Reliability of self reported smoking status by pregnant women for estimating smoking prevalence: a retrospective, cross sectional study.

OBJECTIVE: To determine what impact reliance on self reported smoking status during pregnancy has on both the accuracy of smoking prevalence figures and access to smoking cessation services for pregnant women in Scotland. DESIGN: Retrospective, cross sectional study of cotinine measurements in stored blood samples. PARTICIPANTS: Random sample (n=3475) of the 21 029 pregnant women in the West of Scotland who opted for second trimester prenatal screening over a one year period. MAIN OUTCOME MEASURE: Smoking status validated with cotinine measurement by maternal area deprivation category (Scottish Index of Multiple Deprivation). RESULTS: Reliance on self reported smoking status underestimated true smoking by 25% (1046/3475 (30%) from cotinine measurement v 839/3475 (24%) from self reporting, z score 8.27, P<0.001). Projected figures suggest that in Scotland more than 2400 pregnant smokers go undetected each year. A greater proportion of smokers in the least deprived areas (deprivation categories 1+2) did not report their smoking (39%) compared with women in the most deprived areas (22% in deprivation categories 4+5), but, because smoking was far more common in the most deprived areas (706 (40%) in deprived areas compared with 142 (14%) in affluent areas), projected figures for Scotland suggest that twice as many women in the most deprived areas are undetected (n=1196) than in the least deprived areas (n=642). CONCLUSION: Reliance on self reporting to identify pregnant smokers significantly underestimates the number of pregnant smokers in Scotland and results in a failure to detect over 2400 smokers each year who are therefore not offered smoking cessation services.

First-trimester contingent screening for Down syndrome can reduce the number of nuchal translucency measurements required.

BACKGROUND: To assess the performance of a two-stage screening protocol for Down syndrome based on initial serum marker analysis for all women and nuchal translucency (NT) measurement only in women with intermediate risks. METHODS: Biochemical marker and NT data in 10 189 women who had had combined ultrasound and biochemical (CUB) screening, were re-analysed using the contingent model. A risk was calculated from the results of the pregnancy-associated plasma protein A (PAPP-A) and free beta human chorionic gonadotrophin (FbetahCG) measurements and maternal age. For risks between 1 in 42 and 1 in 1000, the likelihood ratio from the NT measurement was incorporated and assessed against a final cut-off risk of 1 in 250. RESULTS: A total of 3.1% unaffected and 61.4% Down syndrome pregnancies had risks>or=1:42. In women with risks<1 in 42 and >1 in 1000 (29%), a further 2.7% unaffected pregnancies and 27.3% Down syndrome pregnancies had risks above 1 in 250 when NT was incorporated. Overall detection rate was 88.6%, and false positive rate 5.8% (compared with 90.9% and 6.4% for CUB screening). NT measurements were required in 29% of women. CONCLUSIONS: Within first-trimester, contingent screening provides good sensitivity and specificity with the potential for considerable saving in ultrasound resources.

Circulating angiogenic factors in early pregnancy and the risk of preeclampsia, intrauterine growth restriction, spontaneous preterm birth, and stillbirth.

OBJECTIVE: To estimate the relationship between maternal serum levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in early pregnancy with the risk of subsequent adverse outcome. METHODS: A nested, case-control study was performed within a prospective cohort study of Down syndrome screening. Maternal serum levels of sFlt-1 and PlGF at 10-14 weeks of gestation were compared between 939 women with complicated pregnancies and 937 controls. Associations were quantified as the odds ratio for a one decile increase in the corrected level of the analyte. RESULTS: Higher levels of sFlt-1 were not associated with the risk of preeclampsia but were associated with a reduced risk of delivery of a small for gestational age infant (odds ratio [OR] 0.92, 95% confidence interval [CI] 0.88-0.96), extreme (24-32 weeks) spontaneous preterm birth (OR 0.90, 95% CI 0.83-0.99), moderate (33-36 weeks) spontaneous preterm birth (OR 0.93, 95% CI 0.88-0.98), and stillbirth associated with abruption or growth restriction (OR 0.77, 95% CI 0.61-0.95). Higher levels of PlGF were associated with a reduced risk of preeclampsia (OR 0.95, 95% CI 0.90-0.99) and delivery of a small for gestational age infant (OR 0.95, 95% CI 0.91-0.99). Associations were minimally affected by adjustment for maternal characteristics. CONCLUSION: Higher early pregnancy levels of sFlt-1 and PlGF were associated with a decreased risk of adverse perinatal outcome.

Maternal obesity in early pregnancy and risk of spontaneous and elective preterm deliveries: a retrospective cohort study.

OBJECTIVES: We sought to determine the association between maternal body mass index and risk of preterm delivery. METHODS: We assessed 187,290 women in Scotland and estimated adjusted odds ratios for spontaneous and elective preterm deliveries among overweight, obese, and morbidly obese women relative to normal-weight women. RESULTS: Among nulliparous women, the risk of requiring an elective preterm delivery increased with increasing BMI, whereas the risk of spontaneous preterm labor decreased. Morbidly obese nulliparous women were at increased risk of all-cause preterm deliveries, neonatal death, and delivery of an infant weighing less than 1000 g who survived to 1 year of age (a proxy for severe long-term disability). By contrast, obesity and elective preterm delivery were only weakly associated among multiparous women. CONCLUSIONS: Obese nulliparous women are at increased risk of elective preterm deliveries. This in turn leads to an increased risk of perinatal mortality and is likely to lead to increased risks of long-term disability among surviving offspring.

Maternal and biochemical predictors of spontaneous preterm birth among nulliparous women: a systematic analysis in relation to the degree of prematurity.

BACKGROUND: Nulliparous women are at increased risk of spontaneous preterm birth. Other maternal and biochemical risk factors have also been described. However, it is unclear whether these associations are strong enough to offer clinically useful prediction. It is also unclear whether the predictive power of these factors varies in relation to the degree of prematurity. METHODS: The risk of spontaneous preterm birth associated with maternal characteristics and second trimester serum screening data was analysed in a dataset of 84 391 first births in Scotland between 1992 and 2001 using Cox and logistic regression. Variation in the relative risk of preterm birth over the period 24-36 weeks was assessed using a test of the proportional hazards assumption. RESULTS: The risk of spontaneous preterm birth was positively associated with maternal serum levels of alpha-fetoprotein, socioeconomic deprivation, number of previous therapeutic abortions, smoking, and being unmarried and was negatively associated with height and body mass index. The risk of preterm birth at 24-28 weeks, but not later gestations, was increased in association with maternal levels of human chorionic gonadotrophin >95th percentile, maternal age <20, and two or more previous miscarriages. The area under the receiver operating characterise curve (95% CI) for models based on these factors was 0.67 (0.63-0.71) for 24-28 weeks, 0.65 (0.62-0.68) for 29-32 weeks, and 0.62 (0.61-0.63) for 33-36 weeks. CONCLUSIONS: Time to event analytic methods can identify factors that are differentially associated with spontaneous preterm birth according to the degree of prematurity. However, models based on maternal and biochemical data perform poorly as a screening test for any degree of spontaneous preterm birth.

Pregnancy-associated plasma protein A and alpha-fetoprotein and prediction of adverse perinatal outcome.

OBJECTIVE: To describe the association between pregnancy associated plasma protein A (PAPP-A), alpha-fetoprotein (AFP) and adverse perinatal outcome. METHODS: We conducted a multicenter prospective cohort study of 8,483 women attending for prenatal care in southern Scotland between 1998 and 2000. The risk of delivering a small for gestational age infant, delivering preterm, and stillbirth were related to maternal serum levels of PAPP-A and AFP. RESULTS: Women with a low PAPP-A were not more likely to have elevated levels of AFP. Compared with women with a normal PAPP-A and a normal AFP, the odds ratio for delivering a small for gestational age infant for women with a high AFP was 0.9 (95% confidence interval [CI] 0.5-1.6), for women with a low PAPP-A was 2.8 (95% CI 2.0-4.0), and for women with both a high AFP and a low PAPP-A was 8.5 (95% CI 3.6-20.0). The odds ratio for delivering preterm for women with a high AFP was 1.8 (95% CI 1.3-2.7), for women with a low PAPP-A was 1.9 (95% CI 1.3-2.7), and for women with both a low PAPP-A and a high AFP was 9.9 (95% CI 4.4-22.0). These interactions were statistically significant for both outcomes (P = .03 and .04, respectively). There was a nonsignificant trend toward a similar interaction in relation to stillbirth risk. Of the women with the combination of a low PAPP-A and high AFP, 32.1% (95% CI 15.9-52.4) delivered a low birth weight infant. CONCLUSION: Low maternal serum levels of PAPP-A between 10 and 14 weeks and high levels of AFP between 15 and 21 weeks gestation are synergistically associated with adverse perinatal outcome. LEVEL OF EVIDENCE: II-2.

First-trimester placentation and the risk of antepartum stillbirth.

CONTEXT: Preterm birth and low birth weight are determined, at least in part, during the first trimester of pregnancy. However, it is unknown whether the risk of stillbirth is also determined during the first trimester. OBJECTIVE: To determine whether the risk of antepartum stillbirth varies in relation to circulating markers of placental function measured during the first trimester of pregnancy. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, prospective cohort study (conducted in Scotland from 1998 through 2000) of 7934 women who had singleton births at or after 24 weeks' gestation, who had blood taken during the first 10 weeks after conception, and who were entered into national registries of births and perinatal deaths. MAIN OUTCOME MEASURES: Antepartum stillbirths and stillbirths due to specific causes. RESULTS: There were 8 stillbirths among the 400 women with levels of pregnancy-associated plasma protein A (PAPP-A) in the lowest fifth percentile compared with 17 among the remaining 7534 women (incidence rate per 10,000 women per week of gestation: 13.4 vs 1.4, respectively; hazard ratio [HR], 9.2 [95% confidence interval [CI], 4.0-21.4]; P<.001). When analyzed by cause of stillbirth, low level of PAPP-A was strongly associated with stillbirth due to placental dysfunction, defined as abruption or unexplained stillbirth associated with growth restriction (incidence rate: 11.7 vs 0.3, respectively; HR, 46.0 [95% CI, 11.9-178.0]; P<.001), but was not associated with other causes of stillbirth (incidence rate: 1.7 vs 1.1, respectively; HR, 1.4 [95% CI, 0.2-10.6]; P = .75). There was no relationship between having a low level of PAPP-A and maternal age, ethnicity, parity, height, body mass index, race, or marital status. Adjustment for maternal factors did not attenuate the strength of associations observed. There was no association between maternal circulating levels of the free beta subunit of human chorionic gonadotropin and stillbirth risk. CONCLUSION: The risk of stillbirth in late pregnancy may be determined by placental function in the first 10 weeks after conception.

Second-trimester maternal serum levels of alpha-fetoprotein and the subsequent risk of sudden infant death syndrome.

BACKGROUND: Unexplained stillbirth and the sudden infant death syndrome (SIDS) share some features. A raised maternal serum level of alpha-fetoprotein during the second trimester of pregnancy is a marker of placental dysfunction and a strong predictor of the risk of unexplained stillbirth. It is unknown whether alpha-fetoprotein levels also predict the risk of SIDS. METHODS: We linked a prenatal-screening database for women in western Scotland with databases of maternity, perinatal death, and birth and death certifications to assess the association between second-trimester levels of maternal serum alpha-fetoprotein and the subsequent risk of SIDS. RESULTS: Among 214,532 women with singleton births, there were 114 cases of SIDS (incidence, 2.7 per 10,000 births among women with alpha-fetoprotein levels in the lowest quintile and 7.5 per 10,000 births among those with levels in the highest quintile). When the lowest quintile was used as a referent, the unadjusted odds ratios for SIDS for the second through fifth quintiles were 1.7 (95 percent confidence interval, 0.8 to 3.5), 1.8 (95 percent confidence interval, 0.9 to 3.7), 2.5 (95 percent confidence interval, 1.3 to 4.8), and 2.8 (95 percent confidence interval, 1.4 to 5.4), respectively (P for trend = 0.001). The risk of SIDS varied inversely with the birth-weight percentile and the gestational age at delivery; after adjustment for these factors, the odds ratios for SIDS were 1.7 (95 percent confidence interval, 0.8 to 3.5), 1.7 (95 percent confidence interval, 0.8 to 3.5), 2.2 (95 percent confidence interval, 1.1 to 4.4), and 2.2 (95 percent confidence interval, 1.1 to 4.3), respectively (P for trend = 0.01). CONCLUSIONS: There is a direct association between second-trimester maternal serum alpha-fetoprotein levels and the risk of SIDS, which may be mediated in part through impaired fetal growth and preterm birth.

Combined ultrasound and biochemical screening for Down's syndrome in the first trimester: a Scottish multicentre study.

OBJECTIVE: To evaluate the use of ultrasound measurements of fetal nuchal translucency (NT) obtained in a routine antenatal clinic setting in combination with appropriate biochemical markers as a first trimester screening test for Down's Syndrome. DESIGN: Multicentre observational study. SETTING: Fifteen Scottish maternity units. POPULATION: Pregnant women (n = 17,229) attending routine antenatal clinics at 10-14 weeks of gestation. METHODS: NT measurements were attempted in all women along with the measurement of maternal serum free beta human chorionic gonadotrophin (F beta hCG) and pregnancy-associated plasma protein-A (PAPP-A). All results were converted to multiples of the appropriate gestational median (MoM) and using a statistical model the risk of an affected pregnancy was derived. No results were given to participating women but all were offered routine second trimester biochemical screening. All cases of Down's Syndrome within the study group were ascertained and the detection rate for each marker was estimated. MAIN OUTCOME MEASURES: Success rate of obtaining NT measurements and overall effectiveness of ultrasound and biochemical markers individually and in combination for the detection of Down's Syndrome pregnancies. RESULTS: NT measurements were obtained in 72.9% of women and blood samples in 98.4%. Forty-five cases of Down's Syndrome were ascertained (2.6/1,000). NT measurements were obtained in 37 cases (median NT 1.65 MoM), blood samples in 42 cases and both NT and blood in 34 cases. In combination with the a priori maternal age risk, observed detection rates at a 5% false positive rate were 20/37 (54%) for NT, 23/42 (55%) for F beta hCG and PAPP-A and 28/34 (82%) for a combination of NT, F beta hCG and PAPP-A using a cutoff risk of 1:250. The effect of failing to obtain NT measurements in all cases reduces the overall detection rate to 62% (i.e. 28/45) if the entire series of affected pregnancies within the study group is considered. CONCLUSIONS: NT in combination with appropriate serum markers has the potential to detect over 80% of Down's Syndrome fetuses in early pregnancy. However, NT measurement is highly operator-dependent. It requires training, external quality control and adequate time to allow accurate measurement, otherwise suboptimal performance will result.

Early pregnancy levels of pregnancy-associated plasma protein a and the risk of intrauterine growth restriction, premature birth, preeclampsia, and stillbirth.

The risk of adverse perinatal outcome among 8839 women recruited to a multicenter, prospective cohort study was related to maternal circulating concentrations of trophoblast-derived proteins at 8-14 wk gestation. Women with a pregnancy-associated plasma protein A (PAPP-A) in the lowest fifth percentile at 8-14 wk gestation had an increased risk of intrauterine growth restriction [adjusted odds ratio, 2.9; 95% confidence interval (CI), 2.0-4.1], extremely premature delivery (adjusted odds ratio, 2.9; 95% CI, 1.6-5.5), moderately premature delivery (adjusted odds ratio, 2.4; 95% CI, 1.7-3.5), preeclampsia (adjusted odds ratio, 2.3; 95% CI, 1.6-3.3), and stillbirth (adjusted odds ratio, 3.6; 95% CI, 1.2-11.0). The strengths of the associations were similar when the test was performed before 13 wk gestation or between 13 and 14 wk gestation. In contrast, levels of free beta-human CG, another circulating protein synthesized by the syncytiotrophoblast, were not predictive of later outcome in multivariate analysis. PAPP-A has been identified as a protease specific for IGF binding proteins. We conclude that control of the IGF system in the first and early second trimester trophoblast may have a key role in determining subsequent pregnancy outcome.