Howard Berger

Screening for gestational diabetes mellitus

Gestational diabetes mellitus is associated with increased risk of complications for mother and child. Along with the growing epidemic of obesity and type 2 diabetes, the prevalence of gestational diabetes is expected to rise. With adequate and timely treatment, the risk of complications is reduced. Detection of gestational diabetes however is complicated, since often there are no symptoms. Currently no uniform strategy for detection of gestational diabetes exists. This thesis aims to evaluate costs and effects of various screening strategies in order to obtain a uniform (cost-)effective strategy for detection of gestational diabetes.

Substance Use in Pregnancy

OBJECTIVE To improve awareness and knowledge of problematic substance use in pregnancy and to provide evidence-based recommendations for the management of this challenging clinical issue for all health care providers. OPTIONS This guideline reviews the use of screening tools, general approach to care, and recommendations for clinical management of problematic substance use in pregnancy. OUTCOMES Evidence-based recommendations for screening and management of problematic substance use during pregnancy and lactation. EVIDENCE Medline, PubMed, CINAHL, and The Cochrane Library were searched for articles published from 1950 using the following key words: substance-related disorders, mass screening, pregnancy complications, pregnancy, prenatal care, cocaine, cannabis, methadone, opioid, tobacco, nicotine, solvents, hallucinogens, and amphetamines. Results were initially restricted to systematic reviews and randomized control trials/controlled clinical trials. A subsequent search for observational studies was also conducted because there are few RCTs in this field of study. Articles were restricted to human studies published in English. Additional articles were located by hand searching through article reference lists. Searches were updated on a regular basis and incorporated in the guideline up to December 2009. Grey (unpublished) literature was also identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on the Preventive Health Care. Recommendations for practice were ranked according to the method described in that report (Table 1). BENEFITS, HARMS, AND COSTS This guideline is intended to increase the knowledge and comfort level of health care providers caring for pregnant women who have substance use disorders. Improved access to health care and assistance with appropriate addiction care leads to reduced health care costs and decreased maternal and neonatal morbidity and mortality. RECOMMENDATIONS 1. All pregnant women and women of childbearing age should be screened periodically for alcohol, tobacco, and prescription and illicit drug use. (III-A) 2. When testing for substance use is clinically indicated, urine drug screening is the preferred method. (II-2A) Informed consent should be obtained from the woman before maternal drug toxicology testing is ordered. (III-B) 3. Policies and legal requirements with respect to drug testing of newborns may vary by jurisdiction, and caregivers should be familiar with the regulations in their region. (III-A) 4. Health care providers should employ a flexible approach to the care of women who have substance use problems, and they should encourage the use of all available community resources. (II-2B) 5. Women should be counselled about the risks of periconception, antepartum, and postpartum drug use. (III-B) 6. Smoking cessation counselling should be considered as a first-line intervention for pregnant smokers. (I-A) Nicotine replacement therapy and/or pharmacotherapy can be considered if counselling is not successful. (I-A) 7. Methadone maintenance treatment should be standard of care for opioid-dependent women during pregnancy. (II-IA) Other slow-release opioid preparations may be considered if methadone is not available. (II-2B) 8. Opioid detoxification should be reserved for selected women because of the high risk of relapse to opioids. (II-2B) 9. Opiate-dependent women should be informed that neonates exposed to heroin, prescription opioids, methadone, or buprenorphine during pregnancy are monitored closely for symptoms and signs of neonatal withdrawal (neonatal abstinence syndrome). (II-2B) Hospitals providing obstetric care should develop a protocol for assessment and management of neonates exposed to opiates during pregnancy. (III-B) 10. Antenatal planning for intrapartum and postpartum analgesia may be offered for all women in consultation with appropriate health care providers. (III-B) 11. The risks and benefits of breastfeeding should be weighed on an individual basis because methadone maintenance therapy is not a contraindication to breastfeeding. (II-3B).

CYP2D6 polymorphisms and codeine analgesia in postpartum pain management: a pilot study.

Background: Codeine, a common opiate prescribed for pain postcesarean section (c-section), is biotransformed by the highly polymorphic Cytochrome P450 enzyme 2D6 (CYP2D6). Ultrarapid metabolizers (UMs), individuals with multiple active copies of CYP2D6, can biotranform up to 50% more codeine into morphine than normal individuals can. In contrast, poor metabolizers (PMs), individuals who have no active CYP2D6 genes, convert almost no codeine into morphine and as a result may take multiple doses of codeine without attaining analgesia. Objective: The aim was to study the relationship between CYP2D6 genotype and codeine analgesia among women recovering from c-section. Methods: Forty-five mothers prescribed codeine provided a blood sample for CYP2D6 genotyping and recorded their pain level 4 times a day for 3 days immediately after a c-section. Codeine was used on an as-needed basis; doses and times were recorded. The relationship between CYP2D6 genotype, pain scores, need for codeine, and adverse events was studied. Theoretical morphine dose, based on CYP2D6 genotype, was estimated. Results: Women at the genotypic extremes reported codeine effects consistent with their genotype: the 2 PMs of codeine reported no analgesia as a result of taking codeine, whereas 2 of the 3 UMs reported immediate pain relief from codeine but stopped taking it due to dizziness and constipation. Much larger numbers are needed to study similar correlations among extensive and intermediate metabolizers. Conclusions: In this pilot study, the extreme CYP2D6 genotypes (PMs and UMs) seemed to predict pain response and adverse events. Larger sample sizes are needed to correlate the range of genotypes with pain response.

High concentrations of folate and unmetabolized folic acid in a cohort of pregnant Canadian women and umbilical cord blood

BACKGROUND Mandatory fortification, prevalent supplement use, and public health guidelines recommending periconceptional supplementation have increased folic acid intakes in North American pregnant women. However, the effects of increased folic acid intakes during pregnancy on maternal and cord blood folate concentrations have not been well established. OBJECTIVES In this prospective study, we determined maternal and cord blood concentrations of folate and unmetabolized folic acid (UMFA) in a cohort of pregnant Canadian women and their newborns and examined the effect of maternal intakes of folate and folic acid and fetal genetic variants in folate metabolism on folate status. DESIGN Folate and folic acid intakes of 368 Canadian pregnant women were assessed in early (0-16 wk) and late (23-37 wk) pregnancy. Blood concentrations of folate and UMFA were measured with the use of immunoassays and liquid chromatography-mass spectrometry, respectively, in maternal samples in early pregnancy (12-16 wk), at delivery (28-42 wk), and in cord blood. Four fetal genetic variants of the 5,10-methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase (DHFR) genes were assessed for their association with cord blood concentrations of folate and UMFA. RESULTS Geometric mean (95% CI) maternal red blood cell (RBC) folate concentrations were 2417 nmol/L (2362, 2472 nmol/L ) and 2793 nmol/L (2721, 2867 nmol/L ) in early pregnancy and at delivery, respectively. The mean (95% CI) cord RBC folate concentration was 2689 nmol/L (2614, 2765 nmol/L). UMFA was detectable in >90% of maternal and cord plasma samples. Although 3 fetal MTHFR and DHFR genetic variants had no effect, the fetal MTHFR 677TT genotype was associated with significantly lower cord serum (P = 0.03) and higher cord RBC (P = 0.02) folate concentrations than those of the wild type. CONCLUSIONS Notwithstanding differences in assays, maternal and cord RBC folate and plasma UMFA concentrations were higher than previously reported values. Functional ramifications of high folate and UMFA concentrations in maternal and fetal circulation warrant additional investigation because an excess folate status may affect long-term health outcomes of the offspring. This study was registered at www.clinicaltrials.gov as NCT02244684.

Transfer of dabigatran and dabigatran etexilate mesylate across the dually perfused human placenta.

OBJECTIVE: To assess the transplacental pharmacokinetics at term of the oral thrombin inhibitor, dabigatran, and its prodrug, dabigatran etexilate mesylate, to estimate fetal drug exposure. METHODS: Placentae were obtained with informed consent after cesarean delivery of healthy term pregnancies in Toronto, Ontario, Canada. The transplacental transfer of dabigatran and dabigatran etexilate mesylate was separately assessed using the ex vivo dual perfusion of an isolated human placental cotyledon. Dabigatran, at a concentration of 35 ng/mL, was added to the maternal circulation at the start of the experimental phase. Maternal and fetal samples were taken throughout the preexperimental (1 hour) and experimental (3 hours) phases for measurement of dabigatran and markers of placental viability. Separate placenta perfusions with dabigatran etexilate mesylate were conducted at an initial maternal concentration of 3.5 ng/mL. Dabigatran and dabigatran etexilate mesylate were measured using liquid chromatography–tandem mass spectrometry. RESULTS: There was slower transfer of dabigatran compared with antipyrine from the maternal-to-fetal circulation, because the median fetal-to-maternal concentration ratio was 0.33 (interquartile range 0.29–0.38) after 3 hours (n=3). The prodrug, dabigatran etexilate mesylate, had limited placental transfer as characterized by a fetal-to-maternal ratio of 0.17 (interquartile range 0.15–0.17) after 3 hours (n=3). Placental viability markers for all perfusions were within normal ranges. CONCLUSION: This report provides direct evidence of the transfer of dabigatran and its prodrug across the term human placenta from the mother to the fetus. From a clinical perspective, these data suggest that, pending further study, dabigatran should not be used for anticoagulation of pregnant women, because the drug may have an adverse effect on fetal blood coagulation.

A Clinical Tool for Reducing Central Nervous System Depression among Neonates Exposed to Codeine through Breast Milk

Background Neonates are commonly exposed to maternal codeine through breast milk. Central Nervous System (CNS) depression has been reported in up to 24% of nurslings following codeine exposure. In 2009, we developed guidelines to improve the safety of codeine use during breastfeeding based on previously established pharmacogenetic and clinical risk factors. The primary objective of this study was to prospectively evaluate the effectiveness of these guidelines in ensuring neonatal safety. Methods and Findings Women taking codeine for pain following caesarean section were given safety guidelines, including advice to use the lowest codeine dose for no longer than four days and to switch to a non-opioid when possible. Mothers provided a saliva sample for analysis of genes involved in opioid disposition, metabolism and response. A total of 238 consenting women participated. Neonatal sedation was reported in 2.1% (5/238) of breastfeeding women taking codeine according to our safety guidelines. This rate was eight fold lower than that reported in previous prospective studies. Women reporting sedated infants were taking codeine for a significantly longer period of time (4.80±2.59 days vs. 2.52±1.58 days, p = 0.0018). While following the codeine safety guidelines, mothers were less likely to supplement with formula, reported lower rates of sedation in themselves and breastfed more frequently throughout the day when compared to previously reported rates. Genotyping analysis of cytochrome p450 2D6 (CYP2D6), uridine-diphosphate glucuronosyltransferase (UGT) 2B7, p-glycoprotein (ABCB1), the mu-opioid receptor (OPRM1) and catechol-o-demethyltransferase (COMT) did not predict codeine response in breastfeeding mother/infant pairs when following the safety guidelines. Conclusions The only cases of CNS depression occurred when the length of codeine use exceeded the guideline recommendations. Neonatal safety of codeine can be improved using evidence-based guidelines, even in those deemed by genetics to be at high risk for toxicity.

Pregnant Canadian Women Achieve Recommended Intakes of One-Carbon Nutrients through Prenatal Supplementation but the Supplement Composition, Including Choline, Requires Reconsideration

BACKGROUND Folate, vitamin B-6, vitamin B-12, and choline are involved in one-carbon metabolism and play critical roles in pregnancy including prevention of birth defects and promotion of neurodevelopment. However, excessive intakes may adversely affect disease susceptibility in offspring. Intakes of these nutrients during pregnancy are not well characterized. OBJECTIVE Our aim was to determine dietary and supplemental intakes and major dietary sources of one-carbon nutrients during pregnancy. METHODS In pregnant women (n = 368) at ≤16 wk postconception, supplement use >30 d before pregnancy was assessed by maternal recall and supplement and dietary intakes in early (0-16 wk) and late pregnancy (23-37 wk) were assessed by food-frequency questionnaire. RESULTS Preconception, 60.1% (95% CI: 55.8, 64.3) of women used B vitamin-containing supplements. This increased to 92.8% (95% CI: 89.6, 95.2) in early and 89.0% (95% CI: 85.0, 92.3) in late pregnancy. Median supplemental folic acid, vitamin B-12, and vitamin B-6 were 1000 μg/d, 2.6 μg/d, and 1.9 mg/d, respectively. Forty-one percent and 50% of women had dietary intakes of folate and vitamin B-6 less than the estimated average requirement (520 mg/d dietary folate equivalents and 1.6 mg/d, respectively). Eight-seven percent of women had choline intakes less than the Adequate Intake (450 mg/d). Dietary intakes did not change appreciably during pregnancy. Fruits and vegetables and fortified foods contributed ∼57% to total dietary folate intake. Fruits and vegetables contributed ∼32% to total dietary vitamin B-6 intake and dairy and egg products contributed ∼37% to total dietary vitamin B-12 intake. CONCLUSIONS Vitamin supplements were an important source of one-carbon nutrients during pregnancy in our sample. Without supplements, many women would not have consumed quantities of folate and vitamin B-6 consistent with recommendations. Given the importance of choline in pregnancy, further research to consider inclusion in prenatal supplements is warranted. This trial was registered at clinicaltrials.gov as NCT02244684.

Risk of adverse outcomes among infants of immigrant women according to birth-weight curves tailored to maternal world region of origin

Background: Infants of immigrant women in Western nations generally have lower birth weights than infants of native-born women. Whether this difference is physiologic or pathological is unclear. We determined whether the use of birth-weight curves tailored to maternal world region of origin would discriminate adverse neonatal and obstetric outcomes more accurately than a single birth-weight curve based on infants of Canadian-born women. Methods: We performed a retrospective cohort study of in-hospital singleton live births (328 387 to immigrant women, 761 260 to nonimmigrant women) in Ontario between 2002 and 2012 using population health services data linked to the national immigration database. We classified infants as small for gestational age (< 10th percentile) or large for gestational age (≥ 90th percentile) using both Canadian and world region–specific birth-weight curves and compared associations with adverse neonatal and obstetric outcomes. Results: Compared with world region–specific birth-weight curves, the Canadian curve classified 20 431 (6.2%) additional newborns of immigrant women as small for gestational age, of whom 15 467 (75.7%) were of East or South Asian descent. The odds of neonatal death were lower among small-for-gestational-age infants of immigrant women than among those of nonimmigrant women based on the Canadian birth-weight curve (adjusted odds ratio [OR] 0.83, 95% confidence interval [CI] 0.72–0.95), but higher when small for gestational age was defined by the world region–specific curves (adjusted OR 1.24, 95% CI 1.08–1.42). Conversely, the odds of some adverse outcomes were lower among large-for-gestational-age infants of immigrant women than among those of nonimmigrant women based on world region–specific birth-weight curves, but were similar based on the Canadian curve. Interpretation: World region–specific birth-weight curves seemed to be more appropriate than a single Canadian population-based curve for assessing the risk of adverse neonatal and obstetric outcomes among small- and large-for-gestational-age infants born to immigrant women, especially those from the East and South Asian regions.

Congenital megalourethra: prenatal diagnosis and postnatal/autopsy findings in 10 cases

Congenital megalourethra is a rare urogenital malformation characterized by dilation and elongation of the penile urethra associated with absence or hypoplasia of the corpora spongiosa and cavernosa. Postnatal complications include voiding and erectile dysfunction as well as renal insufficiency and pulmonary hypoplasia. To date, only a few prenatally diagnosed cases have been reported. We report on 10 cases diagnosed prenatally and their postnatal/autopsy findings.

Maternal and neonatal separation and mortality associated with concurrent admissions to intensive care units

Background: Concurrent admission of a mother and her newborn to separate intensive care units (herein referred to as co-ICU admission), possibly in different centres, can magnify family discord and stress. We examined the prevalence and predictors of mother–infant separation and mortality associated with co-ICU admissions. Methods: We completed a population-based study of all 1 023 978 singleton live births in Ontario between Apr. 1, 2002, and Mar. 31, 2010. We included data for maternal–infant pairs that had co-ICU admission (n = 1216), maternal ICU admission only (n = 897), neonatal ICU (NICU) admission only (n = 123 236) or no ICU admission (n = 898 629). The primary outcome measure was mother–infant separation because of interfacility transfer. Results: The prevalence of co-ICU admissions was 1.2 per 1000 live births and was higher than maternal ICU admissions (0.9 per 1000). Maternal–newborn separation due to interfacility transfer was 30.8 (95% confidence interval [CI] 26.9–35.3) times more common in the co-ICU group than in the no-ICU group and exceeded the prevalence in the maternal ICU group and NICU group. Short-term infant mortality (< 28 days after birth) was higher in the co-ICU group (18.1 per 1000 live births; maternal age–adjusted hazard ratio [HR] 27.8, 95% CI 18.2–42.6) than in the NICU group (7.6 per 1000; age-adjusted HR 11.5, 95% CI 10.4–12.7), relative to 0.7 per 1000 in the no-ICU group. Short-term maternal mortality (< 42 days after delivery) was also higher in the co-ICU group (15.6 per 1000; age-adjusted HR 328.7, 95% CI 191.2–565.2) than in the maternal ICU group (6.7 per 1000; age-adjusted HR 140.0, 95% CI 59.5–329.2) or the NICU group (0.2 per 1000; age-adjusted HR 4.6, 95% CI 2.8–7.4). Interpretation: Mother–infant pairs in the co-ICU group had the highest prevalence of separation due to interfacility transfer and the highest mortality compared with those in the maternal ICU and NICU groups.