Birth Prevalence of Neural Tube Defects and Orofacial Clefts in India: A Systematic Review and Meta-Analysis

Background

In the last two decades, India has witnessed a substantial decrease in infant mortality attributed to infectious disease and malnutrition. However, the mortality attributed to birth defects remains constant. Studies on the prevalence of birth defects such as neural tube defects and orofacial clefts in India have reported inconsistent results. Therefore, we conducted a systematic review of observational studies to document the birth prevalence of neural tube defects and orofacial clefts.

Methods

A comprehensive literature search for observational studies was conducted in MEDLINE and EMBASE databases using key MeSH terms (neural tube defects OR cleft lip OR cleft palate AND Prevalence AND India). Two reviewers independently reviewed the retrieved studies, and studies satisfying the eligibility were included. The quality of included studies was assessed using selected criteria from STROBE statement.

Results

The overall pooled birth prevalence (random effect) of neural tube defects in India is 4.5 per 1000 total births (95% CI 4.2 to 4.9). The overall pooled birth prevalence (random effect) of orofacial clefts is 1.3 per 1000 total births (95% CI 1.1 to 1.5). Subgroup analyses were performed by region, time period, consanguinity, and gender of newborn.

Conclusion

The overall prevalence of neural tube defects from India is high compared to other regions of the world, while that of orofacial clefts is similar to other countries. The majority of studies included in the review were hospital based. The quality of these studies ranged from low to moderate. Further well-designed, high quality community-based observational studies are needed to accurately estimate the burden of neural tube defects and orofacial clefts in India.     

Maternal Snuff Use and Smoking and the Risk of Oral Cleft Malformations - A Population-Based Cohort Study

Objective

To determine if maternal use of snuff (containing high levels of nicotine, low levels of nitrosamines and no combustion products) is associated with an increased risk of oral cleft malformations in the infant and whether cessation of snuff use or smoking before the antenatal booking influences the risk.

Method

A population-based cohort study was conducted on all live born infants, recorded in the Swedish Medical Birth Register from 1999 through 2009 (n = 1 086 213). Risks of oral clefts were evaluated by multivariate logistic regression analyses (using adjusted odds ratios, with 95% confidence intervals [CI]).

Results

Among 975 866 infants that had information on maternal tobacco use, 1761 cases of oral clefts were diagnosed. More than 50% of the mothers who used snuff or smoked three months prior pregnancy stopped using before the antenatal booking. Almost 8% of the mothers were smoking at the antenatal booking and 1,1% of the mothers used snuff. Compared with infants of non-tobacco users, the adjusted odds ratios (95% CI) of any oral cleft for infants of mothers who continued to use snuff or to smoke were 1.48 [1.00–2.21] and 1.19 [1.01–1.41], respectively. In contrast, in infants of mothers who stopped using snuff or stopped smoking before the antenatal booking, the corresponding risks were not increased (adjusted odds ratios [95% CI] were 0.71 [0.44–1.14] and 0.88 [0.73–1.05], respectively).

Conclusion

Maternal snuff use or smoking in early pregnancy is associated with an increased risk of oral clefts. Infants of mothers who stopped using snuff or stopped smoking before the antenatal booking had no increased risk of oral cleft malformations. Oral snuff or other sources of nicotine should not be recommended as an alternative for smoke-cessation during pregnancy.     

Sex ratios among Canadian liveborn infants of mothers from different countries

Background:

There has been much discussion about whether female feticide occurs in certain immigrant groups in Canada. We examined data on live births in Ontario and compared sex ratios in different groups according to the mother’s country or region of birth and parity.

Methods:

We completed a population-based study of 766 688 singleton live births between 2002 and 2007. We used birth records provided by Ontario Vital Statistics for live births in the province between 23 and 41 weeks’ gestation. We categorized each newborn according to the mother’s country or region of birth, namely Canada (n = 486 599), Europe (n = 58 505), South Korea (n = 3663), China (n = 23 818), Philippines (n = 15 367), rest of East Asia (n = 18 971), Pakistan (n = 18 018), India (n = 31 978), rest of South Asia (n = 20 695) and other countries (n = 89 074). We calculated male:female ratios and 95% confidence intervals (CIs) for all live births by these regions and stratified them by maternal parity at the time of delivery (0, 1, 2 or ≥ 3).

Results:

Among infants of nulliparous women, the male:female ratio was about 1.05 overall. As parity increased, the ratio remained unchanged among infants of Canadian-born women. In contrast, the male:female ratio was significantly higher among infants of primiparous women born in South Korea (1.20, 95% CI 1.09–1.34) and India (1.11, 95% CI 1.07–1.15) than among infants of Canadian-born primiparous women. Among multiparous women, those born in India were significantly more likely than Canadian-born women to have a male infant (parity 2, ratio 1.36, 95% CI 1.27–1.46; parity ≥ 3, ratio 1.25, 95% CI 1.09–1.43).

Interpretation:

Our study of male:female ratios in Ontario showed that multiparous women born in India were significantly more likely than multiparous women born in Canada to have a male infant.Although there are some myths about correctly guessing the sex of a fetus,¹ modern-day prenatal ultrasound enables the identification of whether a fetus is a boy or girl with 99% accuracy.² There has been much discussion about whether female fetuses are at higher risk of pregnancy termination than male fetuses in certain ethnic groups. In India, a study of data from the National Family Health Survey for 265 516 births showed a sharp increase in the male:female ratio among second-order births when the firstborn was a girl, and no significant increase when the firstborn was a boy.³ The authors attributed this trend to the practice of selective abortion of female fetuses. A recent editorial⁴ and news item⁵ in CMAJ suggested that female feticide may also be occurring in Canada.⁶ Rather than using live-birth statistics, the Canadian study cited in CMAJ used data from the 2001 and 2006 Canada Census long-form questionnaires, which were completed by 20% of the population and relied on self-reporting of additional information, including the number of family members in a given household.We used contemporary data on live births in Ontario, Canada’s most populous and ethnically diverse province, and compared sex ratios among infants of Canadian-born women with sex ratios in different immigrant groups. We focused on immigrant groups from countries purported to have the highest rates of preference for a son following the birth of one or more daughters.^3–6 We determined whether the male:female ratio increased with increasing parity in certain immigrant groups, as has been previously suggested.^3,6     

Association between hypertensive disorders during pregnancy and end-stage renal disease: a population-based study

Background:

Studies into the association between hypertensive disorders during pregnancy and end-stage renal disease are limited. We investigated the risk of end-stage renal disease after delivery among women with hypertensive disorders during pregnancy.

Methods:

We used insurance claims data from 1998 to 2009 to identify 26 651 women aged 19–40 years old who experienced hypertensive disorders during pregnancy; these women had no history of hypertension, diabetes, kidney disease or lupus. We also randomly selected 213 397 women without hypertensive disorders during pregnancy as a comparison cohort; the frequency was matched by age and index year of pregnancy. We compared the incidence of end-stage renal disease in the 2 cohorts. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) after controlling for demographic and clinical factors.

Results:

Women with hypertensive disorders during pregnancy had a greater risk of chronic kidney disease and end-stage renal disease, with adjusted HRs of 9.38 (95% CI 7.09–12.4) and 12.4 (95% CI 8.54–18.0), respectively, after controlling for urban status, coronary artery disease, congestive heart failure, hyperlipidemia and abruption. The HR for end-stage renal disease was 2.72 (95% CI 1.76–4.22) after we also controlled for hypertension and diabetes. Women with preeclampsia or eclampsia had a higher risk of end-stage renal disease (adjusted HR 14.0, 95% CI 9.43–20.7) than women who had gestational hypertension only (adjusted HR 9.03, 95% CI 5.20–15.7).

Interpretation:

Women with hypertensive disorders during pregnancy were at a high risk of end-stage renal disease. The risk was much greater for women who had preeclampsia or eclampsia than those who had gestational hypertension only.Hypertensive disorders during pregnancy are major causes of maternal and fetal morbidity and mortality, affecting 5%–10% of pregnancies.^1,2 Hypertensive disorders during pregnancy include gestational hypertension and preeclampsia.³ Gestational hypertension is referred to as new-onset hypertension (blood pressure > 140/90 mm Hg) without proteinuria after 20-weeks’ gestation.³ Preeclampsia is characterized by new-onset hypertension (blood pressure > 140/90 mm Hg) with proteinuria of at least 300 mg in a 24-hour urine sample after 20-weeks’ gestation.³ Gestational hypertension progresses to preeclampsia in 10%–20% of pregnant women.⁴ The risk factors associated with preeclampsia include family history of preeclampsia, first pregnancy, multiple gestation, advanced maternal age, obesity, pre-existing hypertension, renal disease and diabetes mellitus.⁵ Women with a history of hypertensive disorders during pregnancy are at higher risk of hypertension, diabetes mellitus and cardiovascular disease in later life. Hypertensive disorders during pregnancy and cardiovascular disease share several common risk factors, such as obesity, pre-existing hypertension, renal disease and insulin resistance.^6–14 Hypertensive disorders during pregnancy also increase the risk of cardiovascular disease because of long-term metabolic and vascular changes.¹⁵Hypertensive disorders during pregnancy affect the function and morphology of the kidney.¹⁶ Previous studies have reported an increased prevalence of microalbuminuria after pregnancy in women who had a hypertensive disorder during pregnancy.^17,18 In a case–control study, there was an association between biopsy-proven renal disease and a history of preeclampsia.¹⁹ However, studies about whether hypertensive disorders during pregnancy are associated with end-stage renal disease in later life are limited.²⁰ Only 1 study, performed using birth and renal registries from Norway, has reported that women with preeclampsia during their first pregnancy had a 3.2-fold higher risk of end-stage renal disease.²⁰ In the present study, we investigated the risk of end-stage renal disease among Taiwanese women who had a hypertensive disorder during pregnancy.     

Pregnancy complications among women born preterm

Background:

Adults who were born with low birth weights are at increased risk of cardiovascular and metabolic conditions, including pregnancy complications. Low birth weight can result from intrauterine growth restriction, preterm birth or both. We examined the relation between preterm birth and pregnancy complications later in life.

Methods:

We conducted a population-based cohort study in the province of Quebec involving 7405 women born preterm (554 < 32 weeks, 6851 at 32–36 weeks) and a matched cohort of 16 714 born at term between 1976 and 1995 who had a live birth or stillbirth between 1987 and 2008. The primary outcome measures were pregnancy complications (gestational diabetes, gestational hypertension, and preeclampsia or eclampsia).

Results:

Overall, 19.9% of women born at less than 32 weeks, 13.2% born at 32–36 weeks and 11.7% born at term had at least 1 pregnancy complication at least once during the study period (p < 0.001). Women born small for gestational age (both term and preterm) had increased odds of having at least 1 pregnancy complication compared with women born at term and at appropriate weight for gestational age. After adjustment for various factors, including birth weight for gestational age, the odds of pregnancy complications associated with preterm birth was elevated by 1.95-fold (95% confidence interval [CI] 1.54–2.47) among women born before 32 weeks’ gestation and 1.14-fold (95% CI 1.03–1.25) among those born at 32–36 weeks’ gestation relative to women born at term.

Interpretation:

Being born preterm, in addition to, and independent of, being small for gestational age, was associated with a significantly increased risk of later having pregnancy complications.Numerous studies examining cohorts born mostly in the first half of the 20th century have emphasized the inverse relation between low birth weight and incidence later in life of cardiovascular and metabolic conditions, such as hypertension and type 2 diabetes.¹ Epidemiologic studies seldom consider the effects of preterm birth and intrauterine growth restriction separately when studying the relation of these factors to low birth weight. Studies have suggested that adolescents and young adults born preterm have higher incidence of risk factors for metabolic (insulin resistance) and cardiovascular (higher blood pressure) dysfunctions.^2–4 With the increased survival of preterm newborns over the past 30 years, a substantially greater proportion of young adults are born before 37 or even 32 weeks’ gestation and thus may represent a growing population at risk for conditions related to metabolic syndrome as they get older.Pregnancy can be considered a stress test for future cardiovascular and metabolic health. Women with a history of gestational diabetes, gestational hypertension or preeclampsia are at increased risk of metabolic syndrome later in life.^5–7 Furthermore, studies have shown that women born with low birth weights are at increased risk of gestational hypertension, preeclampsia and gestational diabetes.^8–10 However, many of these studies either have not taken into account gestational age or have a number of shortcomings, such as small sample, young population (mostly teenagers), degree of prematurity not specified or study population consisting mostly of late preterm births.^6,11,12In the province of Quebec, weight and gestational age have been recorded in a registry for all births since 1976, and data on all hospital-based diagnoses have been collected since 1987. The aim of our study was to examine the relation between preterm birth and later pregnancy complications, independently of intrauterine growth restriction, among women born preterm in Quebec between 1976 and 1995 who delivered at least 1 newborn between 1987 and 2008. We also examined whether this association represents a dose–response relation, namely, whether the more prematurely born a woman is, the greater her risk of gestational diabetes, gestational hypertension, preeclampsia or eclampsia.     

Ambient Air Pollution and Birth Defects in Brisbane,Australia

Background

Birth defects are a major public health concern as they are the leading cause of neonatal and infant mortality. Observational studies have linked environmental pollution to adverse birth outcomes, including congenital anomalies. This study examined potential associations between ambient air pollution and congenital heart defects and cleft lip or palate among births in Brisbane, Australia (1998–2004).

Methods

Ambient air pollution levels were averaged over weeks 3–8 of pregnancy among 150,308 births. Using a case–control design, we used conditional logistic regression and matched cases to 5 controls. Analyses were conducted using all births, and then births where the mother resided within 6 and 12 kilometers of an ambient air quality monitor.

Findings

When analyzing all births there was no indication that ambient air pollution in Brisbane was associated with a higher risk of cardiac defects. Among births where the mother resided within 6 kilometers of an ambient air quality monitor, a 5 ppb increase in O₃ was associated with an increased risk of pulmonary artery and valve defects (OR 2.96, 95% CI: 1.34, 7.52) while a 0.6 ppb increase in SO₂ was associated with an increased risk of aortic artery and valve defects (OR 10.76, 95% CI: 1.50, 179.8). For oral cleft defects among all births, the only adverse association was between SO₂ and cleft lip with or without cleft palate (OR 1.27, 95% CI: 1.01, 1.62). However, various significant inverse associations were also found between air pollutants and birth defects.

Conclusions

This study found mixed results and it is difficult to conclude whether ambient air pollution in Brisbane has an adverse association with the birth defects examined. Studies using more detailed estimates of air pollution exposure are needed.     

Effects of prenatal multimicronutrient supplementation on pregnancy outcomes: a meta-analysis

Background

Reduced intake of micronutrients during pregnancy exposes women to nutritional deficiencies and may affect fetal growth. We conducted a systematic review to examine the efficacy of prenatal supplementation with multimicronutrients on pregnancy outcomes.

Methods

We searched MEDLINE, EMBASE, CINAHL and the Cochrane Library for relevant articles published in English up to December 2008. We also searched the bibliographies of selected articles as well as clinical trial registries. The primary outcome was low birth weight; secondary outcomes were preterm birth, small-for-gestational-age infants, birth weight and gestational age.

Results

We observed a significant reduction in the risk of low birth weight among infants born to women who received multimicronutrients during pregnancy compared with placebo (relative risk [RR] 0.81, 95% confidence interval [CI] 0.73–0.91) or iron–folic acid supplementation (RR 0.83, 95% CI 0.74–0.93). Birth weight was significantly higher among infants whose mothers were in the multimicronutrient group than among those whose mothers received iron–folic acid supplementation (weighted mean difference 54 g, 95% CI 36 g–72 g). There was no significant differences in the risk of preterm birth or small-for-gestational-age infants between the 3 study groups.

Interpretation

Prenatal multimicronutrient supplementation was associated with a significantly reduced risk of low birth weight and with improved birth weight when compared with iron–folic acid supplementation. There was no significant effect of multimicronutrient supplementation on the risk of preterm birth or small-for-gestational-age infants.Nutrition plays an important role in the growth and development of the fetus. Studies of the nutritional status of pregnant women during the Dutch famine revealed increased risks of infertility, abortion, fetal intrauterine growth restriction and perinatal mortality among malnourished women.¹ In many parts of the world, a similar situation exists for many pregnant women with respect to nutrition. Overall, the diet of pregnant women has been reported to be deficient in calories and micronutrients.² Both macro- and micronutrients are important for a woman to sustain pregnancy and for appropriate growth of the fetus.The exact mechanisms of how supplementation with micronutrients can affect pregnancy outcomes are not completely understood. Possible mechanisms for beneficial effects include a generalized improvement in the immune function of women, with a reduced incidence of infections and subsequent reduced incidence of preterm birth;³ improved energy metabolism and anabolic processes in the mother, with a reduced incidence of fetal intrauterine growth restriction;³ improved ability to respond to stress;³ expansion of plasma volume secondary to fluid retention, with subsequent improvements in fetal growth;⁴ improved hemoglobin levels;⁵ and increased absorption of iron related to intake of vitamin C and riboflavin, with subsequent improvement in hemoglobin levels.⁵Potential disadvantages include adverse interactions of micronutrients when supplied in combination;⁶ enhanced or reduced absorption of one nutrient by other nutrients (e.g., interaction between iron and vitamin C, and iron and zinc);⁷ deleterious effects on the fetus and the mother from overdose of any one component (e.g., vitamin A overdose);⁶ and cost.⁶Potential barriers include the lack of well-defined government policies on maternal health and nutrition.⁶ A multicomponent approach has been criticized from the standpoint that some micronutrients may be necessary, some may not be needed and some may even be harmful.² Generalized or mass supplementation with multimicronutrients may have different effects on pregnancy outcomes depending on the underlying nutritional status of the women.On the basis of a systematic review performed in 2005, the World Health Organization currently recommends iron–folic acid supplementation for all pregnant women.^8,9 The review reported that multimicronutrient supplementation during pregnancy were more efficacious than 2 or fewer micronutrients in reducing the rates of low birth weight and small-for-gestational-age births. However, when multimicronutrients were compared with iron–folic acid supplementation, no evidence of a difference was noted.⁷ Further research in this area was encouraged because information was derived from a few reports. Since then, several randomized controlled trials have evaluated the efficacy of multimicronutrients and have reported varied results. With advancement in our knowledge from recently reported trials,¹⁰ we conducted a systematic review and meta-analysis of the efficacy of supplementation with multimicronutrients during pregnancy in reducing the rates of low birth weight, preterm birth and small-for-gestational-age births compared with placebo or iron–folic acid supplementation.     

Association of macrosomia with perinatal and postneonatal mortality among First Nations people in Quebec

Background

High prevalence of infant macrosomia (up to 36%, the highest in the world) has been reported in some First Nations communities in the Canadian province of Quebec and the eastern area of the province of Ontario. We aimed to assess whether infant macrosomia was associated with elevated risks of perinatal and postneonatal mortality among First Nations people in Quebec.

Methods

We calculated risk ratios (RRs) of perinatal and postneonatal mortality by birthweight for gestational age, comparing births to First Nations women (n = 5193) versus women whose mother tongue is French (n = 653 424, the majority reference group) in Quebec 1991–2000.

Results

The prevalence of infant macrosomia (birthweight for gestational age > 90th percentile) was 27.5% among births to First Nations women, which was 3.3 times (confidence interval [CI] 3.2–3.5) higher than the prevalence (8.3%) among births to women whose mother tongue is French. Risk ratios for perinatal mortality among births to First Nations women were 1.8 (95% CI 1.3–2.5) for births with weight appropriate for gestational age, 4.1 (95% CI 2.4–7.0) for small-for-gestational-age (< 10th percentile) births and < 1 (not significant) for macrosomic births compared to births among women whose mother tongue is French. The RRs for postneonatal mortality were 4.3 (95% CI 2.7–6.7) for infants with appropriate-for-gestational-age birthweight and 8.3 (95% CI 4.0–17.0) for infants with macrosomia.

Interpretation

Macrosomia was associated with a generally protective effect against perinatal death, but substantially greater risks of postneonatal death among births to First Nations women in Quebec versus women whose mother tongue is French.A trend toward higher birthweights has emerged in recent decades.^1–3 Reflected in this trend is a rise in the prevalence of infant macrosomia, commonly defined as either a birthweight greater than 4000 g or a birthweight for gestational age greater than the 90th percentile relative to a fetal growth standard.^4–8 Maternal obesity, impaired glucose tolerance and gestational diabetes mellitus are important risk factors for infant macrosomia^9,10 and are known to afflict a much higher proportion of people in Aboriginal populations than in the general population.^11–14 This is true especially for Aboriginal populations in which a traditional lifestyle has changed to a less physically active, modern lifestyle in recent decades. A high prevalence of infant macrosomia (up to 36%, which, to the best of our knowledge, is the highest in the world) has been reported in some First Nations communities of Quebec and eastern Ontario in Canada.^15–17 However, little is known about the implications of this high prevalence for perinatal and infant health of First Nations people in these regions. We examined whether infant macrosomia was associated with increased risk for perinatal and postneonatal death among First Nations infants in Quebec.     

Rates of stillbirth by gestational age and cause in Inuit and First Nations populations in Quebec

Background:

Inuit and First Nations populations have higher rates of stillbirth than non-Aboriginal populations in Canada do, but little is known about the timing and cause of stillbirth in Aboriginal populations. We compared gestational age– and cause-specific stillbirth rates in Inuit and First Nations populations with the rates in the non-Aboriginal population in Quebec.

Methods:

Data included singleton stillbirths and live births at 24 or more gestational weeks among Quebec residents from 1981 to 2009. We calculated odds ratios (ORs), rate differences and 95% confidence intervals (CIs) for the retrospective cohort of Inuit and First Nations births relative to non-Aboriginal births using fetuses at risk (i.e., ongoing pregnancies) as denominators and adjusting for maternal characteristics. The main outcomes were stillbirth by gestational age (24–27, 28–36, ≥ 37 wk) and cause of death.

Results:

Rates of stillbirth per 1000 births were greater among Inuit (6.8) and First Nations (5.7) than among non-Aboriginal (3.6) residents. Relative to the non-Aboriginal population, the risk of stillbirth was greater at term (≥ 37 wk) than before term for both Inuit (OR 3.1, 95% CI 1.9 to 4.8) and First Nations (OR 2.6, 95% CI 2.1 to 3.3) populations. Causes most strongly associated with stillbirth were poor fetal growth, placental disorders and congenital anomalies among the Inuit, and hypertension and diabetes among the First Nations residents.

Interpretation:

Stillbirth rates in Aboriginal populations were particularly high at term gestation. Poor fetal growth, placental disorders and congenital anomalies were important causes of stillbirth among the Inuit, and diabetic and hypertensive complications were important causes in the First Nations population. Prevention may require improvements in pregnancy and obstetric care.Attention has recently been drawn to the paucity of data on rates and causes of stillbirth, a pregnancy outcome that is largely ignored compared with later deaths.¹ Aboriginal populations in Canada rank at the top of the list of disadvantaged groups with the highest rates of stillbirth in the Western world.¹ First Nations and Inuit, 2 distinct Aboriginal populations in Canada, have stillbirth rates that are 2–3 times that among non-Aboriginal Canadians.^1,2 Although these trends are alarming, little data exist to guide prevention efforts among Aboriginal Canadians. Not much is known about how stillbirth rates in Aboriginal populations vary by gestational age or cause of death, despite evidence that prevention requires knowledge on the timing and cause of stillbirth.³ Opportunities for preventing stillbirth are typically greater after 28 weeks of gestation,⁴ particularly at term, but the absence of gestational age– and cause-specific comparisons between Aboriginal and non-Aboriginal Canadians is a major impediment to reducing stillbirth rates. To gain a better understanding of the timing and causes of stillbirth in Inuit and First Nations populations, we estimated gestational age– and cause-specific fetal death rates in the Aboriginal and non-Aboriginal populations in the province of Quebec, where Inuit and First Nations people can be identified by parental information on birth registration forms.     

Rates and determinants of seasonal influenza vaccination in pregnancy and association with neonatal outcomes

Background:

There is growing evidence that seasonal influenza vaccination in pregnancy has benefits for mother and baby. We determined influenza vaccination rates among pregnant women during the 2 nonpandemic influenza seasons following the 2009 H1N1 pandemic, explored maternal factors as predictors of influenza vaccination status and evaluated the association between maternal influenza vaccination and neonatal outcomes.

Methods:

We used a population-based perinatal database in the province of Nova Scotia, Canada, to examine maternal vaccination rates, determinants of vaccination status and neonatal outcomes. Our cohort included women who gave birth between Nov. 1, 2010, and Mar. 31, 2012. We compared neonatal outcomes between vaccinated and unvaccinated women using logistic regression analysis.

Results:

Overall, 1958 (16.0%) of 12 223 women in our cohort received the influenza vaccine during their pregnancy. Marital status, parity, location of residence (rural v. urban), smoking during pregnancy and maternal influenza risk status were determinants of maternal vaccine receipt. The odds of preterm birth was lower among infants of vaccinated women than among those of nonvaccinated women (adjusted odds ratio [OR] 0.75, 95% confidence interval [CI] 0.60–0.94). The rate of low-birth-weight infants was also lower among vaccinated women (adjusted OR 0.73, 95% CI 0.56–0.95).

Interpretation:

Despite current guidelines advising all pregnant women to receive the seasonal influenza vaccine, influenza vaccination rates among pregnant women in our cohort were low in the aftermath of the 2009 H1N1 pandemic. This study and others have shown an association between maternal influenza vaccination and improved neonatal outcomes, which supports stronger initiatives to promote vaccination during pregnancy.Influenza viruses are the leading cause of serious wintertime respiratory morbidity worldwide. Several studies investigating the effects of influenza-related illness during pregnancy have shown a strong impact on the health of pregnant women in terms of increased rates of hospital admission because of respiratory illness.^1–3 Schanzer and colleagues² found that pregnant women in Canada were at increased risk of influenza-related hospital admission when compared with nonpregnant women of similar age and health status. In addition, influenza-related illness during pregnancy may have a negative impact on neonatal outcomes. A study in Nova Scotia, Canada, showed that infants whose mothers were admitted to hospital because of respiratory illness during influenza season while pregnant were more likely to be small for gestational age and to have lower mean birth weight.⁴By 2007, the cumulative evidence from these and other studies was compelling enough for advisory boards in Canada to recommend routine influenza vaccination for all pregnant women, including those without medical comorbidities.⁵ Despite these recommendations, seasonal vaccination rates among pregnant women have remained low. In a cohort of pregnant women who delivered at the IWK Health Centre, Halifax, from 2006 to 2009, only 20% had received the vaccine during their pregnancy.⁶ Increased vaccination rates among pregnant women were reported for the 2009 H1N1 pandemic year,⁷ but it is unknown whether this has translated into higher rates of seasonal influenza vaccination since then. Studies have shown that concern about vaccine safety is the most commonly cited reason for refusing the vaccine,^8,9 despite much evidence showing it to be safe in pregnancy.¹⁰ A recommendation from a maternity care provider has been shown to be a key factor in increasing vaccination rates.^11,12In light of the growing evidence that influenza vaccination during pregnancy has benefits for both the mother and the infant,^13–18 we evaluated rates of seasonal influenza vaccination among pregnant women in the 2 nonpandemic influenza seasons (2010/11 and 2011/12) following the 2009 H1N1 pandemic. We also assessed whether neonatal outcomes differed between women who received the vaccine during pregnancy and those who did not.     

Pregnancy and the risk of a traffic crash

Introduction:

Pregnancy causes diverse physiologic and lifestyle changes that may contribute to increased driving and driving error. We compared the risk of a serious motor vehicle crash during the second trimester to the baseline risk before pregnancy.

Methods:

We conducted a population-based self-matched longitudinal cohort analysis of women who gave birth in Ontario between April 1, 2006, and March 31, 2011. We excluded women less than age 18 years, those living outside Ontario, those who lacked a valid health card identifier under universal insurance, and those under the care of a midwife. The primary outcome was a motor vehicle crash resulting in a visit to an emergency department.

Results:

A total of 507 262 women gave birth during the study period. These women accounted for 6922 motor vehicle crashes as drivers during the 3-year baseline interval (177 per mo) and 757 motor vehicle crashes as drivers during the second trimester (252 per mo), equivalent to a 42% relative increase (95% confidence interval 32%–53%; p < 0.001). The increased risk extended to diverse populations, varied obstetrical cases and different crash characteristics. The increased risk was largest in the early second trimester and compensated for by the third trimester. No similar increase was observed in crashes as passengers or pedestrians, cases of intentional injury or inadvertent falls, or self-reported risky behaviours.

Interpretation:

Pregnancy is associated with a substantial risk of a serious motor vehicle crash during the second trimester. This risk merits attention for prenatal care.Motor vehicle crashes are the leading cause of fetal death related to maternal trauma.^1–4 The outcomes for survivors are also concerning, given that brain injury in early life can contribute to neurologic deficits in later life.⁵ Emergency care of an injured pregnant woman is further problematic because the physiologic changes of pregnancy can mask the usual signs of acute blood loss (e.g., tachycardia, hypotension), resuscitation science is incomplete (e.g., clinical trials usually exclude pregnant women) and trauma protocols need adjustment (e.g., iodine contrast radiography can potentially harm a fetus).^4,5 Even rudimentary care such as analgesia can be complicated when a pregnant woman is involved.⁶ Every crash creates worry and potential future litigation that might have been avoided if the crash had been prevented.^7,8Motor vehicle crashes occur when human error aligns with system failures.^9,10 In the United States, the net effect is about 15 million crashes annually, resulting in about 2.5 million individuals sent to hospital with fractures, concussions, ruptured vessels, organ lacerations, soft tissue damage or other injuries.¹¹ The specific details of common human errors are not well understood; in contrast, life-threatening defects in the vehicle or roadway are relatively blatant and infrequent.¹² One pattern of human error is that people are overly confident, misjudge their abilities and fail to take protective actions.¹³ The shared nature of many motor vehicle crashes also makes it easy to blame the other person involved and fail to learn from past experience.¹⁴We questioned whether pregnancy might interact with human error and increase the risk of a serious motor vehicle crash. Intermittent nausea, general fatigue, unintended distraction and sleep disruption are common features of a normal pregnancy that sometimes underlie human error.^15–17 Important physiologic changes related to pregnancy can occur before overt changes in anatomy are apparent.¹⁸ Hence, the intermediate stages of pregnancy provide a potential interval of overconfidence when a person could be compromised yet still active.¹⁹ The aim of our study was to examine the risk of a serious motor vehicle crash during pregnancy with special attention to the first, second and third trimesters separately.     

The “hypertriglyceridemic waist” phenotype and glucose intolerance in pregnancy

Background

Abdominal visceral adiposity in early pregnancy has been associated with impaired glucose tolerance in later pregnancy. The “hypertriglyceridemic waist” phenotype (i.e., abdominal obesity in combination with hyper-triglyceridemia) is a clinical marker of visceral obesity. Our study aimed to assess the association between the hyper-triglyceridemic-waist phenotype in early pregnancy and glucose intolerance in later pregnancy.

Methods

Plasma triglycerides and waist girth were measured at 11–14 weeks of gestation among 144 white pregnant women. Glycemia was measured following a 75-g oral glucose tolerance test performed at 24–28 weeks of gestation.

Results

A waist girth greater than 85 cm in combination with a triglyceride level ≥ 1.7 mmol/L in the first trimester was associated with an increased risk of two-hour glucose ≥ 7.8 mmol/L following the 75-g oral glucose tolerance test (odds ratio [OR] 6.1, p = 0.002). This risk remained significant even after we controlled for maternal age, fasting glucose at first trimester and previous history of gestational diabetes (OR 4.7, p = 0.02).

Interpretation

Measurement of waist girth in combination with measurement of triglyceride concentrations in the first trimester of pregnancy could improve early screening for gestational glucose intolerance.Early and accessible screening tools for gestational diabetes mellitus are needed to improve pregnancy-related outcomes for women and children.¹ Diagnostic tools currently used for gestational diabetes (most commonly the fasting oral glucose tolerance test) are expensive, time-consuming, uncomfortable for pregnant women and do not allow diagnosis before the end of the second trimester of pregnancy.² Some earlier screening tools have been suggested, such as a 50-g glucose load followed by a one-hour plasma glucose analysis that can be performed at any time of the day and early in pregnancy. Although this test is less uncomfortable than the fasting oral glucose tolerance test, it remains time-consuming and unpleasant for women. Its use is therefore restricted mainly to women at risk for gestational diabetes.Several attempts have been made to simplify these tests to promote wider use. However, no results have yet identified the means to carry out early and widely accessible screening. Interesting positive and negative predictive values have been obtained for first-trimester fasting glucose and insulin for subsequent gestational diabetes expression.^3–5 However, these studies have been performed among women at risk of gestational diabetes and should be replicated in samples of women with various risk levels. Regardless of pregnancy, a person with normal fasting glucose can still meet the criteria for glucose intolerance or diabetes during an oral glucose tolerance test. Several studies have also shown that maternal pre-pregnancy obesity is directly associated with an increased risk of gestational diabetes. However, results vary widely across studies, possibly because of lack of specificity of tools for measurement of adiposity.⁶ A recent study has suggested that abdominal visceral adiposity, specifically, is associated with risk of gestational diabetes expression.⁷The hypertriglyceridemic-waist phenotype has been identified as a simple, easily available clinical marker of visceral obesity and related metabolic abnormalities.^8,9 It is defined as the simultaneous presence of abdominal obesity (i.e., a waist girth greater than 85 cm in women or greater than 90 cm in men) and hypertriglyceridemia (i.e., a triglyceride concentration ≥ 2 mmol/L). The aim of our study was to document the association between the presence of the hypertriglyceridemic-waist phenotype in early pregnancy and impaired glucose tolerance in later pregnancy.     

Proliferation of prenatal ultrasonography

Background

The extent to which temporal increases in the use of prenatal ultrasonography reflect changes in maternal risk is unknown. In this population-based study, we examined the use of prenatal ultrasonography from 1996 to 2006 in Ontario.

Methods

With fiscal year 1996/97 as the baseline, we evaluated the relative risk (RR) and 95% confidence interval (CI) for the change in rates of ultrasonography for each subsequent year. The RR was adjusted for maternal age, income, rural residence, maternal comorbidities, receipt of genetics consultation or amniocentesis — all in the index pregnancy — and history of complications in a prior pregnancy.

Results

The study sample consisted of 1 399 389 singleton deliveries. The rate of prenatal ultrasonography increased from 2055 per 1000 pregnancies in 1996 to 3264 per 1000 in 2006 (adjusted RR 1.55, 95% CI 1.54–1.55). The rate increased among both women with low-risk pregnancies (adjusted RR 1.54, 95% CI 1.53–1.55) and those with high-risk pregnancies (adjusted RR 1.55, 95% CI 1.54–1.57). The proportion of pregnancies with at least four ultrasound examinations in the second or third trimesters rose from 6.4% in 1996 to 18.7% in 2006 (adjusted RR 2.68, 95% CI 2.61–2.74). Paradoxically, this increase was more pronounced among low-risk pregnancies (adjusted RR 2.92, 95% CI 2.83–3.01) than among high-risk pregnancies (adjusted RR 2.25, 95% CI 2.16–2.35).

Interpretation

Substantial increases in the use of prenatal ultrasonography over the past decade do not appear to reflect changes in maternal risk. Nearly one in five women now undergo four or more ultrasound examinations during the second and third trimesters. Efforts to promote more appropriate use of prenatal ultrasonography for singleton pregnancies appear warranted.The rapid proliferation of diagnostic imaging is a challenge for the containment of health care expenditures and for system sustainability in many countries.¹ The ensuing debate among clinicians, researchers and policy-makers has become increasingly contentious and highly politicized.^2,3 In Canada, the annual operational costs for diagnostic imaging now total more than $2.2 billion.⁴ Prenatal ultrasonography is one of the most rapidly proliferating imaging tests, this expansion being marked most strikingly by an increase in the proportion of women undergoing multiple pre-natal examinations for a single pregnancy.⁵ Although guidelines generally recommend that two ultrasound examinations be performed in a pregnancy without complications — one in the first trimester, for measurement of nuchal translucency to screen for aneuploidy, and one in the second trimester to screen for fetal anomalies — it is conceivable that the proliferation of prenatal ultrasonography reflects changes in maternal risk over time.^6–10In other areas of health care, interventions that are most beneficial to high-risk individuals are frequently directed to low-risk populations.^11–13 We hypothesized that increasing trends in the use of prenatal ultrasonography could not be explained solely by pregnancy risk and would be evident among low-risk pregnancies. Accordingly, we performed a population-based study to examine the annual rates of prenatal ultrasonography, adjusted for maternal risk profiles.     

Maternal selenium status during early gestation and risk for preterm birth

Background

Preterm birth occurs in 5%–13% of pregnancies. It is a leading cause of perinatal mortality and morbidity and has adverse long-term consequences for the health of the child. Because of the role selenium plays in attenuating inflammation, and because low concentrations of selenium have been found in women with preeclampsia, we hypothesized that low maternal selenium status during early gestation would increase the risk of preterm birth.

Methods

White Dutch women with a singleton pregnancy (n = 1197) were followed prospectively from 12 weeks’ gestation. Women with thyroid disease or type 1 diabetes were excluded. At delivery, 1129 women had complete birth-outcome data. Serum concentrations of selenium were measured during the 12th week of pregnancy. Deliveries were classified as preterm or term, and preterm births were subcategorized as iatrogenic, spontaneous or the result of premature rupture of the membranes.

Results

Of the 60 women (5.3%) who had a preterm birth, 21 had premature rupture of the membranes and 13 had preeclampsia. The serum selenium concentration at 12 weeks’ gestation was significantly lower among women who had a preterm birth than among those who delivered at term (mean 0.96 [standard deviation (SD) 0.14] μmol/L v. 1.02 [SD 0.13] μmol/L; t = 2.9, p = 0.001). Women were grouped by quartile of serum selenium concentration at 12 weeks’ gestation. The number of women who had a preterm birth significantly differed by quartile (χ² = 8.01, 3 degrees of freedom], p < 0.05). Women in the lowest quartile of serum selenium had twice the risk of preterm birth as women in the upper three quartiles, even after adjustment for the occurrence of preeclampsia (adjusted odds ratio 2.18, 95% confidence interval 1.25–3.77).

Interpretation

Having low serum selenium at the end of the first trimester was related to preterm birth and was independent of the mother having preeclampsia. Low maternal selenium status during early gestation may increase the risk of preterm premature rupture of the membranes, which is a major cause of preterm birth.Preterm birth occurs in 5%–13% of pregnancies and is a major public health concern worldwide.¹ Preterm birth, defined as delivery before 37 weeks’ gestation, is the leading cause of perinatal mortality and morbidity.² Short- and long-term consequences to the health of the child include cerebral palsy, respiratory distress syndrome, neurodevelopmental impairment, learning difficulties and behavioural problems.² Despite substantial efforts to explain the mechanisms involved, the incidence of preterm birth is on the rise. For example, in the United States, the incidence increased from 9.5% in 1981 to 12.7% in 2005.¹ Consequently, it is important to identify factors that may contribute to preterm birth, particularly those factors that are preventable.Maternal risk factors for preterm birth include a previous preterm delivery, black race, low socioeconomic status, poor nutrition or becoming pregnant soon after a previous delivery.¹ Risk factors for preterm birth during gestation include multiple-gestation pregnancy and an intrauterine infection that triggers an inflammatory response.^1,3 Endocrine conditions such as diabetes and dysfunction of the thyroid have also been associated with preterm birth, sometimes linked to preterm premature rupture of the membranes.^4,5The trace mineral selenium, available from food (though to a greater or lesser extent according to region), can interact with a number of these risk factors.^6–9 It has been implicated in pregnancy outcome,^9–12 and it plays a role in the immune response and the body’s resistance to infection.⁶ Enzymes containing the mineral, selenoenzymes, can attenuate the excessive inflammatory response associated with adverse pregnancy outcomes, downregulating the expression of pro-inflammatory genes.^6–8 A polymorphism in the gene encoding the selenoprotein SEPS1 has been shown to affect the risk of preeclampsia, a condition that has a strong inflammatory component that is an important cause of preterm birth.⁸ In addition, low selenium status has been identified in women with preeclampsia.¹²We hypothesized that low maternal selenium status (as measured by low serum selenium concentration early in gestation would be associated with preterm birth. Previous small studies have compared plasma selenium and plasma/erythrocyte glutathione peroxidase in mothers and their babies during both term and preterm deliveries. Although lower values have often been found in mothers who had their babies preterm than in mothers who had their babies at term, the findings were inconsistent.^13–15 We did a prospective study to assess selenium status in a large cohort of pregnant women who were followed from early gestation to delivery.     

Exposure of Cleft Lip and Palate Patients to Toxic Elements Released during Orthodontic Treatment in the Study of Non-Invasive Matrices

The Objective

The aim of the study was evaluation of metal ions (nickel and chromium) released from orthodontic appliances in cleft lip and palate patients and the usefulness of non-invasive matrices (saliva and hair).

Materials and Methods

The material studied consisted of 100 individuals, including 59 females and 41 males of 5 to 16 years of age, which were divided into 3 groups: experimental–patients with cleft lip and palate (36 individuals, the average treatment time 5.74 years); control group–patients without cleft lip and palate, during orthodontic treatment (32 individuals, the average treatment time 1.78 years) and the control group patients without cleft lip and palate, without any orthodontic appliances (32 individuals). Samples (saliva, hair) were collected and subjects underwent a survey by questionnaire. Multi-elemental analyses of the composition of non-invasive matrices was conducted in an accredited laboratory by inductively coupled plasma spectrometry technique ICP-OES. The results were reported as mean contents of particular elements (Cd, Cr, Cu, Fe, Mn, Mo, Ni, Si) in hair and in saliva.

Results

The concentration of Cr, Ni, Fe and Cu ions in saliva of cleft lip and palate patients were several times higher as compared with not treated orthodontically control groups and higher than in the group with orthodontic appliances. Among the assessed matrices, hair of cleft lip and palate patients seem to be not a meaningful biomarker.

Conclusion

It was found that orthodontic appliances used in long-term treatment of cleft lip and palate patients do not release toxic levels of Cr and Ni ions.     

Effect of maternal weight, adipokines, glucose intolerance and lipids on infant birth weight among women without gestational diabetes mellitus

Background:

The delivery of excess maternal nutrients to the fetus is known to increase the risk of macrosomia, even among infants of women without gestational diabetes mellitus. With the current obesity epidemic, maternal adiposity and its associated effects on circulating adipokines and inflammatory proteins may now have a greater impact on fetal growth. We sought to evaluate the independent effects of maternal glycemia, lipids, obesity, adipokines and inflammation on infant birth weight.

Methods:

We included 472 women who underwent an oral glucose tolerance test in late pregnancy and were found not to have gestational diabetes; 104 (22.0%) had gestational impaired glucose tolerance. We also measured fasting levels of insulin, low-and high-density lipoprotein cholesterol, triglycerides, leptin, adiponectin and C-reactive protein. Obstetric outcomes were assessed at delivery.

Results:

The mean birth weight was 3481 g (standard deviation 493 g); 68 of the infants were large for gestational age. On multiple linear regression analysis, positive determinants of birth weight were length of gestation, male infant, weight gain during pregnancy up to the time of the oral glucose tolerance test, body mass index (BMI) before pregnancy and impaired glucose tolerance in pregnancy. Leptin, adiponectin and C-reactive protein levels were each negatively associated with birth weight. On logistic regression analysis, the significant metabolic predictors of having a large-for-gestational-age infant were BMI before pregnancy (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.05–1.27, per 1 kg/m² increase), weight gain during pregnancy up to the time of the oral glucose tolerance test (OR 1.12, 95% CI 1.05–1.19, per 1 kg increase) and leptin level (OR 0.50, 95% CI 0.30–0.82, per 1 standard deviation change).

Interpretation:

Among women without gestational diabetes, maternal adiposity and leptin levels were the strongest metabolic determinants of having a large-for-gestational-age infant rather than glucose intolerance and lipid levels.In 1952, Jørgen Pedersen proposed that delivery of excess maternal glucose to the fetus may be responsible for the increased risk of macrosomia among infants of women with diabetes during pregnancy.¹ He postulated that maternal hyperglycemia leads to fetal hyperglycemia, which in turn stimulates insulin secretion in the fetus, the anabolic effects of which result in excessive fetal growth. Since its introduction, the Pedersen hypothesis has been further extended by other investigators and accepted as the pathophysiologic basis for increased risk of macrosomia among infants of women with diabetes during pregnancy.^2,3 Accordingly, for pregnant women with either pre-existing diabetes or gestational diabetes, modern clinical practice focuses on normalizing blood glucose levels to reduce the risk of fetal hyperglycemia and hence the risk of fetal macrosomia and its associated adverse clinical outcomes (e.g., shoulder dystocia, birth injury, need for cesarean delivery).It is now recognized that the association between maternal nutrients and fetal growth is not restricted solely to women with diabetes. Several studies have shown associations linking maternal blood glucose and triglyceride levels with infant birth weight among women without gestational diabetes.^4–7 This awareness has led to recent recommendations to lower the diagnostic thresholds for gestational diabetes on glucose tolerance testing in pregnancy, to optimize the detection of women who may be at risk of having a large-for-gestational-age infant.⁸Another important factor relevant to the risk of macrosomia is maternal adiposity.⁹ Indeed, the past decade has seen a marked increase in the prevalence of pre-existing obesity among pregnant women.¹⁰ In the context of the current obesity epidemic, we hypothesized that, in women without gestational diabetes, maternal adiposity and its associated effects on circulating levels of adipokines (e.g., adiponectin and leptin) and inflammatory proteins (C-reactive protein) may now have a greater impact than glucose and lipid levels on fetal growth. We conducted this study to evaluate the independent effects of maternal glycemia, lipid levels, obesity, adipokine levels and inflammation on the infant birth weight in a cohort of women without gestational diabetes.     

Crystal methamphetamine and initiation of injection drug use among street-involved youth in a Canadian setting

Background:

Although injection drug use is known to result in a range of health-related harms, including transmission of HIV and fatal overdose, little is known about the possible role of synthetic drugs in injection initiation. We sought to determine the effect of crystal methamphetamine use on risk of injection initiation among street-involved youth in a Canadian setting.

Methods:

We used Cox regression analyses to identify predictors of injection initiation among injection-naive street-involved youth enrolled in the At-Risk Youth Study, a prospective cohort study of street-involved youth in Vancouver, British Columbia. Data on circumstances of first injection were also obtained.

Results:

Between October 2005 and November 2010, a total of 395 drug injection–naive, street-involved youth provided 1434 observations, with 64 (16.2%) participants initiating injection drug use during the follow-up period, for a cumulative incidence of 21.7 (95% confidence interval [CI] 1.7–41.7) per 100 person-years. In multivariable analysis, recent noninjection use of crystal methamphetamine was positively associated with subsequent injection initiation (adjusted hazard ratio 1.93, 95% CI 1.31–2.85). The drug of first injection was most commonly reported as crystal methamphetamine (14/31 [45%]).

Interpretation:

Noninjection use of crystal methamphetamine predicted subsequent injection initiation, and crystal methamphetamine was the most commonly used drug at the time of first injection. Evidence-based strategies to prevent transition to injection drug use among crystal methamphetamine users are urgently needed.Street-involved youth are at high risk of initiating injection drug use.¹ This situation is of concern, given that injection drug use has been associated with increased risk of transmission of HIV and hepatitis C virus^2,3 and fatal overdose,⁴ as well as a range of other serious negative health and social outcomes. Newly initiated injection drug users have also been identified as a subpopulation at particularly high risk of injection-related harm.^5–8 Unfortunately, despite recent calls to prioritize interventions to prevent the initiation of injection drug use,⁹ there are few evidence-based strategies to prevent injection initiation among street-involved youth.This situation relates, in part, to the fact that little is known about the risk factors for injection initiation within this population. Prospective research from Montréal, Quebec, has alluded to the role that crack and powder cocaine may play in promoting subsequent injection initiation,¹⁰ as has retrospective research conducted among drug users in Baltimore, Maryland.¹¹ Much less is known about the possible role that synthetic drugs, such as methamphetamine, may play in contributing to an increased risk of injection initiation.¹² Globally, amphetamine-type stimulants have emerged as one of the most commonly used groups of illicit drugs, second only to cannabis.¹³ This increase in amphetamine use is reflected in the epidemiology of drug use in some Canadian settings. For instance, in Vancouver, British Columbia, rates of injection use of crystal methamphetamine have increased significantly among adult injection drug users.¹⁴ This pattern is of substantial public health concern, given that crystal methamphetamine has been associated with a range of health and social harms, including the potential to drive high-risk drug-use patterns, including injection.¹⁵ Given these concerns and the well-established health-related harms of injection drug use, we investigated the possible role of crystal methamphetamine use in the incidence of first injection drug use within a cohort of street-involved youth in a Canadian setting.