Association of Prenatal Exposure to Maternal Drinking and Smoking With the Risk of Stillbirth.

Importance: Prenatal smoking is a known modifiable risk factor for stillbirth; however, the contribution of prenatal drinking or the combination of smoking and drinking is uncertain. Objective: To examine whether prenatal exposure to alcohol and tobacco cigarettes is associated with the risk of stillbirth. Design, Setting, and Participants: The Safe Passage Study was a longitudinal, prospective cohort study with data collection conducted between August 1, 2007, and January 31, 2015. Pregnant women from Cape Town, South Africa, and the Northern Plains region of the US were recruited and followed up throughout pregnancy. Data analysis was performed from November 1, 2018, to November 20, 2020. Exposure: Maternal consumption of alcohol and tobacco cigarettes in the prenatal period. Main Outcomes and Measures: The main outcomes were stillbirth, defined as fetal death at 20 or more weeks' gestation, and late stillbirth, defined as fetal death at 28 or more weeks' gestation. Self-reported alcohol and tobacco cigarette consumption was captured at the recruitment interview and up to 3 scheduled visits during pregnancy. Participants were followed up during pregnancy to obtain delivery outcome. Results: Of 11663 pregnancies (mean [SD] gestational age at enrollment, 18.6 [6.6] weeks) in 8506 women for whom the pregnancy outcome was known by 20 weeks' gestation or later and who did not terminate their pregnancies, there were 145 stillbirths (12.4 per 1000 pregnancies) and 82 late stillbirths (7.1 per 1000 pregnancies). A total of 59% of pregnancies were in women from South Africa, 59% were in multiracial women, 23% were in White women, 17% were in American Indian women, and 0.9% were in women of other races. A total of 8% were older than 35 years. In 51% of pregnancies, women reported no alcohol or tobacco cigarette exposure (risk of stillbirth, 4 per 1000 pregnancies). After the first trimester, 18% drank and smoked (risk of stillbirth, 15 per 1000 births), 9% drank only (risk of stillbirth, 10 per 1000 pregnancies), and 22% smoked only (risk of stillbirth, 8 per 1000 pregnancies). Compared with the reference group (pregnancies not prenatally exposed or without any exposure after the first trimester), the adjusted relative risk of late stillbirth was 2.78 (98.3% CI, 1.12-6.67) for pregnancies prenatally exposed to drinking and smoking, 2.22 (98.3% CI, 0.78-6.18) for pregnancies prenatally exposed to drinking only after the first trimester, and 1.60 (98.3% CI, 0.64-3.98) for pregnancies prenatally exposed to smoking only after the first trimester. The adjusted relative risk for all stillbirths was 1.75 (98.3% CI, 0.96-3.18) for dual exposure, 1.26 (98.3% CI, 0.58-2.74) for drinking only, and 1.27 (98.3% CI, 0.69-2.35) for smoking only compared with the reference group. Conclusions and Relevance: These results suggest that combined drinking and smoking after the first trimester of pregnancy, compared with no exposure or quitting before the end of the first trimester, may be associated with a significantly increased risk of late stillbirth.

Concurrent prenatal drinking and smoking increases risk for SIDS: Safe Passage Study report.

BACKGROUND: Sudden infant death syndrome (SIDS) is the leading cause of postneonatal mortality. Although the rate has plateaued, any unexpected death of an infant is a family tragedy thus finding causes and contributors to risk remains a major public health concern. The primary objective of this investigation was to determine patterns of drinking and smoking during pregnancy that increase risk of SIDS. METHODS: The Safe Passage Study was a prospective, multi-center, observational study with 10,088 women, 11,892 pregnancies, and 12,029 fetuses, followed to 1-year post delivery. Subjects were from two sites in Cape Town, South Africa and five United States sites, including two American Indian Reservations. Group-based trajectory modeling was utilized to categorize patterns of drinking and smoking exposure during pregnancy. FINDINGS: One-year outcome was ascertained in 94·2% infants, with 28 SIDS (2·43/1000) and 38 known causes of death (3·30/1000). The increase in relative risk for SIDS, adjusted for key demographic and clinical characteristics, was 11·79 (98·3% CI: 2·59-53·7, p < 0·001) in infants whose mothers reported both prenatal drinking and smoking beyond the first trimester, 3.95 (98·3% CI: 0·44-35·83, p = 0·14), for drinking only beyond the first trimester and 4·86 (95% CI: 0·97-24·27, p = 0·02) for smoking only beyond the first trimester as compared to those unexposed or reported quitting early in pregnancy. INTERPRETATION: Infants prenatally exposed to both alcohol and cigarettes continuing beyond the first trimester have a substantially higher risk for SIDS compared to those unexposed, exposed to alcohol or cigarettes alone, or when mother reported quitting early in pregnancy. Given that prenatal drinking and smoking are modifiable risk factors, these results address a major global public health problem. FUNDING: National Institute on Alcohol Abuse and Alcoholism, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute on Deafness and Other Communication Disorders.

A modified Timeline Followback assessment to capture alcohol exposure in pregnant women: Application in the Safe Passage Study.

Prenatal alcohol exposure (PAE) has been linked to poor pregnancy outcomes, yet there is no recognized standard for PAE assessment, and the specific effects of quantity, frequency, and timing remain largely unknown. The Safe Passage Study was designed to investigate the role of PAE in a continuum of poor peri- and postnatal outcomes. The objective of this manuscript is to describe the rationale for, and feasibility of, modifications to the traditional Timeline Followback (TLFB) for collecting PAE information in a large cohort of pregnant women. Participants from the Northern Plains region (in the United States) and Cape Town, South Africa, were followed prospectively using a modified 30-day TLFB interview, administered up to five times, to obtain detailed PAE information. Required modifications for our population included capturing information regarding sharing, type/brand, container size, and duration, in order to accurately record the amount of alcohol consumed. PAE status was defined for 99.9% of the 11,892 enrolled pregnancies at least once during pregnancy and for 92% across all trimesters. Of 53,823 drinks reported, 98% had all items necessary for standard drink computation. Sharing was reported for 74% of drinks in Cape Town, South Africa and for 10% in the Northern Plains. Compared to referent values from the traditional TLFB, 74% and 67% of drinks had different alcohol-by-volume and container size, respectively. Furthermore, a statistically significant difference was found between the number of containers reported and the number of standard drinks computed, using information from the modified TLFB. This is the first study of this size to wholly encompass all of these changes into a single measure in order to more accurately calculate daily consumption and assess patterns over time. The methods used to collect PAE information and create alcohol exposure measures likely increased the accuracy of standard drinks reported and could be generalized to other populations.

Drinking and smoking patterns during pregnancy: Development of group-based trajectories in the Safe Passage Study.

Precise identification of drinking and smoking patterns during pregnancy is crucial to better understand the risk to the fetus. The purpose of this manuscript is to describe the methodological approach used to define prenatal drinking and smoking trajectories from a large prospective pregnancy cohort, and to describe maternal characteristics associated with different exposure patterns. In the Safe Passage Study, detailed information regarding quantity, frequency, and timing of exposure was self-reported up to four times during pregnancy and at 1 month post-delivery. Exposure trajectories were developed using data from 11,692 pregnancies (9912 women) where pregnancy outcome was known. Women were from three diverse populations: white (23%) and American Indian (17%) in the Northern Plains, US, and mixed ancestry (59%) in South Africa (other/not specified [1%]). Group-based trajectory modeling was used to identify 5 unique drinking trajectories (1 none/minimal, 2 quitting groups, 2 continuous groups) and 7 smoking trajectories (1 none/minimal, 2 quitting groups, 4 continuous groups). Women with pregnancies assigned to the low- or high-continuous drinking groups were less likely to have completed high school and were more likely to have enrolled in the study in the third trimester, be of mixed ancestry, or be depressed than those assigned to the none/minimal or quit-drinking groups. Results were similar when comparing continuous smokers to none/minimal and quit-smoking groups. Further, women classified as high- or low-continuous drinkers were more likely to smoke at moderate-, high-, and very high-continuous levels, as compared to women classified as non-drinkers and quitters. This is the first study of this size to utilize group-based trajectory modeling to identify unique prenatal drinking and smoking trajectories. These trajectories will be used in future analyses to determine which specific exposure patterns subsequently manifest as poor peri- and postnatal outcomes.

Clinical measures in transthyretin familial amyloid polyneuropathy.

INTRODUCTION: This observational, cross-sectional, single-center study aimed to identify instruments capable of measuring disease progression in transthyretin familial amyloid polyneuropathy (TTR-FAP). METHODS: The relationship between disease stage and Neuropathy Impairment Score-Lower Limbs (NIS-LL) and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score was assessed in 61 (stages 1-3) patients with TTR-FAP (V30M variant) and 16 healthy controls. Composite measures of large- and small-nerve fiber function, and modified body mass index (mBMI) were also assessed. RESULTS: Ordinal-based NIS-LL and Norfolk QOL-DN scores discriminated between disease stages (P < 0.0001 for NIS-LL and Norfolk QOL-DN). Longer disease duration correlated with worse NIS-LL and Norfolk QOL-DN. Karnofsky performance score declined progressively by disease stage. Composite measures of nerve fiber function differentiated stage 1 from stage 2 disease. The mBMI declined with advancing disease. CONCLUSIONS: NIS-LL, Norfolk QOL-DN score, composite endpoints of nerve fiber function, and mBMI are valid, reliable measures of TTR-FAP severity. Muscle Nerve 55: 323-332, 2017.

Clinical sensitivity and specificity of meconium fatty acid ethyl ester, ethyl glucuronide, and ethyl sulfate for detecting maternal drinking during pregnancy.

BACKGROUND: We investigated agreement between self-reported prenatal alcohol exposure (PAE) and objective meconium alcohol markers to determine the optimal meconium marker and threshold for identifying PAE. METHODS: Meconium fatty acid ethyl esters (FAEE), ethyl glucuronide (EtG), and ethyl sulfate (EtS) were quantified by LC-MS/MS in 0.1 g meconium from infants of Safe Passage Study participants. Detailed PAE information was collected from women with a validated timeline follow-back interview. Because meconium formation begins during weeks 12-20, maternal self-reported drinking at or beyond 19 weeks was our exposure variable. RESULTS: Of 107 women, 33 reported no alcohol consumption in pregnancy, 16 stopped drinking by week 19, and 58 drank beyond 19 weeks (including 45 third-trimester drinkers). There was moderate to substantial agreement between self-reported PAE at ≥19 weeks and meconium EtG ≥30 ng/g (κ = 0.57, 95% CI 0.41-0.73). This biomarker and associated cutoff was superior to a 7 FAEE sum ≥2 nmol/g and all other individual and combination marker cutoffs. With meconium EtG ≥30 ng/g as the gold standard condition and maternal self-report at ≥19 weeks' gestation as the test condition, 82% clinical sensitivity (95% CI 71.6-92.0) and 75% specificity (95% CI 63.2-86.8) were observed. A significant dose-concentration relationship between self-reported drinks per drinking day and meconium EtG ≥30 ng/g also was observed (all P < 0.01). CONCLUSIONS: Maternal alcohol consumption at ≥19 weeks was better represented by meconium EtG ≥30 ng/g than currently used FAEE cutoffs.

Effects of tafamidis on transthyretin stabilization and clinical outcomes in patients with non-Val30Met transthyretin amyloidosis.

This phase II, open-label, single-treatment arm study evaluated the pharmacodynamics, efficacy, and safety of tafamidis in patients with non-Val30Met transthyretin (TTR) amyloidosis. Twenty-one patients with eight different non-Val30Met mutations received 20 mg QD of tafamidis meglumine for 12 months. The primary outcome, TTR stabilization at Week 6, was achieved in 18 (94.7%) of 19 patients with evaluable data. TTR was stabilized in 100% of patients with non-missing data at Months 6 (n = 18) and 12 (n = 17). Exploratory efficacy measures demonstrated some worsening of neurological function. However, health-related quality of life, cardiac biomarker N-terminal pro-hormone brain natriuretic peptide, echocardiographic parameters, and modified body mass index did not demonstrate clinically relevant worsening during the 12 months of treatment. Tafamidis was well tolerated. In conclusion, our findings suggest that tafamidis 20 mg QD effectively stabilized TTR associated with several non-Val30Met variants.

First- and second-trimester screening: detection of aneuploidies other than Down syndrome.

OBJECTIVE: To evaluate the performance of first- and second-trimester screening methods for the detection of aneuploidies other than Down syndrome. METHODS: Patients with singleton pregnancies at 10 weeks 3 days through 13 weeks 6 days of gestation were recruited at 15 U.S. centers. All patients had a first-trimester nuchal translucency scan, and those without cystic hygroma had a combined test (nuchal translucency, pregnancy-associated plasma protein A, and free beta-hCG) and returned at 15-18 weeks for a second-trimester quadruple screen (serum alpha-fetoprotein, total hCG, unconjugated estriol, and inhibin-A). Risk cutoff levels of 1:300 for Down syndrome and 1:100 for trisomy 18 were selected. RESULTS: Thirty-six thousand one hundred seventy-one patients completed first-trimester screening, and 35,236 completed second-trimester screening. There were 77 cases of non-Down syndrome aneuploidies identified in this population; 41 were positive for a cystic hygroma in the first trimester, and a further 36 had a combined test, of whom 29 proceeded to quadruple screening. First-trimester screening, by cystic hygroma determination or combined screening had a 78% detection rate for all non-Down syndrome aneuploidies, with an overall false-positive rate of 6.0%. Sixty-nine percent of non-Down syndrome aneuploidies were identified as screen-positive by the second-trimester quadruple screen, at a false-positive rate of 8.9%. In the combined test, the use of trisomy 18 risks did not detect any additional non-Down syndrome aneuploidies compared with the Down syndrome risk alone. In second-trimester quadruple screening, a trisomy 18-specific algorithm detected an additional 41% non-Down syndrome aneuploidies not detected using the Down syndrome algorithm. CONCLUSION: First-trimester Down syndrome screening protocols can detect the majority of cases of non-Down aneuploidies. Addition of a trisomy 18-specific risk algorithm in the second trimester achieves high detection rates for aneuploidies other than Down syndrome. LEVEL OF EVIDENCE: II.

Nuchal translucency and the risk of congenital heart disease.

OBJECTIVE: To estimate whether nuchal translucency assessment is a useful screening tool for major congenital heart disease (CHD) in the absence of aneuploidy. METHODS: Unselected patients with singleton pregnancies at 10(3/7) to 13(6/7) weeks of gestation were recruited at 15 U.S. centers to undergo nuchal translucency sonography. Screening characteristics of nuchal translucency in the detection of major CHD were determined using different cutoffs (2.0 or more multiples of the median [MoM], 2.5 or more MoM, 3.0 or more MoM). RESULTS: A total of 34,266 euploid fetuses with cardiac outcome data were available for analysis. There were 224 cases of CHD (incidence 6.5 per 1,000), of which 52 (23.2%) were major (incidence 1.5 per 1,000). The incidence of major CHD increased with increasing nuchal translucency: 14.1 per 1,000, 33.5 per 1,000, and 49.5 per 1,000 at 2.0 or more MoM, 2.5 or more MoM, and 3.0 or more MoM cutoffs, respectively. Sensitivity, specificity, and positive predictive values were 15.4%, 98.4%, and 1.4% at 2.0 or more MoM; 13.5%, 99.4%, and 3.3% at 2.5 or more MoM; and 9.6%, 99.7%, and 5.0% at 3.0 or more MoM. Nuchal translucency of 2.5 or more MoM (99th percentile) had a likelihood ratio (95% confidence interval) of 22.5 (11.4-45.5) for major CHD. Based on our data, for every 100 patients referred for fetal echocardiography with a nuchal translucency of 99th percentile or more, three will have a major cardiac anomaly. CONCLUSION: Nuchal translucency sonography in the first trimester lacks the characteristics of a good screening tool for major CHD in a large unselected population. However, nuchal translucency of 2.5 or more MoM (99th percentile or more) should be considered an indication for fetal echocardiography. LEVEL OF EVIDENCE: II.

First-trimester nasal bone evaluation for aneuploidy in the general population.

OBJECTIVE: To evaluate the role of fetal nasal bone imaging at 10 3/7 to 13 6/7 weeks as a screening tool for aneuploidy, in a prospective multicenter trial. METHODS: Unselected patients from the general population with viable singleton pregnancies at 10 3/7 to 13 6/7 weeks were recruited at 15 U.S. centers. All had screening with nuchal translucency (NT) ultrasound by specially trained sonographers. In the last 8 months of this trial, first trimester nasal bone evaluation was added to the screening protocol. Nasal bones were described as present, absent, or unable to determine. RESULTS: A total of 38,189 patients completed first trimester NT screening, of whom 6,324 also underwent nasal bone sonography. An acceptable nasal image was obtained in 4,801 cases (76%), with nasal bones described as present in 4,779 (99.5%), and absent in 22 (0.5%). There were 11 identified cases of trisomy-21 in the population of 6,324 patients. In 9 of the 11 cases (82%) the nasal bones were described as present, and 2 cases were described as unable to determine. The only other aneuploidies were 2 cases of trisomy-18, in 1 of which the nasal bones were described as absent, and in 1 present. Absence of nasal bones had sensitivity for aneuploidy of 7.7%, false-positive rate 0.3%, and positive predictive value 4.5%. CONCLUSION: First-trimester nasal bone evaluation was not a useful test for population screening for trisomy-21 and added little to first-trimester NT screening. The difficulty in performing first-trimester nasal bone sonography consistently, in the general population setting, will significantly limit the usefulness of this aneuploidy screening technique.