Two-dimensional (2D) placental ultrasound measurements - The correlation with placental volume measured by magnetic resonance imaging (MRI).

INTRODUCTION: Information about placental size in ongoing pregnancies may aid the identification of pregnancies with increased risk of adverse outcome. Placental volume can be measured using magnetic resonance imaging (MRI). However, this method is not universally available in antenatal care. Ultrasound is the diagnostic tool of choice in pregnancy. Therefore, we studied whether simple two-dimensional (2D) ultrasound placental measurements were correlated with placental volume measured by MRI. METHODS: We examined a convenience sample of 104 ongoing pregnancies at gestational week 27, using both ultrasound and MRI. The ultrasound measurements included placental length, width and thickness. Placental volume was measured using MRI. The correlation between each 2D placental ultrasound measurement and placental volume was estimated by applying Pearson's correlation coefficient (r). RESULTS: Mean placental length was 17.2 cm (SD 2.1 cm), mean width was 14.7 cm (SD 2.1 cm), and mean thickness was 3.2 cm (SD 0.6 cm). Mean placental volume was 536 cm3 (SD 137 cm3). The 2D ultrasound measurements showed poor correlation with placental volume (placental length; r = 0.27, width; r = 0.37, and thickness r = 0.13). DISCUSSION: Simple 2D ultrasound measurements of the placenta were poorly correlated with placental volume and cannot be used as proximate measures of placental volume. Our finding may be explained by the large variation between pregnancies in intrauterine placental shape.

Placental size at gestational week 36: Comparisons between ongoing pregnancies and deliveries.

INTRODUCTION: We aimed to compare placental size and placental size relative to fetal size (ratio) in ongoing pregnancies examined by magnetic resonance imaging (MRI) at gestational week 36 with placental size among all deliveries at gestational week 36 during the same time period. MATERIAL AND METHODS: Ongoing unselected singleton pregnancies (n = 89) were examined by MRI at median gestational week 36+5 days during 2017-2018, and placental and fetal volumes (cm3 ) were calculated. The placental size and ratio in ongoing pregnancies were compared with placental size and ratio among all deliveries in Norway at gestational week 36 (median gestational week 36+4 days) during 2016-2019 (n = 5582). For comparison of size, we converted volume (cm3 ) in ongoing pregnancies into grams as: cm3 × 1.05 (density of placental and fetal tissue). RESULTS: In ongoing pregnancies, median placental size was 873 (interquartile range [IQR] 265) grams and median size of all delivered placentas was 613 (IQR 290) grams. Placental size was smaller among the delivered placentas independent of delivery mode: 760 (IQR 387) grams among elective cesarean deliveries (n = 465) and 590 (IQR 189) grams among vaginal deliveries after spontaneous onset of labor (n = 2478). Median ratio in ongoing pregnancies was higher than among deliveries: 0.31 (IQR 0.08) vs 0.21 (IQR 0.08). The ratio was higher in ongoing pregnancies independent of delivery mode: 0.24 (IQR 0.17) among elective cesarean deliveries vs 0.21 (IQR 0.05) among vaginal deliveries after spontaneous onset of labor. CONCLUSIONS: The placenta is larger in ongoing pregnancies than among deliveries. This finding suggests that placental size decreases during labor and delivery, possibly by transfer of blood to the fetus. Our finding also suggests that reference values of placental size based on delivered placentas are not valid for ongoing pregnancies.

Placental size at gestational week 27 and 37: The associations with pulsatility index in the uterine and the fetal-placental arteries.

INTRODUCTION: Fetal growth restriction is known to be related to decreased fetal and placental blood flow. It is not known, however, whether placental size is related to fetal and placental blood flow. We studied the correlations of intrauterine placental volume and placental-fetal-ratio with pulsatility index (PI) in the uterine arteries, fetal middle cerebral artery, and umbilical artery. METHODS: We followed a convenience sample of 104 singleton pregnancies, and we measured placental and fetal volumes using magnetic resonance imaging (MRI) at gestational week 27 and 37 (n = 89). Pulsatility index (PI) was measured using Doppler ultrasound. We calculated cerebroplacental ratio as fetal middle cerebral artery PI/umbilical artery PI and placental-fetal-ratio as placental volume (cm3)/fetal volume (cm3). RESULTS: At gestational week 27, placental volume was negatively correlated with uterine artery PI (r = -0.237, p = 0.015, Pearson's correlation coefficient), and positively correlated with fetal middle cerebral artery PI (r = 0.247, p = 0.012) and cerebroplacental ratio (r = 0.208, p = 0.035). Corresponding correlations for placental-fetal-ratio were -0.273 (p = 0.005), 0.233 (p = 0.018) and 0.183 (p = 0.064). Umbilical artery PI was not correlated with placental volume. At gestational week 37, we found weaker and no significant correlations between placental volume and the pulsatility indices. CONCLUSIONS: Our results suggest that placental size is correlated with placental and fetal blood flow at gestational week 27.

Har svangerskapsavbrudd betydning for nedgangen i antall fødsler?

BACKGROUND: Birth rates in Norway are declining, and fewer women are having more than two children. Pregnancy termination may impact birth rates. We aimed to study the distribution of pregnancies in Norway according to parity, and whether the proportions of pregnancies ending in termination has changed. MATERIAL AND METHOD: We retrieved figures for pregnancies in Norway during the period 2008-20, based on number of births in the Medical Birth Registry and number of pregnancy terminations in the Registry of Pregnancy Termination. We calculated the proportion of pregnancies resulting in termination according to parity and year. RESULTS: The sum of births and pregnancy terminations fell by 16.4 % during the study period. The absolute decline was most pronounced among nulliparous women, from 34 647 in 2008 to 28 606 in 2020 (17.4 % decline). Of these, the proportion of pregnancies that resulted in a pregnancy termination fell from 25.2 % to 20.5 %. The proportion of pregnancy terminations among women with two, three, four or more previous births was 26.1 %, 34.6 % and 28.2 % in 2008, and 26.1 %, 34.0 % and 29.1 % in 2020, respectively. INTERPRETATION: Both the number of births and the number of pregnancy terminations in Norway fell during the period 2008-20, in all parity groups. The decline was most pronounced in nulliparous women. The number of pregnancy terminations fell more than the number of births. Pregnancy terminations can therefore not explain the decline in birth rates in Norway.

Inter-pregnancy interval and placental weight. A population based follow-up study in Norway.

INTRODUCTION: We studied changes in placental weight from the first to the second delivery according to length of the inter-pregnancy interval. METHODS: We followed all women in Norway from their first to their second successive singleton pregnancy during the years 1999-2019, a total of 271 184 women. We used data from the Medical Birth Registry of Norway and studied changes in placental weight (in grams (g)) according to the length of the inter-pregnancy. Adjustments were made for year and maternal age at first delivery, changes in the prevalence of maternal diseases (hypertension and diabetes), and a new father to the second pregnancy. RESULTS: Mean placental weight increased from 655 g at the first delivery to 680 g at the second. The adjusted increase in placental weight was highest at inter-pregnancy intervals <6 months; 38.2 g (95 % CI 33.0g-43.4 g) versus 23.2 g (95 % CI 18.8g-27.7 g) at inter-pregnancy interval 6-17 months. At inter-pregnancy intervals ≥18 months, placental weight remained higher than at the first delivery, but was non-different from inter-pregnancy intervals 6-17 months. Also, after additional adjustment for daily smoking and body mass index in sub-samples, we found the highest increase in placental weight at the shortest inter-pregnancy interval. We estimated no difference in gestational age at delivery or placental to birthweight ratio according to inter-pregnancy interval. DISCUSSION: Placental weight increased from the first to the second pregnancy, and the increase was most pronounced at short inter-pregnancy intervals. The biological causes and implications of such findings remain to be studied.

The dose-response relationship of pre-menopausal alcohol consumption with age at menopause: a population study of 280 497 women in Norway.

BACKGROUND: Previous research suggests that alcohol consumption is associated with high age at menopause. Yet, knowledge about the dose-response relationship is inconsistent. Thus, we studied the pattern of the association of pre-menopausal alcohol consumption with age at natural menopause. METHODS: We performed a retrospective population-based study using self-reported data from 280 497 women aged 50-69 years attending the Norwegian breast cancer screening programme (BreastScreen Norway) during 2006-15. Associations of weekly alcohol consumption between the age of 20 and 49 years with age at menopause were estimated as hazard ratios (HRs) using Cox proportional hazard models with restricted cubic splines to allow for non-linear associations. We adjusted for year and place of birth, number of childbirths, educational level, body mass index and smoking habits. RESULTS: Mean age at natural menopause was 51.20 years (interquartile range: 49-54 years). The adjusted HR of reaching menopause was highest for women with no alcohol consumption (reference) and the HR decreased by alcohol consumption up to 50 grams per week (adjusted HR 0.87; 95% CI: 0.86-0.88). Above 50 grams, there was no further decrease in the HR of reaching menopause (P for non-linearity of <0.001). CONCLUSIONS: Women who did not consume alcohol were youngest at menopause. The lack of a dose-response association among alcohol consumers implies virtually no relation of alcohol consumption with age at menopause. Our findings may suggest that characteristics of the women who did not consume alcohol, not accounted for in the data analyses, explain their younger age at menopause.

Automatic placental and fetal volume estimation by a convolutional neural network.

INTRODUCTION: We aimed to develop an artificial intelligence (AI) deep learning algorithm to efficiently estimate placental and fetal volumes from magnetic resonance (MR) scans. METHODS: Manually annotated images from an MRI sequence was used as input to the neural network DenseVNet. We included data from 193 normal pregnancies at gestational week 27 and 37. The data were split into 163 scans for training, 10 scans for validation and 20 scans for testing. The neural network segmentations were compared to the manual annotation (ground truth) using the Dice Score Coefficient (DSC). RESULTS: The mean ground truth placental volume at gestational week 27 and 37 was 571 cm3 (Standard Deviation (SD) 293 cm3) and 853 cm3 (SD 186 cm3), respectively. Mean fetal volume was 979 cm3 (SD 117 cm3) and 2715 cm3 (SD 360 cm3). The best fitting neural network model was attained at 22,000 training iterations with mean DSC 0.925 (SD 0.041). The neural network estimated mean placental volumes at gestational week 27-870 cm3 (SD 202 cm3) (DSC 0.887 (SD 0.034), and to 950 cm3 (SD 316 cm3) at gestational week 37 (DSC 0.896 (SD 0.030)). Mean fetal volumes were 1292 cm3 (SD 191 cm3) and 2712 cm3 (SD 540 cm3), with mean DSC of 0.952 (SD 0.008) and 0.970 (SD 0.040). The time spent for volume estimation was reduced from 60 to 90 min by manual annotation, to less than 10 s by the neural network. CONCLUSION: The correctness of neural network volume estimation is comparable to human performance; the efficiency is substantially improved.

Is the increasing prevalence of labor induction accompanied by changes in pregnancy outcomes? An observational study of all singleton births at gestational weeks 37-42 in Norway during 1999-2019.

INTRODUCTION: Induction of labor is often performed to prevent adverse perinatal and maternal outcomes, and has become increasingly common. We studied whether changes in prevalence of labor induction in gestational weeks 37-42 weeks were accompanied by changes in adverse pregnancy outcomes or mode of delivery. MATERIAL AND METHODS: We used data from the Medical Birth Registry of Norway, and included all singleton births in gestational weeks 37-42 in Norway, 1999-2019 (n = 1 127 945). We calculated the prevalence of labor induction and outcome measures according to year of birth. We repeated these calculations for each gestational week at birth. RESULTS: The prevalence of labor induction increased from 9.7% to 25.9%, and the increase was particularly high in gestational week 41. A modest decline in fetal deaths was observed in all gestational weeks, except gestational week 41. The overall decline was from 0.18% in 1999-2004 to 0.13% during 2015-2019. There were no overall changes in other perinatal outcomes. The prevalence of postpartum hemorrhage ≥500 ml increased from 11.4% in 1999 to 30.1% in 2019, and operative deliveries increased slightly. The prevalence of acute cesarean section increased from 6.5% to 9.3%, whereas vacuum and/or forceps assisted deliveries increased from 7.8% to 10.4%. CONCLUSIONS: A high increase in labor inductions was accompanied by a modest decline in fetal deaths, but no decline in other adverse perinatal outcomes. In settings where the prevalence of adverse perinatal outcomes is low, the beneficial effect of increased use of labor induction may not outweigh the side effects or the costs.

Is the risk of cardiovascular disease in women with pre-eclampsia modified by very low or very high offspring birth weight? A nationwide cohort study in Norway.

OBJECTIVES: To examine whether the risk of cardiovascular disease (CVD) in women with pre-eclampsia is modified by very low or very high offspring birth weight. Further, we studied whether diabetes in pregnancy modified this risk. DESIGN: Nationwide cohort study. SETTING: Norwegian population registries. PARTICIPANTS: 618 644 women who gave birth to their first child during 1980-2009. METHODS: The women were followed from delivery until the development of CVD or censoring, by linkage of the Medical Birth Registry of Norway to the Cardiovascular Disease in Norway project, and the Norwegian Cause of Death Registry. PRIMARY OUTCOME MEASURE: CVD. RESULTS: Compared with normotensive women with normal offspring birth weight, women with pre-eclampsia had increased risk of CVD (HR 2.16; 95% CI 2.05 to 2.26). The CVD risk was even higher when pre-eclampsia was accompanied with a large for gestational age offspring (LGA, z-score >2.0) (HR 2.57; 95% CI 2.08 to 3.18). Women with pre-eclampsia and a small for gestational age offspring (SGA, z-score <-2.0) had an HR of 1.54 (95% CI 1.23 to 1.93) compared with normotensive women with normal offspring birth weight.Also, women with diabetes had increased CVD risk, but no additional risk associated with an LGA or SGA offspring. CONCLUSIONS: Women with pre-eclampsia and an LGA offspring had higher risk of CVD than pre-eclamptic women with a normal weight (z-score -2.0 to 2.0) or SGA offspring. These findings suggest that factors causing pre-eclampsia and an LGA offspring are also linked to development of CVD.

The impact of the introduction of intrapartum fetal ECG ST segment analysis. A population study.

INTRODUCTION: ST segment analysis (STAN) of the fetal electrocardiogram was introduced as an adjunct to cardiotocography for intrapartum fetal monitoring 30 years ago. We examined the impact of the introduction of STAN on changes in the occurrence of fetal and neonatal deaths, Apgar scores of <7 at 5 min, intrapartum cesarean sections, and instrumental vaginal deliveries while controlling for time- and hospital-specific trends and maternal risk factors. MATERIAL AND METHODS: Data were retrieved from the Medical Birth Registry of Norway from 1985 to 2014. Individual data were linked to the Education Registry and the Central Person Registry. The study sample included 1 132 022 singleton births with a gestational age of 36 weeks or beyond. Information about the year of STAN introduction was collected from every birth unit in Norway using a questionnaire. Our data structure consisted of a hospital-year panel. We applied a linear probability model with hospital-fixed effects and with adjustment for potentially confounding factors. The prevalence of the outcomes before and after the introduction of STAN were compared within each birth unit. RESULTS: In total, 23 birth units, representing 76% of all births in Norway, had introduced the STAN technology. During the study period, stillbirths declined from 2.6 to 1.9 per 1000 births, neonatal deaths declined from 1.7 to 0.7 per 1000 live births, babies with Apgar score <7 at 5 min after birth increased from 7.4 to 9.5 per 1000 births, intrapartum cesarean sections increased from 6.4% to 9.5%, and instrumental vaginal deliveries increased from 7.8% to 10.9%. Our analyses found that the introduction of STAN was not associated with the decline in proportion of stillbirths (p =0.76) and neonatal deaths (p =0.76) or with the increase in intrapartum cesarean sections (p =0.92) and instrumental vaginal deliveries (p =0.78). However, it was associated with the increased occurrence of Apgar score <7 at 5 min (p =0.01). CONCLUSIONS: There is no evidence that the introduction of STAN contributed to changes in the rates of stillbirths, neonatal deaths, intrapartum cesarean sections, or instrumental vaginal deliveries. There was an association between the introduction of STAN and a small increase in neonates with low Apgar scores.

Prevalence of antibodies against SARS-CoV-2 among pregnant women in Norway during the period December 2019 through December 2020.

We studied severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence among pregnant women in Norway by including all women who were first trimester pregnant (n = 6520), each month from December 2019 through December 2020, in the catchment region of Norway's second-largest hospital. We used sera that had been frozen stored after compulsory testing for syphilis antibodies in antenatal care. The sera were analysed with the Elecsys® Anti-SARS-CoV-2 immunoassay (Roche Diagnostics, Cobas e801). This immunoassay detects IgG/IgM against SARS-CoV-2 nucleocapsid antigen. Sera with equivocal or positive test results were retested with the Liaison® SARS-CoV-2 S1/S2 IgG (DiaSorin), which detects IgG against the spike (S)1 and S2 protein on the SARS-CoV-2 virus. In total, 98 women (adjusted prevalence 1.7%) had SARS CoV-2 antibodies. The adjusted seroprevalence increased from 0.3% (1/445) in December 2019 to 5.7% (21/418) in December 2020. Out of the 98 seropositive women, 36 (36.7%) had serological signs of current SARS-CoV-2 infection at the time of serum sampling, and the incidence remained low during the study period. This study suggests that SARS CoV-2 was present in the first half of December 2019, 6 weeks before the first case was recognised in Norway. The low occurrence of SARS-CoV-2 infection during 2020, may be explained by high compliance to extensive preventive measures implemented early in the epidemic.

Does the use of Doppler ultrasound reduce fetal mortality? A population study of all deliveries in Norway 1990-2014.

BACKGROUND: The aim of the present study was to examine the effect that the introduction of Doppler ultrasound in obstetric care has had on fetal death in Norway. One mechanism by which Doppler ultrasound may reduce fetal death may be through the increased use of Caesarean delivery. Therefore, we also examined the effect that the use of Doppler ultrasound has had on the use of Caesarean delivery. METHODS: The Medical Birth Registry of Norway provided detailed medical information for ∼1.2 million deliveries from 1990 to 2014. Information about the year of introduction of Doppler ultrasound was collected directly from the maternity units, using a questionnaire. The data were analysed using a hospital fixed-effects regression model with fetal death as the outcome measure. The key independent variable was the introduction of Doppler ultrasound at each maternity ward. Hospital-specific trends and risk factors of the mother for fetal death were included as covariates. RESULTS: For pre-term deliveries, the introduction of Doppler ultrasound contributed to a reduction in fetal death of ∼30% and to an increase in planned Caesarean section of ∼15%. There were no effects for emergency Caesarean sections or inductions pre-term. The introduction of Doppler ultrasound had no effect on fetal death or Caesarean section for term deliveries. CONCLUSIONS: The introduction of Doppler ultrasound during the 1990s and 2000s made a significant contribution to the decline in the number of pre-term fetal deaths in Norway. Increased use of Caesarean section may have contributed to this reduction.

The relation of number of childbirths with age at natural menopause: a population study of 310 147 women in Norway.

STUDY QUESTION: Does age at natural menopause increase with increasing of number of childbirths? SUMMARY ANSWER: Age at menopause increased with increasing number of childbirths up to three childbirths; however, we found no further increase in age at menopause beyond three childbirths. WHAT IS KNOWN ALREADY: Pregnancies interrupt ovulation, and a high number of pregnancies have therefore been assumed to delay menopause. Previous studies have had insufficient statistical power to study women with a high number of childbirths. Thus, the shape of the association of number of childbirths with age at menopause remains unknown. STUDY DESIGN, SIZE, DURATION: A retrospective population study of 310 147 women in Norway who were 50-69 years old at data collection. PARTICIPANTS/MATERIALS, SETTING, METHODS: The data were obtained by two self-administered questionnaires completed by women attending BreastScreen Norway, a population-based screening program for breast cancer. The associations of number of childbirths with age at menopause were estimated as hazard ratios by applying Cox proportional hazard models, adjusting for the woman's year of birth, cigarette smoking, educational level, country of birth, oral contraceptive use and body mass index. MAIN RESULTS AND THE ROLE OF CHANCE: Women with three childbirths had the highest mean age at menopause (51.36 years; 95% CI: 51.33-51.40 years), and women with no childbirths had the lowest (50.55 years; 95% CI: 50.48-50.62 years). Thus, women with no childbirths had higher hazard ratio of reaching menopause compared to women with three childbirths (reference group) (adjusted hazard ratio, 1.24; 95% CI: 1.22-1.27). Beyond three childbirths, we estimated no further increase in age at menopause. These findings were confirmed in sub-analyses among (i) women who had never used hormonal intrauterine device and/or systemic menopausal hormonal therapy; (ii) women who were born before 1950 and (iii) women who were born in 1950 or after. LIMITATIONS, REASONS FOR CAUTION: Information about age at menopause was based on self-reports. WIDER IMPLICATIONS OF THE FINDINGS: If pregnancies truly delay menopause, one would expect that women with the highest number of childbirths had the highest age at menopause. Our results question the assumption that interrupted ovulation during pregnancy delays menopause. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the South-Eastern Norway Regional Health Authority [2016112 to M.S.G.] and by the Norwegian Cancer Society [6863294-2015 to E.K.B.]. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Offspring birthweight and placental weight-does the type of maternal diabetes matter? A population-based study of 319 076 pregnancies.

INTRODUCTION: Our aim was to estimate the difference in birthweight and in placental weight in pregnancies with type 1 diabetes, type 2 diabetes, and gestational diabetes compared with pregnancies without diabetes. MATERIAL AND METHODS: By using data from the Medical Birth Registry of Norway during the years 2009-2017, we included 319 076 singleton pregnancies with delivery after the 21st week of pregnancy. We used linear regression analyses to estimate the difference in birthweight and in placental weight in grams (g) in pregnancies with type 1 diabetes, type 2 diabetes, and gestational diabetes, using pregnancies without diabetes as the reference. Adjustments were made for pregnancy duration and pre-pregnancy body mass index. RESULTS: In pregnancies without diabetes, mean crude birthweight was 3527 g (SD 552 g). The adjusted mean birthweight was 525 g (95% CI 502-548 g) higher in pregnancies with type 1 diabetes compared with pregnancies without diabetes. In pregnancies with type 2 diabetes, and pregnancies with gestational diabetes, birthweights were 192 g (95% CI 160-223 g) and 102 g (95% CI 93-110 g) higher, respectively. Mean crude placental weight was 664 g (SD 147 g) in pregnancies without diabetes. Compared with pregnancies without diabetes, the adjusted mean placental weight was 109 g (95% CI 101-116 g) higher in pregnancies with type 1 diabetes, 50 g (95% CI 39-60 g) higher in pregnancies with type 2 diabetes, and 31 g (95% CI 28-34 g) higher in pregnancies with gestational diabetes. CONCLUSIONS: The increase in birthweight and in placental weight associated with maternal diabetes was most pronounced for type 1 diabetes, followed by type 2 diabetes, and gestational diabetes.

Placental volume in gestational week 27 measured by three-dimensional ultrasound and magnetic resonance imaging.

INTRODUCTION: Ultrasound is the diagnostic tool of choice in pregnancy. We lack valid ultrasound methods for placental size measurements. Our aim was therefore to compare three-dimensional (3D) ultrasound with magnetic resonance imaging (MRI) for measurements of placental volume. MATERIAL AND METHODS: We measured placental volume by 3D ultrasound and MRI in 100 unselected pregnancies at 27 weeks of gestation (25+4 -28+4  weeks). The 3D ultrasound acquisitions were analyzed offline, and the placental outline was manually traced using the virtual organ computer-aided analysis (VOCAL) 30° rotational technique. The MRI examinations included a T2-weighted gradient echo sequence in the sagittal plane, with 5-mm slices through the entire uterus. The placental outline was manually traced in each slice. The correlation between 3D ultrasound and MRI placental volumes was estimated by intraclass correlation coefficients. Bland-Altman analysis was applied to visualize systematic bias and limits of agreement, in which the ratio MRI placental volume/3D ultrasound placental volume was plotted against the average of the two methods. RESULTS: The intraclass correlation coefficient between 3D ultrasound and MRI measurements was 0.49 (95% confidence interval 0.33-0.63). In general, 3D ultrasound measured smaller placental volumes (median 373 cm3 , interquartile range 309-434 cm3 ) than MRI (median 507 cm3 , interquartile range 429-595 cm3 ) and the systematic bias was 1.44. The 95% limits of agreement between the two methods were wide (0.68-2.21). CONCLUSIONS: We found poor to moderate correlation between 3D ultrasound and MRI placental volume measurements. Generally, 3D ultrasound measured smaller placental volumes than MRI, suggesting that 3D ultrasound failed to visualize the entire placenta. Our findings may hopefully contribute to the improvement of ultrasound methods for placental measurements.

Validation and development of models using clinical, biochemical and ultrasound markers for predicting pre-eclampsia: an individual participant data meta-analysis.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management. OBJECTIVES: To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers. DESIGN: This was an individual participant data meta-analysis of cohort studies. SETTING: Source data from secondary and tertiary care. PREDICTORS: We identified predictors from systematic reviews, and prioritised for importance in an international survey. PRIMARY OUTCOMES: Early-onset (delivery at < 34 weeks' gestation), late-onset (delivery at ≥ 34 weeks' gestation) and any-onset pre-eclampsia. ANALYSIS: We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for C-statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using I2 and τ2. A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals. RESULTS: The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary C-statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia. LIMITATIONS: Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data. CONCLUSION: For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings. FUTURE WORK: Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015029349. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 72. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Pre-eclampsia, a condition in pregnancy that results in raised blood pressure and protein in the urine, is a major cause of complications for the mother and baby. WHAT IS NEEDED?: A way of accurately identifying women at high risk of pre-eclampsia to allow clinicians to start preventative interventions such as administering aspirin or frequently monitoring women during pregnancy. WHERE ARE THE RESEARCH GAPS?: Although over 100 tools (models) have been reported worldwide to predict pre-eclampsia, to date their performance in women managed in the UK NHS is unknown. WHAT DID WE PLAN TO DO?: We planned to comprehensively identify all published models that predict the risk of pre-eclampsia occurring at any time during pregnancy and to assess if this prediction is accurate in the UK population. If the existing models did not perform satisfactorily, we aimed to develop new prediction models. WHAT DID WE FIND?: We formed the International Prediction of Pregnancy Complications network, which provided data from a large number of studies (78 studies, 25 countries, 125 researchers, 3,570,993 singleton pregnancies). We were able to assess the performance of 24 out of the 131 models published to predict pre-eclampsia in 11 UK data sets. The models did not accurately predict the risk of pre-eclampsia across all UK data sets, and their performance varied within individual data sets. We developed new prediction models that showed promising performance on average across all data sets, but their ability to correctly identify women who develop pre-eclampsia varied between populations. The models were more clinically useful when used in the care of first-time mothers pregnant with one child, compared to a strategy of treating them all as if they were at high-risk of pre-eclampsia. WHAT DOES THIS MEAN?: Before using the International Prediction of Pregnancy Complications models in various populations, they need to be adjusted for characteristics of the particular population and the setting of application.