First-trimester pre-eclampsia biomarker profiles in Asian population: multicenter cohort study.

OBJECTIVES: To (i) evaluate the applicability of the European-derived biomarker multiples of the median (MoM) formulae for risk assessment of preterm pre-eclampsia (PE) in seven Asian populations, spanning the east, southeast and south regions of the continent, (ii) perform quality-assurance (QA) assessment of the biomarker measurements and (iii) establish criteria for prospective ongoing QA assessment of biomarker measurements. METHODS: This was a prospective, non-intervention, multicenter study in 4023 singleton pregnancies, at 11 to 13 + 6 weeks' gestation, in 11 recruiting centers in China, Hong Kong, India, Japan, Singapore, Taiwan and Thailand. Women were screened for preterm PE between December 2016 and June 2018 and gave written informed consent to participate in the study. Maternal and pregnancy characteristics were recorded and mean arterial pressure (MAP), mean uterine artery pulsatility index (UtA-PI) and maternal serum placental growth factor (PlGF) were measured in accordance with The Fetal Medicine Foundation (FMF) standardized measurement protocols. MAP, UtA-PI and PlGF were transformed into MoMs using the published FMF formulae, derived from a largely Caucasian population in Europe, which adjust for gestational age and covariates that affect directly the biomarker levels. Variations in biomarker MoM values and their dispersion (SD) and cumulative sum tests over time were evaluated in order to identify systematic deviations in biomarker measurements from the expected distributions. RESULTS: In the total screened population, the median (95% CI) MoM values of MAP, UtA-PI and PlGF were 0.961 (0.956-0.965), 1.018 (0.996-1.030) and 0.891 (0.861-0.909), respectively. Women in this largely Asian cohort had approximately 4% and 11% lower MAP and PlGF MoM levels, respectively, compared with those expected from normal median formulae, based on a largely Caucasian population, whilst UtA-PI MoM values were similar. UtA-PI and PlGF MoMs were beyond the 0.4 to 2.5 MoM range (truncation limits) in 16 (0.4%) and 256 (6.4%) pregnancies, respectively. QA assessment tools indicated that women in all centers had consistently lower MAP MoM values than expected, but were within 10% of the expected value. UtA-PI MoM values were within 10% of the expected value at all sites except one. Most PlGF MoM values were systematically 10% lower than the expected value, except for those derived from a South Asian population, which were 37% higher. CONCLUSIONS: Owing to the anthropometric differences in Asian compared with Caucasian women, significant differences in biomarker MoM values for PE screening, particularly MAP and PlGF MoMs, were noted in Asian populations compared with the expected values based on European-derived formulae. If reliable and consistent patient-specific risks for preterm PE are to be reported, adjustment for additional factors or development of Asian-specific formulae for the calculation of biomarker MoMs is required. We have also demonstrated the importance and need for regular quality assessment of biomarker values. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Vitamin D status and its determinants in healthy pregnant women living in Switzerland in the first trimester of pregnancy.

OBJECTIVES: Our study aimed at assessing the prevalence and determinants of vitamin D deficiency (25-hydroxy-vitamin D [25(OH)D] < 20 ng/mL) in pregnant women in the first trimester living in Switzerland. METHODS: From September 2014 through December 2015, 204 pregnant women were conveniently recruited during their first clinical appointment at the Clinic of Obstetrics of the University Hospital Zurich (between week 6 and 12 of pregnancy). Blood samples were collected and a questionnaire focusing on lifestyle and skin colour was completed face-to-face with the responsible physician. Logistic regression analyses were performed with vitamin D status as dependent variable. RESULTS: 63.2% of the participating women were vitamin D deficient, and the median vitamin D concentration in the overall sample was 17.1 ng/mL [Q1, Q3: 9.78, 22.3]. The highest proportions of vitamin D deficiency were detected in women originating from Africa and Middle East (91.4% deficient, median vitamin D concentration of 10.7 ng/mL [Q1, Q3: 6.55, 14.45]) and from South-East Asia/Pacific (88.5% deficient, median vitamin D concentration of 8.4 ng/mL [Q1, Q3: 6.10, 14.88]). Multivariable logistic regression showed that significant risk factors of vitamin D deficiency were country of origin (women born in Switzerland and Germany had a lower risk than women born in other countries), smoking status (lower risk for former smokers) and intake of vitamin D supplements. CONCLUSIONS: Our results confirm a high prevalence of vitamin D deficiency in this Swiss cohort, in particular in women coming from Asian and African countries, and underline the importance of appropriate counseling and vitamin D supplementation in early pregnancy.

Effect of Iodine Nutrition on Pregnancy Outcomes in an Iodine-Sufficient Area in China.

Many studies focused on the association between thyroid disease and pregnancy outcomes. The present study explored the effect of iodine nutrition during the first trimester on pregnancy outcomes. One thousand five hundred sixty-nine pregnant, euthyroid women at ≤12 weeks of gestation in an iodine-sufficient area in China were recruited. According to the World Health Organization (WHO) criteria for iodine nutrition during pregnancy, participants were divided into four groups: adequate iodine (median urinary iodine concentration (UIC), 150-249 µg/L), mild deficiency (UIC, 100-150 µg/L), moderate and severe deficiency (UIC, <100 µg/L), and more than adequate and excessive (UIC, ≥250 µg/L) groups. Pregnancy outcomes, including abortion, gestational hypertension, pre-eclampsia, gestational diabetes mellitus (GDM), placenta previa, placental abruption, preterm labor, low birth weight infants, macrosomia, breech presentation, and cord entanglement, were obtained during follow-up. The results showed that there was no significant difference in general characteristics, including age, body mass index, abdominal circumference, systolic blood pressure, diastolic blood pressure, heart rate, smoking rate, and drinking rate, among the four groups. In the more than adequate and excessive group, thyroid-stimulating hormone (TSH) was greater and free thyroxine (FT4) was lower than any other groups but still within normal range. The thyroglobulin (Tg) level was greater in the moderate and severe deficiency group. The incidence of GDM was significantly greater in women with mild iodine deficiency than in women with adequate iodine nutriture (18.38 vs. 13.70%, p < 0.05). Compared with the adequate group, incidence of macrosomia was significantly greater in the more than adequate and excessive group (12.42 vs. 9.79%, p < 0.05). Mild iodine deficiency was an independent risk factor for GDM (odds ratio = 1.566, 95% confidence interval = 1.060-2.313, p = 0.024); more than adequate and excessive iodine was an independent risk factor for macrosomia (OR = 1.917, CI = 1.128-3.256, p = 0.016). In summary, during 1st trimester, both mild iodine deficiency and excessive iodine intake had adverse impacts on pregnancy outcomes in an iodine-sufficient area.

Epidemiology of Dysglycemia in Pregnant Oklahoma American Indian Women.

CONTEXT: Minority communities are disproportionately affected by diabetes, and minority women are at an increased risk for glucose intolerance (dysglycemia) during pregnancy. OBJECTIVES: In pregnant American Indian women, the objectives of the study were to use current criteria to estimate the prevalence of first-trimester (Tr1) dysglycemia and second-trimester (Tr2) incidence of gestational diabetes mellitus (GDM) and to explore new candidate measures and identify associated clinical factors. DESIGN: This was a prospective cohort study. In Tr1 we performed a 75-g, 2-hour oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) to determine the following: fasting insulin; homeostasis model assessment of insulin resistance; serum 1,5-anhydroglucitol; noninvasive skin autofluorescence (SCOUT). We defined dysglycemia by American Diabetes Association and Endocrine Society criteria and as HbA1c of 5.7% or greater. In Tr2 in an available subset, we performed a repeat OGTT and SCOUT. PARTICIPANTS: Pregnant American Indian women (n = 244 at Tr1; n = 114 at Tr2) participated in the study. OUTCOMES: The prevalence of dysglycemia at Tr1 and incidence of GDM at Tr2 were measured. RESULTS: At Tr1, one woman had overt diabetes; 36 (15%) had impaired glucose tolerance (American Diabetes Association criteria and/or abnormal HbA1c) and 59 (24%) had GDM-Tr1 (Endocrine Society criteria). Overall, 74 (30%) had some form of dysglycemia. Associated factors were body mass index, hypertension, waist/hip circumferences, SCOUT score, fasting insulin, and homeostasis model assessment of insulin resistance. At Tr2, 114 of the Tr1 cohort underwent a repeat OGTT and SCOUT, and 26 (23%) had GDM. GDM-Tr2 was associated with increased SCOUT scores (P = .029) and Tr1 body mass index, waist/hip circumferences, diastolic blood pressure, fasting insulin, and triglyceride levels. Overall, dysglycemia at Tr1 and/or Tr2 affected 38% of the women. CONCLUSIONS: Dysglycemia at some point during pregnancy was common among American Indian women. It was associated with features of insulin resistance and may confer long-term health risks for mother and child.

Effect of ethnicity on first trimester biomarkers for combined trisomy 21 screening: results from a multicenter study in six Asian countries.

OBJECTIVE: To assess differences between first trimester trisomy 21 screening markers free beta chain of the human chorionic gonadotrophin (ßhCG) and pregnancy-associated plasma protein A (PAPP-A) in pregnant women of six different Asian countries (China, Indonesia, Korea, Taiwan, Thailand, and Vietnam) and compare serum levels with those in women of European countries. METHODS: Median and multiple of median (MoM) values of free ßhCG and PAPP-A were determined in more than 3000 pregnant women from the Asian countries during their first trimester of pregnancy. Differences in MoM values between a European reference group from a previous multicenter evaluation and the Asian population were evaluated. Two different types of population correction factors for T21 risk estimation were assessed. RESULTS: An at least 10% difference of median MoMs between European and Asian PAPP-A values was found to be statistically significant (p < 0.0001). The specificity of the screening did not show a big difference in individual countries, when using the country-specific correction factor compared with the overall Asian correction factor (<1.4%). CONCLUSIONS: The use of a correction factor is recommended based on the differences in European and Asian MoM values. Developing country-specific medians in larger study populations can help identify clinical relevant differences and give the opportunity to explore a more accurate risk calculation.

The fetal frontomaxillary facial angle in normal and trisomy 21 ultrasounds at 11-13(+6) weeks of gestation: findings among the ethnic Chinese compared with Caucasian.

OBJECTIVE: The aim of this research was to compare the fetal frontomaxillary facial (FMF) angle between normal and trisomy 21 fetuses at 11(+0) -13(+6) weeks gestation in a Chinese population. METHODS: A prospective observational study was performed that included 640 euploid and 45 trisomy 21 singleton pregnancies undergoing first trimester ultrasound screening between 11 and 13(+6) weeks of gestation. The FMF angle was measured in the midsagittal plane using the standard technique. RESULTS: The fetal mean FMF angle decreased with the increasing crown-rump length (CRL) from 88.6°at a CRL of 45 mm to 78.5° at a CRL of 84 mm (FMF angle = 100.212 - 0.258 × CRL, R(2) = 0.222, p < 0.001). The overall mean FMF angle in the euploid population was 82.9° ± 4.1° and in trisomy 21 cases, 92.3° ± 5.2°. CONCLUSIONS: Fetal FMF angle is affected by gestational age in a Chinese population, although it remains a significant predictor of fetal trisomy 21.

AlphaLISA for the determination of median levels of the free ß subunit of human chorionic gonadotropin in the serum of pregnant women.

Measurement of the free ß subunit of human chorionic gonadotropin (free ß-hCG) in serum is useful for prenatal screening. Concentrations of free ß-hCG vary in different races. Conventional assays used for such measurements have limitations. We applied the AlphaLISA to measure levels of free ß-hCG in maternal serum during 8-20 weeks of gestation in women from southern China. Two anti-free ß-hCG antibodies were used: one was coated on AlphaLISA acceptor beads and the one was biotinylated. The assay also contained donor beads coated with streptavidin. The AlphaLISA assay detection limit was 0.11 ng/mL, and the analytical range was 0.11-200 ng/mL. The intra- and interassay coefficients of variation were 1.32%-2.50% and 3.44%-5.45%, respectively. The correlation with commercial Eu(3+)-labeled free ß-HCG-TRFIA assay was good (y = 1.045x + 1.580, r(2) = 0.978). Median levels of free ß-hCG in maternal serum at 8-20 weeks gestation were higher in women from southern China compared with those reported in women from other countries. The AlphaLISA for free ß-HCG could become the assay of choice for applications in clinical diagnostics. The established median value of free ß-HCG is helpful in clinical diagnosis specific for southern Chinese women.

Correction of first trimester biochemical aneuploidy screening markers for smoking status: influence of gestational age, maternal ethnicity and cigarette dosage.

OBJECTIVE: To examine the gestational age, maternal ethnicity and cigarette dosage effects of the reduction of maternal serum pregnancy-associated plasma protein A (PAPP-A) and free-ß human chorionic gonadotrophin (free hCGß) in smokers. METHODS: Maternal serum PAPP-A and free hCGß corrected for confounders, excluding smoking, in first trimester smokers and nonsmokers were compared by gestational age, maternal ethnicity and cigarette dosage. A small set of second trimester smokers and nonsmoker controls were analysed for PAPP-A along with free hCGß and assessed for gestational age effects of smoking. RESULTS: Pregnancy-associated plasma protein A reduction by smoking in the first trimester was not influenced by gestational age, however free hCGß levels were only significantly reduced in weeks 12 and 13 in smokers. Ethnicity and cigarette dosage were also found to influence the reduction of both makers in smokers in the first trimester. In second trimester smokers, PAPP-A was found to be reduced by less and free hCGß reduced by more than in the first trimester, although no second trimester gestational age effect on smoking was found. CONCLUSIONS: Current methods of correcting for smoking status may be an oversimplification of a more complex subject.

First-trimester prediction of preeclampsia in nulliparous women at low risk.

OBJECTIVE: To identify clinical characteristics and biochemical markers in first-trimester samples that would possibly predict the subsequent development of preeclampsia. METHODS: We conducted a multicenter observational study in 2,434 nulliparous women at low risk to identify biomarkers that possibly predict preeclampsia. Clinical history, complete blood count, and biochemical markers were assessed in the first trimester. The trophoblast and angiogenesis markers ADAM-12, pregnancy-associated plasma protein-A, placental protein 13, placental growth factor, soluble fms-like tyrosine kinase-1, and endoglin were measured in a case-control subset of 174 women with preeclampsia and 509 women in the control group. RESULTS: Univariable analysis revealed maternal age, race, marital status, years of education, source of medical payment, prenatal caregiver, body mass index (BMI, calculated as weight (kg)/[height (m)]), and systolic blood pressure at enrollment were significantly associated with preeclampsia. Mean platelet volume was greater at enrollment in women who later had development of preeclampsia (median 9.4 compared with 9.0 femtoliter (fl); P=.02). First-trimester concentrations (multiples of the median) of ADAM-12 (1.14 compared with 1.04; P=.003), pregnancy-associated plasma protein-A (0.94 compared with 0.98; P=.04), and placental growth factor (0.83 compared with 1.04; P<.001) were significantly different in women who had development of preeclampsia compared with women in the control group. The optimal multivariable model included African American race, systolic blood pressure, BMI, education level, ADAM-12, pregnancy-associated plasma protein-A, and placental growth factor, and yielded an area under the curve of 0.73 (95% confidence interval 0.69-0.77) and a sensitivity of 46.1% (95% confidence interval 38.3-54.0) for 80% specificity. CONCLUSION: A multivariable analysis of clinical data and biochemical markers in the first trimester did not identify a model that had clinical utility for predicting preeclampsia in a nulliparous population at low risk. LEVEL OF EVIDENCE: II.

Serum placental growth factor and fms-like tyrosine kinase 1 during first trimester in Chinese women with pre-eclampsia--a case-control study.

OBJECTIVE: To investigate the association between first trimester maternal placental growth factor (PlGF) and fms-like tyrosine kinase 1 (sFlt-1) levels with subsequent development of pre-eclampsia (PE). METHODS: This is a matched case-control study using stored serum samples collected from non-smoking Chinese women with singleton pregnancies who underwent first trimester screening for aneuploidy. Each case that developed PE was matched with a control whose maternal age, weight, gestational age and date of blood collection were within ± 2 years, ± 5 kg, ± 1 day, and ± 2 weeks of the index case, respectively. Non-parametric paired test was used to compare the PlGF and sFlt-1 levels. PlGF and sFlt-1 were transformed to their equivalent multiple of the median (MoM) using the matched control as the expected median value. The 95% confidence interval (CI) of the estimated median PlGF and sFlt-1 MoM in those with PE was determined. RESULTS: The median PlGF level in the 27 study cases with PE was lower than that of the matched controls (42.9 pg/ml versus 59.8 pg/ml; p = 0.001). The median PIGF MoM was 0.71 (95% CI 0.63-0.92). There was no statistically significant difference in sFlt-1 levels between those with PE and their matched control (p = 0.648). The median sFlt-1 MoM was 1.01 (95% CI 0.65-1.3). CONCLUSIONS: Women who developed PE had lower serum PlGF levels but normal sFlt-1 levels in the first trimester.

The relationship between PTH and 25-hydroxy vitamin D early in pregnancy.

OBJECTIVE: Measure serum PTH and 25(OH)D in a cross-sectional sample of pregnant women at 11th through 13th weeks' gestation to examine vitamin D status and consider implications. DESIGN: Observational: we retrieved residual sera stored at -20 °C after routine first trimester Down's syndrome screening, distributed over 12 months. PATIENTS: 430 African American women and 586 Caucasian women. MEASUREMENTS: PTH and 25-hydroxy vitamin D [25(OH)D] immunoassays. RESULTS: PTH medians were: 1·33 pmol/l (African American women); 1·20 pmol/l (Caucasian women) (t = 0·43, P = 0·7). Concentrations were highest in winter and decreased significantly in spring, fall, and summer. There was a direct PTH/weight relationship in Caucasian (t = 3·12, P < 0·002), but not African American women (t = 1·34, P = 0·18). Median 25(OH)D concentrations were 47·5 nmol/l (African American women) and 65 nmol/l (Caucasian women) (t = 13·7, P < 0·001). Concentrations were lowest in winter and rose significantly in spring, fall, and summer. Reciprocal 25(OH)D/weight relationships existed for both racial groups (t =-4·31 P < 0·001; t = 4·54, P < 0·001, respectively). Among 68 Caucasian women who smoked, median PTH and 25(OH)D concentrations were somewhat lower (P = ns). In separate regression models with PTH and 25(OH)D [dependent variables] and season, weight and smoking [independent variables], the only qualifying interactive term was in the Caucasian PTH model (season*1/weight). A regression model applied to adjusted scatter plots of PTH vs 25(OH)D indicated a weak relationship. CONCLUSIONS: The PTH/25(OH)D relationship is weaker during early pregnancy than in non-pregnant adults, making it unreliable for estimating vitamin D sufficiency. A suitable reference point for sufficiency might be the maternal 25(OH)D level considered sufficient for adequate transfer to neonates.

Assessing first trimester growth: the influence of ethnic background and maternal age.

BACKGROUND: First trimester growth restriction may predict miscarriage or adverse outcome later in the pregnancy, but determinants of early growth are not well described. Our objective was to examine factors influencing fetal and gestational sac size in the first trimester. METHODS: Prospective observational study of 1828 singleton pregnancies before 12 weeks gestation. Maternal characteristics (ethnicity, maternal age, obstetric history, abdominal pain and vaginal bleeding), crown rump length (CRL) and mean gestational sac diameter (MSD) were recorded. A stepwise linear mixed effects analysis was performed to determine factors influencing rate of change in CRL and MSD. RESULTS: 1063 scans, in 464 women, were included. Rate of increase in CRL was higher in women of black ethnic origin (P = 0.0261) compared with white, and increased with advancing maternal age (P = 0.0046). Maternal age also influenced MSD: older women had gestational sacs which were 0.118 mm larger for each one year increase in maternal age (P = 0.0073). Bleeding, pain and prior obstetric history did not influence CRL or MSD. CONCLUSIONS: Rate of increase in CRL was greater in fetuses of black versus white women and increased with advancing maternal age. As CRL is used to date pregnancies, and this influences further growth assessment, consideration should be given to the use of individualized growth charts which take account of maternal factors found to influence first trimester growth.

Association of first-trimester thyroid function test values with thyroperoxidase antibody status, smoking, and multivitamin use.

OBJECTIVE: To determine first-trimester thyroid function values and associations with thyroperoxidase antibody (TPO-Ab) status, smoking, emesis, and iodine-containing multivitamin use. METHODS: We collected information by interview, questionnaire, and blood draw at the initial obstetric visit in 668 pregnant women without known thyroid disease. We compared thyroid-stimulating hormone (TSH), total thyroxine (T4), and free T4 index (FT4I) values by TPO-Ab status. Multiple regression was used to identify characteristics associated with thyroid function values. RESULTS: The following median (range containing 95% of the data points) thyroid function test values were obtained in 585 TPO-Ab-negative women: TSH, 1.1 mIU/L (0.04-3.6); FT4I, 2.1 (1.5-2.9); and T4, 9.9 microg/dL (7.0-14.0). The following median (range containing 95% of the data points) thyroid function test values were obtained in 83 TPO-Ab-positive women: TSH, 1.8 mIU/L (0.3-6.4) (P<.001); FT4I, 2.0 (1.4-2.7) (P = .06); and T4, 9.3 microg/dL (6.8-13.0) (P = .03) (P values denote statistically significant differences between TPO-Ab-positive and negative participants). Among TPO-Ab-negative participants, TSH level was not associated with use of iodine-containing multivitamins, smoking, or race. TSH increased 0.03 mIU/L for every year of maternal age (P = .03) and decreased by 0.3 mIU/L for every increase in parity (P<.001). T4 decreased 0.04 microg/dL for every year of maternal age (P = .04). Mean FT4I was 2.05 in smokers and 2.20 in nonsmokers (P<.01). There were no relationships between T4 or FT4I and parity, race, or iodine-containing multivitamin use. CONCLUSION: TPO-Ab status of pregnant women should be considered when constructing trimester-specific reference ranges because elevated serum TPO-Ab levels are associated with higher TSH and lower T4 values.

[Requested abortions in Oslo 2000-2003]. / Nemndbehandlede svangerskapsavbrudd i Oslo 2000-03.

BACKGROUND: Women of non-Western origin are over-represented among women requesting induced abortion before the end of the 12th week of pregnancy, in Oslo, Norway. Our aim was to find out if that was also the case for women requesting induced abortion after week 12. MATERIAL AND METHODS: We assessed differences between Western and non-Western women in duration of pregnancy at request for induced abortion and the proportion accepted for abortion. All women requesting induced abortion after the 12th week of pregnancy at Ullevål University Hospital, Oslo from January 2000 to September 2003 (n = 378) were included. Information about the number of fertile women in Oslo according to ethnic background was found in the municipality of Oslo's statistical office. Other data were obtained from patient medical records. RESULTS: 23% (87/378) of all women requesting late induced abortion and 15.5% (20,636/132,843) of women aged 15-50 years in Oslo had non-Western background (p < 0.05). The mean gestational age at the time of requested abortion among non-Western women was 16.4 weeks and among Western women it was 15.6 weeks (p = 0.01). There was a non-significant increased risk of having the abortion request rejected for non-Western as compared to Western women (adjusted odds ratio 1.6; 95% CI 0.5-5.5), after control for gestational age and maternal age. INTERPRETATION: It is known that non-Western women in Oslo are over-represented among women giving birth and women requesting induced abortion in general. This study shows that non-western women are also over-represented among women requesting induced abortion after the 12th pregnancy week.