Naomi Greene

Sequential pathways of testing after first-trimester screening for trisomy 21

OBJECTIVE: To evaluate the performance and use of second-trimester multiple-marker maternal serum screening for trisomy 21 by women who had previously undergone first-trimester combined screening (nuchal translucency, pregnancy-associated plasma protein A, and free β-hCG), with disclosure of risk estimates. METHODS: In a multicenter, first-trimester screening study sponsored by the National Institute of Child Health and Human Development, multiple-marker maternal serum screening with alpha-fetoprotein, unconjugated estriol, and total hCG was performed in 4,145 (7 with trisomy 21) of 7,392 (9 with trisomy 21) women who were first-trimester screen-negative and 180 (7 with trisomy 21) of 813 (52 with trisomy 21) who were first-trimester screen-positive. Second-trimester risks were calculated using multiples of the median and a standardized risk algorithm with a cutoff risk of 1:270. RESULTS: Among the first-trimester screen-negative cohort, 6 of 7 (86%) trisomy 21 cases were detected by second-trimester multiple-marker maternal serum screening with a false-positive rate of 8.9%. Among the first-trimester screen-positive cohort, all 7 trisomy 21 cases were also detected in the second trimester, albeit with a 38.7% false-positive rate. CONCLUSION: Our data demonstrate that a sequential screening program that provides patients with first-trimester results and offers the option for early invasive testing or additional serum screening in the second trimester can detect 98% of trisomy 21–affected pregnancies. However, such an approach will result in 17% of patients being considered at risk and, hence, potentially having an invasive test. LEVEL OF EVIDENCE: II-2

Estimating bias from loss to follow-up in the Danish National Birth Cohort.

Loss to follow-up in cohort studies may result in biased association estimates. Of 61,895 women entering the Danish National Birth Cohort and completing the first data-collection phase, 37,178 (60%) opted to be in the 7-year follow-up. Using national registry data to obtain end point information on all members of the cohort, we estimated associations in the baseline and the 7-year follow-up participant populations for 5 exposure-outcome associations: (a) size at birth and childhood asthma, (b) assisted reproductive treatment and childhood hospitalizations, (c) prepregnancy body mass index and childhood infections, (d) alcohol drinking in early pregnancy and childhood developmental disorders, and (e) maternal smoking in pregnancy and childhood attention-deficit hyperactivity disorder (ADHD). We estimated follow-up bias in the odds or rate ratios by calculating relative ratios. For all but one of the above analyses, the bias appeared to be small, between −10% and +8%. For maternal smoking in pregnancy and childhood ADHD, we estimated a positive bias of approximately 33% (95% bootstrap limits of −30% and +152%). The presence and magnitude of bias due to loss to follow-up depended on the nature of the factors or outcomes examined, with the most pronounced contribution in this study coming from maternal smoking. Our methods and results may inform bias analyses in future pregnancy cohort studies.

Maternal psychosocial adversity during pregnancy is associated with length of gestation and offspring size at birth: evidence from a population-based cohort study.

Objective: To study in a large-scale cohort with prospective data the associations of psychosocial adversities during pregnancy with length of gestation and offspring size at birth. Methods: We defined a priori two types of psychosocial adversity during pregnancy: life stress (perceived burdens in major areas of life) and emotional symptoms (e.g. anxiety). Measures of offspring size at birth, including body weight, body length, abdominal and head circumference, were obtained from a national medical birth registry. We included in the analyses gestational age and offspring size at birth controlled for length of gestation; the latter was calculated by gestational-age-specific z scores (ZS) reported in 10−3. We conducted multiple regression analyses adjusted for potential confounders to estimate the association between exposures and birth outcomes (n = 78017 pregnancies). Results: Life stress (per score increase by 1; range, 0-18) was associated with shorter length of gestation (days; B, −0.14; 95% confidence interval (CI), −0.19, −0.10), increased offspring body weight (ZS; B, 9.14; 95% CI, 4.99, 13.28), body length (ZS; B, 6.58; 95% CI, 2.39, 10.77), abdominal circumference (ZS; B, 9.96; 95% CI, 5.77, 14.16), and head circumference (ZS; B, 6.13; 95% CI, 1.95, 10.30). Emotional symptoms were associated with shorter length of gestation (days; B, −0.04; 95% CI, −0.07, −0.004) and decreased body length (ZS; B, −4.44; 95% CI, −7.57, −1.32) only. Conclusions: Life stress and emotional symptoms both predicted a shorter length of gestation, while only life stress predicted an increased offspring size at birth controlled for length of gestation; yet, the associations were rather small. The fetoplacental-maternal unit may regulate fetal growth according to the type of psychosocial adversity and even increase fetal growth in response to maternal stress in major areas of life. This potentially reflects a basic principle of intrauterine human development in response to stress. BMI = body mass index; DNBC = Danish National Birth Cohort;IL1B = interleukin 1, beta.

Stress during Pregnancy and Offspring Pediatric Disease: A National Cohort Study

Background: Identifying risk factors for adverse health outcomes in children is important. The intrauterine environment plays a pivotal role for health and disease across life. Objectives: We conducted a comprehensive study to determine whether common psychosocial stress during pregnancy is a risk factor for a wide spectrum of pediatric diseases in the offspring. Methods: The study was conducted using prospective data in a population-based sample of mothers with live singleton births (n = 66,203; 71.4% of those eligible) from the Danish National Birth Cohort. We estimated the association between maternal stress during pregnancy (classified based on two a priori–defined indicators of common stress forms, life stress and emotional stress) and offspring diseases during childhood (grouped into 16 categories of diagnoses from the International Classification of Diseases, 10th Revision, based on data from national registries), controlling for maternal stress after pregnancy. Results: Median age at end of follow-up was 6.2 (range, 3.6–8.9) years. Life stress (highest compared with lowest quartile) was associated with an increased risk of conditions originating in the perinatal period [odds ratio (OR) = 1.13; 95% confidence interval (CI): 1.06, 1.21] and congenital malformations (OR=1.17; CI: 1.06, 1.28) and of the first diagnosis of infection [hazard ratio (HR) = 1.28; CI: 1.17, 1.39], mental disorders (age 0–2.5 years: HR = 2.03; CI: 1.32, 3.14), and eye (age 0–4.5 years: HR = 1.27; CI: 1.06, 1.53), ear (HR = 1.36; CI: 1.23, 1.51), respiratory (HR = 1.27; CI; 1.19, 1.35), digestive (HR = 1.23; CI: 1.11, 1.37), skin (HR = 1.24; CI: 1.09, 1.43), musculoskeletal (HR = 1.15; CI: 1.01–1.30), and genitourinary diseases (HR = 1.25; CI; 1.08, 1.45). Emotional stress was associated with an increased risk for the first diagnosis of infection (HR = 1.09; CI: 1.01, 1.18) and a decreased risk for the first diagnosis of endocrine (HR = 0.81; CI; 0.67, 0.99), eye (HR = 0.84; CI; 0.71, 0.99), and circulatory diseases (age 0–3 years: HR = 0.63; CI: 0.42, 0.95). Conclusions: Maternal life stress during pregnancy may be a common risk factor for impaired child health. The results suggest new approaches to reduce childhood diseases.

Three-dimensional ultrasonography in obstetrics and gynecology: Preliminary experience☆☆☆★★★

OBJECTIVE Technologic advances in ultrasonographic imaging have revolutionized the management of womens health care. We recently began to evaluate the clinical applications of three-dimensional ultrasonography. STUDY DESIGN This study prospectively evaluated 161 obstetric and gynecologic patients. Both two- and three-dimensional imaging data were acquired from real-time ultrasonography. Three orthogonal planes were displayed on a monitor and were used to create the rendered three-dimensional images. RESULTS To date, 201 three-dimensional ultrasonographic studies have been performed, 165 transabdominally and 36 transvaginally. Transabdominally, an average of eight acquisitions per patient were obtained. Of the clinically suspected abnormalities, 29 of 32 (91%) were confirmed by three-dimensional imaging. Three of 32 (9%) improved the diagnostic capabilities or changed the diagnosis. Of the 36 transvaginal studies, an average of four acquisitions per patient were done. Thirty (83%) of these patients had suspected abnormalities and all were confirmed. CONCLUSIONS Three-dimensional ultrasonographic imaging appears to be highly promising in the clinical setting.

Maternal Psychosocial Stress during Pregnancy and Placenta Weight: Evidence from a National Cohort Study

Background To study in a large-scale cohort with prospective data the associations between psychosocial stress during pregnancy and placenta weight at birth. Animal data suggest that the placenta is involved in stress-related fetal programming. Methodology/Principal Findings We defined a priori two types of psychosocial stress during pregnancy, life stress (perceived burdens in major areas of life) and emotional symptoms (e.g. anxiety). We estimated the associations of maternal stress during pregnancy with placenta weight at birth, controlled for length of gestation, by predicting gestational age- and sex-specific z-scores of placenta weight through multiple regression analysis, adjusted for potential confounders (N = 78017 singleton pregnancies). Life stress (per increase in stress score by 1, range: 0–18) during pregnancy was associated with increased placenta weight at birth (z-score, reported in 10−3; B, 14.33; CI, 10.12–18.54). In contrast, emotional symptoms during pregnancy were not associated with placenta weight at birth. Conclusions/Significance Maternal life stress but not emotional symptoms during pregnancy was associated with increased placenta weight at birth; yet, the association-estimate was rather small. Our results may contribute to a better understanding of the role of the placenta in the regulation of intrauterine processes in response to maternal stress.

Inhaled glucocorticoids during pregnancy and offspring pediatric diseases: a national cohort study.

RATIONALE Glucocorticoid inhalation is the preferred asthma treatment during pregnancy. Previous studies on its safety focused on obstetric outcomes and offspring malformations. OBJECTIVES To determine whether glucocorticoid inhalation during pregnancy is a risk factor for offspring pediatric diseases. METHODS We studied offspring (live singletons) of pregnant women suffering from asthma during pregnancy (prevalence = 6.3%; n = 4,083 mother-child pairs) from the Danish National Birth Cohort (births, 1996-2002; prospective data). We estimated the associations between use of inhaled glucocorticoids for asthma treatment during pregnancy (n = 1231; 79.9% budesonide, 17.6% fluticasone, 5.4% beclomethasone, and 0.9% other or unspecified glucocorticoids) and offspring diseases (International Classification of Diseases-10th Revision, diagnoses) during childhood. We conducted Cox or logistic regression analyses for each International Classification of Diseases-10th Revision category, controlling for use of non-glucocorticoid-containing inhalants, and confirmed results by addressing confounding by treatment indication using propensity score. MEASUREMENTS AND MAIN RESULTS Offspring median age at end of follow-up was 6.1 (range, 3.6-8.9) years. Glucocorticoid inhalation was not associated with offspring disease risk in most categories, except for offspring endocrine, metabolic, and nutritional disorders (hazard ratio, 1.84; 95% confidence interval, 1.13-2.99). When repeating analyses with the major subgroup that used budesonide only, association estimates were of similar magnitude. CONCLUSIONS Regarding most disease categories, data are reassuring, supporting the use of inhaled glucocorticoids during pregnancy. In line with animal data, glucocorticoid inhalation during pregnancy may be a risk factor for offspring endocrine and metabolic disturbances, which should be considered further.

The isolated choroid plexus cyst

Objective To describe the karyotypes of a population of fetuses with choroid plexus cysts and compare affected fetuses with and without additional ultrasonographic findings. Methods The study population included all patients undergoing second-trimester ultrasound examination in a prenatal diagnostic program between January 1993 and October 1995. The records of all cases in which a choroid plexus cyst was found were reviewed, and information was abstracted regarding the fetal karyotype and the presence of other sonographic abnormalities. Results Two hundred ten cases of choroid plexus cysts were identified among 7617 patients (2.8%) who underwent second-trimester ultrasound examination. The majority of the cases (181, or 86%) involved isolated choroid plexus cysts and the remaining 29 (14%) were associated with additional ultrasonographic findings. Autosomal aneuploidy was found in one patient with an isolated choroid plexus cyst (trisomy 21) and in another with additional findings (trisomy 18); the mothers of both of these patients were at least 35 years old. For those fetuses with known outcome, the risk of aneuploidy with isolated choroid plexus cyst (one in 180) was not statistically significantly different from that associated with choroid plexus cyst accompanied by other sonographic findings (one in 26). More than 1000 fetuses with choroid plexus cysts would have to be studied to determine whether such a difference was real. Conclusion Because of the rarity of aneuploidy, the reported risk for a fetus with an isolated choroid plexus cyst must be interpreted cautiously and should include the baseline risk.

Prenatal prescription corticosteroids and offspring diabetes: A national cohort study

BACKGROUND Foetal exposure to excess glucocorticoids has been associated with altered development of multiple foetal systems that may persist after birth and lead to an increased risk of diseases. The purpose of this study is to investigate the role of prenatal prescription corticosteroids for the development of diabetes among offspring. METHODS We conducted a national birth cohort study of children from singleton pregnancies born in Denmark between 1 January 1997 and 31 December 2004 with follow-up through 31 December 2008. Four Danish nationwide administrative registries were linked to identify specific exposures, outcomes and covariates of interest among 505 386 children from singleton pregnancies born alive to 360 484 women. We calculated hazard ratios (HRs) comparing diabetes incidence (separately for type 1 and type 2 diabetes/elevated blood glucose) in children exposed vs unexposed to prescription corticosteroids prenatally. RESULTS Prenatal exposure to prescription corticosteroids was associated with a small increase in offspring type 1 diabetes incidence rate [HR = 1.20, 95% confidence limits (CL) = 0.94, 1.53] and with a 51% increase in type 2 diabetes/elevated blood glucose hazard ratio when comparing children exposed prenatally to prescription corticosteroids with those unexposed (HR = 1.51, 95% CL = 0.69, 3.31). The data were consistent with a monotonic increase in overall diabetes hazard ratios with increasing strength of the corticosteroid. CONCLUSIONS There may be a relation between prenatal prescription corticosteroid use and childhood diabetes but further studies with more extensive assessment of foetal exposures are warranted. If prenatal prescription corticosteroids contribute to the development of offspring diabetes, the public health implications could be substantial.

Practitioner-specific medians for nuchal translucency to improve first-trimester screening performance.

OBJECTIVE: Nuchal translucency medians are used to convert nuchal translucency measurements to multiple of the median values for use in risk assessment. There has been much debate about the use of practitioner–specific medians instead of population-based medians to correct for practitioner bias. This study examined data from the California Prenatal Screening Program to evaluate the effect of individual medians on screening performance. METHODS: For this retrospective study, we identified first-trimester specimens in the California Prenatal Screening Program database for which screening results were calculated using a practitioner–specific median (n=55,286) and recalculated risk assessment using a population-based median. We looked at positive rates for Down syndrome and Trisomy 18 as well as overall screening results. We also looked at the recalculated risks for cases in which there has been a positive diagnosis of a chromosomal abnormality to determine if cases would have been missed if practitioner–specific medians had not been used. RESULTS: Nuchal translucency multiples of the median would be lower for the majority of nuchal translucency practitioners if a population-based median were used instead of practitioner–specific medians. Outcomes data from the California Prenatal Screening Programs database indicate that 14 positively diagnosed cases would have been missed by the screening program if population-based medians had been used. CONCLUSION: The use of practitioner–specific medians corrects for practitioner bias in measuring nuchal translucency. Practitioner–specific medians improve screening performance and help meet detection rate goals. LEVEL OF EVIDENCE: II