Pregnancy and risk of COVID-19: a Norwegian registry-linkage study.

OBJECTIVE: To compare the risk of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and contact with specialist healthcare services for coronavirus disease 2019 (COVID-19) between pregnant and non-pregnant women. POPULATION OR SAMPLE: All women ages 15-45 living in Norway on 1 March 2020 (n = 1 033 699). METHODS: We linked information from the national birth, patient, communicable diseases and education databases using unique national identifiers. MAIN OUTCOME MEASURE: We estimated hazard ratios (HR) among pregnant compared to non-pregnant women of having a positive test for SARS-CoV-2, a diagnosis of COVID-19 in specialist healthcare, or hospitalisation with COVID-19 using Cox regression. Multivariable analyses adjusted for age, marital status, education, income, country of birth and underlying medical conditions. RESULTS: Pregnant women were not more likely to be tested for or to a have a positive SARS-CoV-2 test (adjusted HR 0.99; 95% CI 0.92-1.07). Pregnant women had higher risk of hospitalisation with COVID-19 (HR 4.70, 95% CI 3.51-6.30) and any type of specialist care for COVID-19 (HR 3.46, 95% CI 2.89-4.14). Pregnant women born outside Scandinavia were less likely to be tested, and at higher risk of a positive test (HR 2.37, 95% CI 2.51-8.87). Compared with pregnant Scandinavian-born women, pregnant women with minority background had a higher risk of hospitalisation with COVID-19 (HR 4.72, 95% CI 2.51-8.87). CONCLUSION: Pregnant women were not more likely to be infected with SARS-CoV-2. Still, pregnant women with COVID-19, especially those born outside of Scandinavia, were more likely to be hospitalised. TWEETABLE ABSTRACT: Pregnant women are at increased risk of hospitalisation for COVID-19.

A Population-Based Study of Effects of Genetic Loci on Orofacial Clefts.

Prior genome-wide association studies for oral clefts have focused on clinic-based samples with unclear generalizability. Prior samples were also small for investigating effects by cleft type and exclusively studied isolated clefts (those occurring without other birth defects). We estimated the effects of 17 top loci on cleft types in both isolated and nonisolated cases in the largest consortium to date of European-descent population-based studies. Our analytic approach focused on a mother-child dyad case-control design, but it also allowed analyzing mother-only or child-only genotypes to maximize power. Our total sample included 1,875 cases with isolated clefts, 459 cases with nonisolated clefts, and 3,749 controls. After correcting for multiple testing, we observed significant associations between fetal single-nucleotide polymorphisms (SNPs) at IRF6, PAX7, 8q21.3, 8q24, KIAA1598-VAX1, and MAFB and isolated cleft lip only (CLO) and cleft lip and palate (CLP). Significant associations were observed between isolated CLO and fetal SNPs near TPM1 and NOG1 and between CLP and fetal SNPs at ABCA4-ARHGAP29, THADA, FOXE1, and SPRY2. Overall, effects were similar for isolated CLO and CLP, except for ABCA4-ARHGAP29. A protective effect was observed for the fetal NOG1 SNP on cleft palate only, opposite in direction to the effect on CLO. For most fetal SNPs, a dose-response allelic effect was observed. No evidence of parent-of-origin or maternal genome effects was observed. Overall, effect direction and magnitude were similar between isolated and nonisolated clefts, suggesting that several loci are modifiers of cleft risk in both isolated and nonisolated forms. Our results provide reliable estimates of the effects of top loci on risks of oral clefts in a population of European descent.

Fetal size monitoring and birth-weight prediction: a new population-based approach.

OBJECTIVE: To develop a complete, population-based system for ultrasound-based fetal size monitoring and birth-weight prediction for use in the second and third trimesters of pregnancy. METHODS: Using 31 516 ultrasound examinations from a population-based Norwegian clinical database, we constructed fetal size charts for biparietal diameter, femur length and abdominal circumference from 24 to 42 weeks' gestation. A reference curve of median birth weight for gestational age was estimated using 45 037 birth weights. We determined how individual deviations from the expected ultrasound measures predicted individual percentage deviations from expected birth weight. The predictive quality was assessed by explained variance of birth weight and receiver-operating characteristics curves for prediction of small-for-gestational age. A curve for intrauterine estimated fetal weight was constructed. Charts were smoothed using the gamlss non-linear regression method. RESULTS: The population-based approach, using bias-free ultrasound gestational age, produces stable estimates of size-for-age and weight-for-age curves in the range 24-42 weeks' gestation. There is a close correspondence between percentage deviations and percentiles of birth weight by gestational age, making it easy to convert between the two. The variance of birth weight that can be 'explained' by ultrasound increases from 8% at 20 weeks up to 67% around term. Intrauterine estimated fetal weight is 0-106 g higher than median birth weight in the preterm period. CONCLUSIONS: The new population-based birth-weight prediction model provides a simple summary measure, the 'percentage birth-weight deviation', to be used for fetal size monitoring throughout the third trimester. Predictive quality of the model can be measured directly from the population data. The model computes both median observed birth weight and intrauterine estimated fetal weight. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Prediction of gestational age based on genome-wide differentially methylated regions.

BACKGROUND: We explored the association between gestational age and cord blood DNA methylation at birth and whether DNA methylation could be effective in predicting gestational age due to limitations with the presently used methods. We used data from the Norwegian Mother and Child Birth Cohort study (MoBa) with Illumina HumanMethylation450 data measured for 1753 newborns in two batches: MoBa 1, n = 1068; and MoBa 2, n = 685. Gestational age was computed using both ultrasound and the last menstrual period. We evaluated associations between DNA methylation and gestational age and developed a statistical model for predicting gestational age using MoBa 1 for training and MoBa 2 for predictions. The prediction model was additionally used to compare ultrasound and last menstrual period-based gestational age predictions. Furthermore, both CpGs and associated genes detected in the training models were compared to those detected in a published prediction model for chronological age. RESULTS: There were 5474 CpGs associated with ultrasound gestational age after adjustment for a set of covariates, including estimated cell type proportions, and Bonferroni-correction for multiple testing. Our model predicted ultrasound gestational age more accurately than it predicted last menstrual period gestational age. CONCLUSIONS: DNA methylation at birth appears to be a good predictor of gestational age. Ultrasound gestational age is more strongly associated with methylation than last menstrual period gestational age. The CpGs linked with our gestational age prediction model, and their associated genes, differed substantially from the corresponding CpGs and genes associated with a chronological age prediction model.

Prediction of small-for-gestational-age status by symphysis-fundus height: a registry-based population cohort study.

OBJECTIVE: To develop a chart for risk of small-for-gestational-age (SGA) at birth depending on deviations in symphysis-fundus (SF) height values for gestational age during pregnancy weeks 24-42. DESIGN: Registry-based population cohort study. SETTING: Antenatal clinics, Västra Götaland County, Sweden, 2005-2010. POPULATION: The study included 42 018 women with ultrasound-dated singleton pregnancies who delivered at Sahlgrenska University Hospital. Data (including 282 713 SF height measurements) were extracted from the hospital's computerised obstetric database. METHODS: Linear and binary regression analyses were used to derive prediction models with deviations in birthweight (BW) and SF height by gestational age as dependent and independent variables, respectively. Receiver operating characteristic curves were generated to evaluate the predictive value of the model in detecting SGA. MAIN OUTCOME MEASURES: Birthweight and small-for-gestational-age. RESULTS: Symphysis-fundus height accounted for 3% of individual BW variance at 24 weeks, increasing gradually to 20% at 40 weeks. Maternal factors explained an additional 10 percentage points of BW variance. Receiver operating characteristic curves confirmed that SF height was a stronger SGA predictor in late than in early pregnancy. Using an SGA relative risk cut-off limit of ≥2-fold, the overall sensitivity was 50% and the overall specificity 80%. Only the most recent SF measurement was useful in predicting BW deviation; previous measurements added nothing to the predictive value. CONCLUSIONS: The ability of SF measurements to detect SGA status at birth increases with gestational age. Only the most recent SF measurement has predictive value; a static or falling pattern of SF values did not increase SGA likelihood. TWEETABLE ABSTRACT: New SF curves predict SGA best in late pregnancy; only the most recent SF measurement has predictive value.

Advantages of the population-based approach to pregnancy dating: results from 23,020 ultrasound examinations.

OBJECTIVE: To confirm the results from two previous evaluations of term prediction models, including two sample-based models and one population-based model, in a third population. METHODS: In a study population of 23,020 second-trimester ultrasound examinations, data were prospectively collected and registered over the period 1988-2009. Three different models for ultrasonically estimated date of delivery were applied to the measurements of fetal biparietal diameter (BPD) and two models were applied to the femur length (FL) measurements; the resulting term estimations were compared with the actual time of delivery. The difference between the actual and the predicted dates of delivery (the median bias) was calculated for each of the models, for three BPD/FL-measurement subgroups and for the study population as a whole. RESULTS: For the population-based model, the median bias was + 0.4 days for the BPD-based predictions and - 0.4 days for the FL-based predictions, and the biases were stable over the inclusion ranges. The biases of the two traditional models varied with the size of the fetus at examination; median biases were - 0.87 and + 2.2 days, respectively, with extremes - 4.2 and + 4.8 days for the BPD-based predictions, and the median bias was + 1.72 days with range - 0.8 to + 4.5 days for FL-based predictions. The disagreement between the two sample-based models was never less than 2 days for the BPD-based predictions. CONCLUSION: This study confirms the results from previous studies; median biases were negligible with term predictions from the population-based model, while those from the traditional models varied substantially. The biases, which have clinical implications, seem inevitable with the sample-based models, which, even if overall biases were removed, will perform unsatisfactorily.

Narrowed beam width in newer ultrasound machines shortens measurements in the lateral direction: fetal measurement charts may be obsolete.

OBJECTIVES: Fetal ultrasound measurements are made in axial, lateral and oblique directions. Lateral resolution is influenced by the beam width of the ultrasound system. To improve lateral resolution and image quality, the beam width has been made narrower; consequently, measurements in the lateral direction are affected and apparently made shorter, approaching the true length. The aims of this study were to explore our database to reveal time-dependent shortening of ultrasound measurements made in the lateral direction, and to assess the extent of beam-width changes by comparing beam-width measurements made on old and new ultrasound machines. METHODS: A total of 41,941 femur length measurements, collected during the time-period 1987-2005, were analyzed, with time as a covariate. Using three ultrasound machines from the 1990s and three newer machines from 2007, we performed 25 series of blinded beam-width measurements on a tissue-mimicking phantom, measuring at depths of 3-8 cm with a 5-MHz transducer. RESULTS: Regression analysis showed time to be a significant covariate. At the same gestational age, femur length measurement was 1.15 (95% CI, 1.08-1.23) mm shorter in the time-period 1999-2005 than in the time-period 1987-1992. Overall, the beam width was 1.08 (95% CI, 0.50-1.65) mm narrower with the new machines than with the old machines. CONCLUSIONS: Technical improvements in modern ultrasound machines that have reduced the beam width affect fetal measurements in the lateral direction. This has clinical implications and new measurement charts are needed.

A new population-based term prediction model vs. two traditional sample-based models: validation on 9046 ultrasound examinations.

OBJECTIVES: To compare results of predictions of date of delivery from a new population-based model with those from two traditional regression models. METHODS: We included 9046 fetal biparietal diameter (BPD) measurements and 8776 femur length (FL) measurements from the routine ultrasound examinations at Stavanger University Hospital between 2001 and 2007. The prediction models to be validated were applied to the data, and the resulting predictions were compared with the actual time of the subsequent deliveries. The primary measure was the median bias (the difference between the true and the predicted date of delivery), calculated for each method, for the study population as a whole and for three subgroups of BPD/FL measurements. We also assessed the proportion of births within ± 14 days of the predicted day, and rates of preterm and post-term deliveries, which were regarded as secondary measures. RESULTS: For the population-based model, the median bias was -0.15 days (95% confidence interval (CI), -0.43 to 0.12) for the BPD-based, and -0.48 days (95% CI, -0.86 to -0.46) for the FL-based predictions, and both biases were stable over the inclusion ranges. The biases of the traditional regression models varied, depending on the fetal size at the time of the examination; the extremes were -3.2 and + 4.5 days for the BPD-based, and -1.0 and + 5.0 days for the FL-based predictions. CONCLUSIONS: The overall biases, as well as the biases for the subgroups, were all smaller with the population-based model than with the traditional regression models, which exhibited substantial biases in some BPD and FL subcategories. For the population-based model, the FL-based predictions were in accordance with the BPD-based predictions.

Biases of traditional term prediction models: results from different sample-based models evaluated on 41 343 ultrasound examinations.

OBJECTIVE: To evaluate two Norwegian traditional, sample-based term prediction models as applied to the data from a large population-based registry. The two models were also compared with an established German model. METHODS: Our database included information from 41 343 non-selected ultrasound scans registered over the years 1987-2005. The prediction models were applied to measurements from the ultrasound examinations, and the resulting term predictions were compared with the actual times of the deliveries. The median bias (the difference between the true and the predicted date of delivery) was calculated for each model, both for the study population as a whole and for subgroups of measurements of biparietal diameter (BPD) and femur length (FL). Secondary measures, i.e. proportion of births within ± 14 days and the rates of preterm and post-term deliveries, were also assessed. RESULTS: The analyses showed that the models had significant biases, predicting delivery date either too late or too early. For each model the size of the bias varied, depending on the fetal size at the time of the examination; the extremes were minus 4 and plus 4 days for the BPD-based predictions. There were similar results with the FL-based predictions. CONCLUSION: Term predictions made with traditional sample-based models had significant biases that varied over each method's measurement range. These models have important shortcomings, probably because of strict selection criteria in the process of constructing the models, and because the methods primarily aim at estimating the last menstrual period-based day of conception, not the day of birth.

Biometrical modeling of twin and family data using standard mixed model software.

Biometrical genetic modeling of twin or other family data can be used to decompose the variance of an observed response or 'phenotype' into genetic and environmental components. Convenient parameterizations requiring few random effects are proposed, which allow such models to be estimated using widely available software for linear mixed models (continuous phenotypes) or generalized linear mixed models (categorical phenotypes). We illustrate the proposed approach by modeling family data on the continuous phenotype birth weight and twin data on the dichotomous phenotype depression. The example data sets and commands for Stata and R/S-PLUS are available at the Biometrics website.

A direct method for ultrasound prediction of day of delivery: a new, population-based approach.

OBJECTIVES: To introduce a direct population-based method for prediction of term based on ultrasound measurements of the biparietal diameter and femur length in the second trimester of pregnancy. METHODS: Our data consisted of 41 343 ultrasound scans from a non-selected population, prospectively collected during the years 1987-2004. Using measurements of biparietal diameter and femur length, we constructed prediction curves for term by computing median remaining time of pregnancy from the ultrasound measurement to birth. A local linear quantile regression method was used to smooth the median and quantile curves. RESULTS: The quality of term prediction was stable over the prediction range for both biparietal diameter (25-60 mm) and femur length (11-42 mm). The femur-based predictions were nearly as good as those of the biparietal diameter. For the biparietal diameter, the median of the prediction residual was -0.09 days; 87.2% of the births fell within +/- 14 days of the predicted day of delivery, 3.5% births were classified as preterm and 4.3% as post-term. The corresponding figures for femur length were - 0.04 days, 86.7%, 3.6% and 4.5%. The covariates maternal age, parity, mother's smoking habits, sex of the fetus and examination year generally affected the predicted term by less than 1 day. CONCLUSIONS: This direct ultrasound-based prediction of term using population-based data avoids selection biases possibly present in smaller prospective samples. The model obviates the dependence on last menstrual period found in standard methods for term prediction, and allows an immediate assessment of prediction quality in a population setting. The femur-based predictions had a quality similar to those based on the biparietal diameter. The model can be updated continuously as new data are collected.

Case-parent triads: estimating single- and double-dose effects of fetal and maternal disease gene haplotypes.

Case-parent triad data are considered a robust basis for studying association between variants of a gene and a disease. Methods evaluating statistical significance of association, like the TDT-test and its extensions, are frequently used. When there are prior hypotheses of a causal effect of the gene under study, however, methods measuring penetrance of alleles or haplotypes as relative risks will be more informative. Log-linear models have been proposed as a flexible tool for such relative risk estimation. We demonstrate an extension of the log-linear model to a natural framework for also estimating effects of multiple alleles or haplotypes, incorporating both single- and double-dose effects. The model also incorporates effects of single- and double-dose maternal haplotypes on a fetus during pregnancy. Unknown phase of haplotypes as well as missing parents are accounted for by the EM algorithm. A number of numerical improvements to maximum likelihood estimation are also implemented to facilitate a larger number of haplotypes. Software for these analyses, HAPLIN, is publicly available through our web site. As an illustration we have re-analyzed data on the MSX1 homeobox-gene on chromosome 4 to show how haplotypes may influence the risk of oral clefts.

Paternal contribution to birth weight.

STUDY OBJECTIVE: Understanding causes of variation in birth weight has been limited by lack of sufficient sets of data that include paternal birth weight. The objective was to estimate risks of low birth weight dependent on parental birth weights and to estimate father-mother-offspring correlations for birth weight to explain the variability in birth weight in terms of effects of genes and environmental factors. DESIGN: A family design, using trios of father-mother-firstborn child. SETTING: The complete birth population in Norway 1967-98. PARTICIPANTS: 67 795 families. MAIN RESULTS: The birth weight correlations were 0.226 for mother-child and 0.126 for father-child. The spousal correlation was low, 0.020. The relative risk of low birth weight in the first born child was 8.2 if both parents were low birth weight themselves, with both parents being above 4 kg as the reference. The estimate of heritability is about 0.25 for birth weight, under the assumption that cultural transmission on the paternal side has no effect on offspring prenatal growth. CONCLUSIONS: Paternal birth weight is a significant and independent predictor of low birth weight in offspring. The estimate of the heritability of birth weight in this study is lower than previously estimated from data within one generation in the Norwegian population.

Pneumococcal pulmonary infection, septicaemia and survival in young zinc-depleted mice.

The aim of the present study was to explore whether mice fed a diet low in Zn (2.0 mg Zn/kg diet) for a relatively short period of time were more prone to severe Streptococcus pneumoniae infection than mice fed a normal diet (25 mg elemental Zn/kg). The Zn-deficient mice were compared with mice in two Zn-adequate control groups; one pair-fed and another with free access to the diet. After 2 weeks feeding, the mice were infected intranasally under anaesthesia with a suspension containing about 10(7) pneumococci. Clinical status was observed every day and blood samples were examined for S. pneumoniae every second day for a week. All infected mice examined carried the infecting strain intranasally. The survival time and time before positive blood culture were significantly shorter in the Zn-depleted group than in the pair-fed Zn-adequate group (hazard ratios 15.6 and 3.2, and respectively). At the end of the observation period, ten of the twelve mice in the Zn-deficient group were dead while one of twelve and two of twelve were dead in the two Zn-adequate control groups. This study shows that even acutely-induced Zn deficiency dramatically increases the risk of serious pneumococcal infection in mice.

New standards for birth weight by gestational age using family data.

OBJECTIVE: This study was undertaken to provide new standards for birth weight according to gestational age through the addition of family data on maternal birth weight and birth weights of previous siblings. STUDY DESIGN: The analyses were based on 1.7 million births in Norway from 1967 through 1998. These population data were arranged into sibships and mother-offspring units through unique personal numbers. We categorized first births by sex and maternal birth weight and second births by sex and birth weight of the older sibling. RESULTS: Standards for birth weight per gestational age percentiles differed by >1100 g when the birth weight of an older sibling was considered and by almost 700 g when maternal birth weight was considered. The value of these new standards for birth weight according to gestational age was demonstrated through variation in perinatal mortality. CONCLUSION: Maternal birth weight and birth weights of previous siblings allow improved predictions of birth weight according to gestational age and should be used for classification of small-for-gestational-age births.

Birthweight by gestational age in Norway.

OBJECTIVE: To describe birthweight by gestational age in Norway for the period 1967-1998, evaluate secular trends and provide new standards for small for gestational age for 16 to 44 weeks of gestation. SUBJECTS AND METHODS: The analyses were based on more than 1.8 million singleton births, covering all births in Norway for a 32 year period. Percentiles for birthweight by gestational age were estimated using smoothed means and standard deviations. In the preterm weeks, means and standard deviations were carefully screened for birthweight-gestational age consistency, adapting a method of Wilcox and Russell. Differences in birthweight by gestational age for stillbirths and livebirths in extremely preterm weeks (16-28) are presented, and the effects of cesarean section are evaluated. We observed a clear increase in birthweight by gestational age for all term weeks, but a decrease for most of the preterm weeks over the same period. This decrease was related to the increase in deliveries by cesarean section. CONCLUSIONS: Percentiles for birthweight by gestational age are presented for clinical use, based on a current period 1987-98, covering 20-44 completed gestational weeks. In the final standards we excluded stillbirths, infants born with malformations and cesarean sections. Birthweights in the Scandinavian populations are high and standards from other populations may not be representative, especially for the term weeks. Also, the secular changes demonstrated in this study indicate that old birthweight by gestational age standards need revision, especially due to changes in obstetrical routines influencing preterm data.

Infants' length at birth: an independent effect on perinatal mortality.

AIM: To investigate whether variations in birth length (crown-heel-length) were associated with perinatal mortality rate independent of birth weight. MATERIAL: The study population was singleton live- and stillbirths from 16 weeks of gestation compiled in the Medical Birth Registry of Norway from 1967 to 1997, totaling 1,705,652 births. METHOD: The total population was analyzed using z-scores for length at birth, birth weight and gestational age. Variation in perinatal mortality by length at birth was studied within birth weight strata (250 g) by logistic regression. RESULTS: Perinatal mortality varied more by birth length than by birth weight or gestational age, especially for values above the population means. Within birth weight strata, the association between perinatal mortality and length was similar in all 250 g birth weight categories above 1,500 grams: mortality was lowest at birth lengths 0-2 cm below average, with mortality rates increasing exponentially in either direction. CONCLUSION: Within all birth weight strata, and adjusted for gestational age, long infants had the higher risk of perinatal death, suggesting that length at birth may be a valuable predictor when assessing the risk of perinatal mortality.

Measurement of specific IgA in faecal extracts and intestinal lavage fluid for monitoring of mucosal immune responses.

Currently available methods for the evaluation of antigen-specific immune responses in the intestine, i.e. measurement of IgA in intestinal lavage and antibody secreting cells (ASC) in peripheral blood, are not applicable to large-scale immunogenicity studies or to kinetic studies where repeated sampling is required. Simple and reliable methods need to be developed. Intestinal lavage and faecal samples were collected from 12 mice on days 0, 14, 21, 28 and 35 following initial immunization with four doses of cholera toxin (CT) by the gastric or rectal routes. The concentrations of anti-CT IgA in the faecal extracts showed a high level of correlation with those in the lavage samples (Spearman's correlation coefficient=0.85, P<0. 0001) regardless of the route of CT administration. Moreover, the kinetics of the immune response as reflected in the faecal extracts mirrored those in the lavage samples regardless of immunization route. As compared to gastric immunization, rectal administration of CT yielded higher levels of anti-CT IgA in both intestinal lavage fluids and in faecal extracts. The use of rectal immunization and the measurement of IgA in faecal extracts for monitoring mucosal immune responses may be relevant for the development of effective enteric vaccines.

Mortality after total hip replacement: 0-10-year follow-up of 39,543 patients in the Norwegian Arthroplasty Register.

We have studied the mortality after total hip replacement (THR) of 39,543 patients, having a mean age of 69 years, who were reported to the Norwegian Arthroplasty Register. The median follow-up time was 5.2 (0-10.4) years. 323 of 6201 deaths occurred during the first 60 postoperative days. The patient mortality was compared with the mortality in the Norwegian population, using standardized mortality ratios (SMR). The SMRs were compared and adjusted for age, gender, and other possible confounders in a Cox regression model incorporating the population mortality. We observed a lower mortality in patients with THR than in the Norwegian population (8-year patient mortality was 25%, versus 30% in the corresponding Norwegian population. SMR = 0.81). There was an increased standardized mortality ratio in patients less than 50 years (SMR = 2.50), patients 50-59 years (SMR = 1.16), patients with THR due to rheumatoid arthritis (SMR = 1.48), and patients with femoral neck fracture (SMR = 1.11). The SMR decreased with increasing age at the time of THR surgery. After revision surgery, the SMR was similar to that after the first primary operation, whereas a second primary operation in the opposite hip was associated with a further reduction in the SMR (SMR = 0.65). During the first 60 postoperative days, all patient categories had a higher mortality than the general population (0.8% mortality, SMR = 1.39).

Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine study.

BACKGROUND: Total homocysteine (tHcy) measured in serum or plasma is a marker of folate status and a risk factor for cardiovascular disease. OBJECTIVE: Our objective was to investigate associations between tHcy and complications and adverse outcomes of pregnancy. DESIGN: Plasma tHcy values measured in 1992-1993 in 5883 women aged 40-42 y were compared with outcomes and complications of 14492 pregnancies in the same women that were reported to the Medical Birth Registry of Norway from 1967 to 1996. RESULTS: When we compared the upper with the lower quartile of plasma tHcy, the adjusted risk for preeclampsia was 32% higher [odds ratio (OR): 1. 32; 95% CI: 0.98, 1.77; P for trend = 0.02], that for prematurity was 38% higher (OR: 1.38; 95% CI: 1.09, 1.75; P for trend = 0.005), and that for very low birth weight was 101% higher (OR: 2.01; 95% CI: 1.23, 3.27; P for trend = 0.003). These associations were stronger during the years closest to the tHcy determination (1980-1996), when there was also a significant relation between tHcy concentration and stillbirth (OR: 2.03; 95% CI: 0.98, 4.21; P for trend = 0.02). Neural tube defects and clubfoot had significant associations with plasma tHcy. Placental abruption had no relation with tHcy quartile, but the adjusted OR when tHcy concentrations >15 micromol/L were compared with lower values was 3.13 (95% CI: 1.63, 6. 03; P = 0.001). CONCLUSION: Elevated tHcy concentration is associated with common pregnancy complications and adverse pregnancy outcomes.