean origin (12 [6.6%] vs 64 948 [3.3%]; standardized difference, 0.15). The most frequent SMM indicators were intensive care unit admission (81 [44.8%]), invasive ventilation (77 [42.5%]), cardiac conditions (69 [38.1%]), complications of obstetric surgery or procedures (32 [17.7%]), and postpartum hemorrhage with blood transfusion (31 [17.1%]). The rate of maternal mortality increased exponentially with the number of SMM indicators: 0 indicators (3.0 per 100 000 births), 1 (71.7 per 100 000 births), 2 (385.9 per 100 000 births), 3 (1274.2 per 100 000 births), 4 (2236.8 per 100 000 births), 5 (4285.7 per 100 000 births), and 6 or more (9422.5 per 100 000 births). Adjusted relative risks for maternal death ranged from 20.1 (95% CI, 11.6-34.7) with 1 SMM indicator to 2192.0 (95% CI, 1287.0-3735.0) with 6 or more SMM indicators compared with 0 indicators. Conclusions and Relevance: Maternal death may be associated with the number of SMM indicators and occur in certain identifiable groups of women; targeting preventable SMM indicators or limiting their progression may reduce the number of maternal deaths.

Markers of Vascular Dysfunction After Hypertensive Disorders of Pregnancy: A Systematic Review and Meta-Analysis.

Women with prior hypertensive disorders of pregnancy (HDP) are at twice the risk of cardiovascular disease compared with women with prior normotensive pregnancy, possibly because of sustained vascular dysfunction after delivery. The aim of this systematic review and meta-analysis is to summarize evidence of vascular dysfunction at least 3 months after HDP. Articles in all languages were retrieved from principal databases. Studies included were observational, with HDP as the main exposure and measurements of vascular dysfunction via imaging modalities or serum biomarkers as the main outcome, assessed at least 3 months postpartum. We pooled results of modalities reported in >3 studies using a random effects model. Of 6109 potentially relevant studies, 72 were included that evaluated 10 imaging modalities and 11 serum biomarkers in 8702 women. There was evidence of vascular dysfunction in women post HDP compared with women with prior normal pregnancy when measured by carotid-femoral pulse wave velocity (0.64 m/s [0.17-1.11]), carotid intima-media thickness (0.025 mm [0.004-0.045]), and augmentation index (5.48% [1.58-9.37]), as well as mean levels of soluble fms-like tyrosine kinase (6.12 pg/mL [1.91-10.33]). Between-groups differences in measures of vascular dysfunction were more pronounced when assessments were performed in younger women (<40 years) or closer to the index pregnancy for almost all modalities. In conclusion, pooled data from studies evaluating vascular imaging suggest that some vascular dysfunction persists after HDP as compared with women with prior normal pregnancy.

Health services costs and their determinants in women with fibromyalgia.

OBJECTIVE: Patients with fibromyalgia (FM) use health services extensively. Knowledge about costs of FM is limited because of non-inclusiveness in assessing direct costs, because attempts to assess indirect costs are largely absent, and because determinants of costs have yet to be identified. We investigated the 6-month costs (direct and indirect) in women with primary FM, and we identified determinants of direct costs. METHODS: Subjects (n = 180 women) completed a health resource questionnaire as well as measures of pain, psychological distress, comorbidity, and disability. Unit costs for resources were obtained from government, hospital, laboratory, and professional association sources. Regression modeling for 6-month direct cost included age, disability, comorbidity, pain intensity, psychological distress, education, and work status. RESULTS: The average 6-month direct cost was $CDN 2298 (SD 2303). The largest components were medications ($CDN 758; SD 654), complementary and alternative medicine (CAM; $CDN 398; SD 776), and diagnostic tests ($CDN 356; SD 580). Our most conservative estimate of average 6-month indirect cost was $CDN 5035 (SD 7439). Comorbidity and FM disability were statistically significant contributors to direct costs in the multivariate analysis. Costs increased by approximately 20% with each additional comorbid condition. CONCLUSION: Women with FM are high consumers of both conventional and CAM services. Our estimates of costs exceed those from most other studies; this may be due to our inclusion of a broader set of health services, medications, and indirect costs. Although in univariate analyses the number of comorbidities and indices of the effect of FM, psychological distress, and pain intensity were associated with higher direct cost, in a multiple regression analysis, only the measure of FM disability and the number of comorbidities were significant direct-cost determinants. FM also imposes important indirect costs, which were nearly 70% of the economic burden.