The significance of mitochondrial haplogroups in preeclampsia risk.

OBJECTIVE: To determine whether mitochondrial haplogroups function as disease-modifiers or as susceptibility factors in preeclampsia using a traditional haplogroup association model. METHODS: This retrospective study haplotyped 235 control and 78 preeclamptic pregnancies from Denmark using either real-time PCR or Sanger sequencing depending on the rarity of the haplogroup. RESULTS: No significant association between haplogroups and the risk of preeclampsia was found, nor was any role for haplogroups in disease severity uncovered. CONCLUSION: Mitochondrial haplogroups are not associated with preeclampsia or the severity of preeclampsia in the Danish population. However, this study cannot exclude a role for less common mtDNA variation. Models that can examine these should be applied in preeclamptic patients.

First-Trimester Maternal Serum Adiponectin/Leptin Ratio in Pre-Eclampsia and Fetal Growth.

The serum adiponectin/leptin ratio (A/L ratio) is a surrogate marker of insulin sensitivity. Pre-eclampsia (PE) is associated with maternal metabolic syndrome and occasionally impaired fetal growth. We assessed whether the A/L ratio in first-trimester maternal serum was associated with PE and/or birth weight. Adiponectin and leptin were quantitated in first-trimester blood samples (gestational week 10+3−13+6) from 126 women who later developed PE with proteinuria (98 mild PE; 21 severe PE; 7 HELLP syndrome), and 297 controls, recruited from the Copenhagen First-Trimester Screening Study. The A/L ratio was reduced in PE pregnancies, median 0.17 (IQR: 0.12−0.27) compared with controls, median 0.32 (IQR: 0.19−0.62) (p < 0.001). A multiple logistic regression showed that PE was negatively associated with log A/L ratio independent of maternal BMI (odds ratio = 0.315, 95% CI = 0.191 to 0.519). Adiponectin (AUC = 0.632) and PAPP-A (AUC = 0.605) were negatively associated with PE, and leptin (AUC = 0.712) was positively associated with PE. However, the A/L ratio was a better predictor of PE (AUC = 0.737), albeit not clinically relevant as a single marker. No significant association was found between A/L ratio and clinical severity of pre-eclampsia or preterm birth. PE was associated with a significantly lower relative birth weight (p < 0.001). A significant negative correlation was found between relative birth weight and A/L ratio in controls (ß = −0.165, p < 0.05) but not in PE pregnancies), independent of maternal BMI. After correction for maternal BMI, leptin was significantly associated with relative birth weight (ß = 2.98, p < 0.05), while adiponectin was not significantly associated. Our findings suggest that an impairment of the A/L ratio (as seen in metabolic syndrome) in the first trimester is characteristic of PE, while aberrant fetal growth in PE is not dependent on insulin sensitivity, but rather on leptin-associated pathways.

Risk factors for and pregnancy outcomes after SARS-CoV-2 in pregnancy according to disease severity: A nationwide cohort study with validation of the SARS-CoV-2 diagnosis.

INTRODUCTION: We identified risk factors and outcomes associated with SARS-CoV-2 infection in pregnancy in a universally tested population according to disease severity and validated information on SARS-CoV-2 during pregnancy in national health registers in Denmark. MATERIAL AND METHODS: Cohort study using data from national registers and medical records including all pregnancies between March 1, 2020 and February 28, 2021. We compared women with a validated positive SARS-CoV-2 test during pregnancy with non-infected pregnant women. Risk factors and pregnancy outcomes were assessed by Poisson and Cox regression models and stratified according to disease severity defined by hospital admission status and admission reason (COVID-19 symptoms or other). Using medical record data on actual period of pregnancy, we calculated predictive values of the SARS-CoV-2 diagnosis in pregnancy in the registers. RESULTS: SARS-CoV-2 infection was detected in 1819 (1.6%) of 111 185 pregnancies. Asthma was associated with infection (relative risk [RR] 1.63, 95% confidence interval [CI] 1.28-2.07). Risk factors for severe COVID-19 disease requiring hospital admission were high body mass index (median ratio 1.06, 95% CI 1.04-1.09), asthma (RR 7.47, 95% CI 3.51-15.90) and gestational age at the time of infection (gestational age 28-36 vs < 22: RR 3.53, 95% CI 1.75-7.10). SARS-CoV-2-infected women more frequently had hypertensive disorders in pregnancy (adjusted hazard ratio [aHR] 1.31, 95% CI 1.04-1.64), early pregnancy loss (aHR 1.37, 95% CI 1.00-1.88), preterm delivery before gestational age 28 (aHR 2.31, 95% CI 1.01-5.26), iatrogenically preterm delivery before gestational age 37 (aHR 1.49, 95% CI 1.01-2.19) and small-for-gestational age children (aHR 1.28, 95% CI 1.05-1.54). The associations were stronger among women admitted to hospital for any reason. The validity of the SARS-CoV-2 diagnosis in relation to pregnancy in the registers compared with medical records showed a negative predictive value of 99.9 (95% CI 99.9-100.0) and a positive predictive value of 82.1 (95% CI 80.4-83.7). CONCLUSIONS: Women infected with SARS-CoV-2 during pregnancy were at increased risk of hypertensive disorders in pregnancy, early pregnancy loss, preterm delivery and having children small for gestational age. The validity of Danish national registers was acceptable for identification of SARS-CoV-2 infection during pregnancy.

SARS-CoV-2 infection in pregnancy in Denmark-characteristics and outcomes after confirmed infection in pregnancy: A nationwide, prospective, population-based cohort study.

INTRODUCTION: Assessing the risk factors for and consequences of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy is essential to guide clinical care. Previous studies on SARS-CoV-2 infection in pregnancy have been among hospitalized patients, which may have exaggerated risk estimates of severe outcomes because all cases of SARS-CoV-2 infection in the pregnant population were not included. The objectives of this study were to identify risk factors for and outcomes after SARS-CoV-2 infection in pregnancy independent of severity of infection in a universally tested population, and to identify risk factors for and outcomes after severe infection requiring hospital admission. MATERIAL AND METHODS: This was a prospective population-based cohort study in Denmark using data from the Danish National Patient Register and Danish Microbiology Database and prospectively registered data from medical records. We included all pregnancies between March 1 and October 31, 2020 and compared women with a positive SARS-CoV-2 test during pregnancy to non-infected pregnant women. Cases of SARS-CoV-2 infection in pregnancy were both identified prospectively and through register linkage to ensure that all cases were identified and that cases were pregnant during infection. Main outcome measures were pregnancy, delivery, maternal, and neonatal outcomes. Severe infection was defined as hospital admission due to coronavirus disease 2019 (COVID-19) symptoms. RESULTS: Among 82 682 pregnancies, 418 women had SARS-CoV-2 infection during pregnancy, corresponding to an incidence of 5.1 per 1000 pregnancies, 23 (5.5%) of which required hospital admission due to COVID-19. Risk factors for infection were asthma (odds ratio [OR] 2.19, 95% CI 1.41-3.41) and being foreign born (OR 2.12, 95% CI 1.70-2.64). Risk factors for hospital admission due to COVID-19 included obesity (OR 2.74, 95% CI 1.00-7.51), smoking (OR 4.69, 95% CI 1.58-13.90), infection after gestational age (GA) 22 weeks (GA 22-27 weeks: OR 3.77, 95% CI 1.16-12.29; GA 28-36 weeks: OR 4.76, 95% CI 1.60-14.12), and having asthma (OR 4.53, 95% CI 1.39-14.79). We found no difference in any obstetrical or neonatal outcomes. CONCLUSIONS: Only 1 in 20 women with SARS-CoV-2 infection during pregnancy required admission to hospital due to COVID-19. Risk factors for admission comprised obesity, smoking, asthma, and infection after GA 22 weeks. Severe adverse outcomes of SARS-CoV-2 infection in pregnancy were rare.

Placental protein-13 (PP13) in combination with PAPP-A and free leptin index (fLI) in first trimester maternal serum screening for severe and early preeclampsia.

BACKGROUND: Placental protein-13 (PP13) is involved in placental invasion and has been suggested as a maternal serum marker of preeclampsia (PE) development. However, the discriminatory ability of PP13 in first trimester has not been completely clarified. METHODS: PP13 was measured in first trimester (week 10+3-13+6) maternal serum from 120 PE pregnancies and 267 control pregnancies and was correlated with clinical parameters. The population screening performance of PP13 in combination with the PE markers pregnancy associated plasma protein A (PAPPA) and free leptin index (fLI) was assessed by Monte Carlo simulation. RESULTS: In severe PE (including HELLP) cases (n=26) the median PP13 concentration was 35.8 pg/mL (range: 17.8-85.5 pg/mL) and in PE pregnancies (n=10) with birth prior to week 34, the median PP13 concentration was 30.6 pg/mL (13.1-50.1 pg/mL), compared to controls with a median of 54.8 pg/mL (range: 15.4-142.6 pg/mL) (p<0.04). The population screening detection rate (DR) for a false-positive rate of 10% for severe PE and HELLP was 26% for PP13, 28% for PP13+PAPP-A, 33% for PP13+fLI, and 40% for PP13+PAPP-A+fLI. CONCLUSIONS: PP13 is a marker of severe PE and HELLP syndrome. The screening performance of PP13 can be markedly improved by combining it with fLI and PAPP-A.

Maternal Serum Resistin Is Reduced in First Trimester Preeclampsia Pregnancies and Is a Marker of Clinical Severity.

OBJECTIVE: To examine whether resistin levels in first trimester maternal serum are associated with insulin resistance or preeclampsia (PE). METHODS: A case-control study of maternal serum resistin concentration conducted using 285 normal pregnancies and 123 PE pregnancies matched for gestational age, parity and maternal age. Samples were taken in gestational weeks 10+0-13+6. RESULTS: There was a negative correlation between resistin and clinical severity of PE, but no correlation with IS, TNF-α, body mass index, birth weight and pregnancy length. CONCLUSIONS: Resistin is reduced in first trimester of PE pregnancies, particularly in severe PE. Inflammation and IS cannot explain this phenomenon.

[Defect at uterine incision from prior Caesarean section]. / Defekt i uterotomi efter tidligere sectio.

A case of asymptomatic uterine fenestration in 26+3 gestational weeks in a patient who had previously undergone Caesarean section is presented. Controls were planned. In gestational week 34+1 the woman was hospitalized due to lower abdominal pain, but with otherwise normal objective parameters. Ten days later the patient had increasing pain, and a caesarean section was performed. Fenestration was confirmed. This leads to reflections on how to treat and observe such cases, and further discussion about whether early identification of risk patients by ultrasound is possible.

Free leptin index and PAPP-A: a first trimester maternal serum screening test for pre-eclampsia.

BACKGROUND: Prophylaxis with low-dose aspirin may reduce the risk of pre-eclampsia (PE) if introduced in first trimester. The performance of first trimester maternal serum screening for PE using free leptin index (fLI) and PAPP-A, where fLI = leptin/leptin soluble receptor was studied. METHODS: First trimester serum samples from 126 PE pregnancies and 289 control pregnancies were studied. fLI and PAPP-A were converted into gestational age and maternal weight independent log MoM values of PAPP-A and fLI. The screening performance of markers was studied by receiver-operator-characteristics curves. The performance of population screening was estimated by Monte Carlo simulation. RESULTS: fLI was significantly (p < 0.001) elevated [mean log MoM 0.2165 (SD: 0.2604)] compared to controls [mean log MoM -0.0368 (SD: 0.3132)] and PAPP-A was significantly (p < 0.001) reduced [mean log MoM -0.0133 (SD: 0.2661)] compared to controls [mean log MoM 0.0474 (SD: 0.2521)] in PE pregnancies. There was no correlation between fLI and PAPP-A in control or PE pregnancies. Combined fLI and PAPP-A screening for PE had estimated population detection rates of 22% and 35% for false positives rates of 6% and 12%, respectively. CONCLUSION: Combining PAPP-A and fLI improves screening performance for PE compared to single marker screening.

Polymorphisms in the tumor necrosis factor alpha and interleukin 1-beta promoters with possible gene regulatory functions increase the risk of preterm birth.

OBJECTIVE: To investigate the relation between 19 selected single nucleotide polymorphisms in three cytokine genes, tumor necrosis factor alpha (TNFA), interleukin 1-beta (IL1B) and interleukin 6 (IL6) and preterm birth (<37 weeks' gestation). DESIGN: Case-control association study. SAMPLE: A total of 117 singleton pregnant Danish Caucasian women, including 62 preterm birth cases and 55 controls (birth>or=37 weeks). METHODS: Genotyping was performed using TaqMan probes and traditional sequencing. Descriptive statistics were carried out with Fisher's exact test and Wilcoxon rank-sum test. All genetic data were tested for Hardy-Weinberg equilibrium and analyzed using logistic regression, 2x2 proportions or chi(2). Haplotypes were estimated for each gene and permutation used for association testing. RESULTS: Women carrying the TNFA -857 C>T rare allele (T) and those homozygous for the IL1B -31 T>C and IL1B -511 C>T rare alleles (C and T) have an increased risk of preterm birth with OR 3.1 (95% CI: 1.0-10.3) and OR 6.4 (95% CI: 1.3-60.5), respectively. Two estimated TNFA haplotypes were associated with preterm birth with OR 3.1 (p=0.037) and OR 2.7 (p=0.045). CONCLUSION: Polymorphisms in the cytokine genes TNFA and IL1B may increase the risk of preterm birth, possibly by a dysregulation of the immune system in pregnancy.

Early fetal size and growth as predictors of adverse outcome.

OBJECTIVE: To evaluate the association between fetal size and growth between the first and second trimesters and subsequent adverse pregnancy outcome. METHODS: A cohort was created of 7,642 singleton pregnancies cared for in three obstetric units associated with Copenhagen University. Data were obtained from ultrasound measurements at 11-14 weeks (crown-rump length, biparietal diameter) and 17-21 weeks (biparietal diameter). Fetal size was assessed by gestation-specific z scores, and fetal growth between the first and second trimester was calculated individually using conditional centiles. The main outcome measures were preterm delivery, smallness for gestational age, and perinatal death. RESULTS: Slow growth of the biparietal diameter less than the 10th and less than the 2.5th conditional centiles between first and second trimesters occurred in 10.4% and 3.6% of the population, respectively. Biparietal diameter growth less than the 10th centile was associated with perinatal death before 34 weeks (risk 0.5% compared with 0.04%, odds ratio [OR] 16.0, confidence interval [CI] 2.9-88.7). Biparietal diameter growth less than the 2.5th centile was the best predictor of perinatal death at any gestation, with a positive likelihood ratio of 4.7 and an OR of 7.3 (CI 2.4-22.2). In contrast, the biparietal diameter, dated by crown-rump length, did not have an increased risk of perinatal death; however, there was a mildly increased risk of small for gestational age birth weight (less than the 10th customized centile) if the biparietal diameter was below the 10th centile in the first trimester (risk 17% compared with 12%, OR 1.5, CI 1.2-1.8) or in the second trimester (risk 15.8% compared with 12.4%, OR 1.3, CI 1.1-1.5). CONCLUSION: Slow growth of the fetal biparietal diameter between the first and second trimesters of pregnancy is a strong predictor of perinatal death before 34 weeks.

[Prenatal diagnosis of congenital insulin-resistant diabetes (Donohue's syndrome)]. / Praenatal diagnostik for kongenit insulinresistent diabetes (Donohues syndrom).

A consanguineous Turkish couple was expecting their third child. Two years earlier their second child had died from a severe form of insulin-resistant diabetes causing Donohue's syndrome. A novel mutation (V335) in the insulin receptor gene was found to be disrupting the structure and function of the receptor. The parents, as well as their first child, were asymptomatic, heterozygous carriers. The family received genetic counselling, and chorion villus sampling was performed early in pregnancy. Genotyping showed that the child in utero was heterozygous for the mutation. Subsequently the mother gave birth to a healthy boy.

Nuchal translucency measurements are highly correlated in both mono- and dichorionic twin pairs.

OBJECTIVES: To establish the distribution of serological and ultrasound first-trimester Down syndrome markers in twins and identify correlations of significance for risk calculation. METHODS: Nuchal translucency (NT), PAPP-A and betahCG data were extracted from 181 twin pregnancies (31 mono- and 150 dichorionic) with a normal outcome. All pregnancies were consecutively and prospectively included and examined in the Copenhagen First-Trimester Study. The variance of the sum and the difference of log MoM NT values in twin pairs was used to calculate the correlation. RESULTS: The serological markers did not correlate and were nearly twice the value seen in singleton pregnancies with a median PAPP-A MoM of 2.14 and a median free betahCG MoM of 2.06. Chorionicity was not found to influence the level of biochemical markers. In all twin pairs (r = 0.343, p < 0.001, F-test), as well as mono- (r = 0.404, p = 0.011, F-test) and dichorionic twins (r = 0.316, p < 0.001, F-test) there was a significant correlation between log MoM NT in each pair. CONCLUSION: As the NT values of fetuses in subsequent pregnancies from the same woman do not correlate, the correlation between NTs in twins reflects that the NT is influenced by placental and maternal factors specific for the particular pregnancy, for example, nutrient supply or vascularisation. The correlation may be useful to improve the precision of the prenatal risk assessment for Down syndrome in first-trimester twin pregnancies. The serological markers were elevated in the examined twins as previously described.

Reduction of the disintegrin and metalloprotease ADAM12 in preeclampsia.

OBJECTIVES: The secreted form of ADAM12 is a metalloprotease that may be involved in placental and fetal growth. We examined whether the concentration of ADAM12 in first-trimester maternal serum could be used as a marker for preeclampsia. METHODS: We developed a semiautomated, time-resolved, immunofluorometric assay for the quantification of ADAM12 in serum. The assay detected ADAM12 in a range of 78-1248 microg/L. Serum samples derived from women in the first trimester of a normal pregnancy (n = 324) and from women who later developed preeclampsia during pregnancy (n = 160) were obtained from the First Trimester Copenhagen Study. ADAM12 levels were assayed in these serum samples. Serum levels of ADAM12 were converted to multiples of the median (MoM) after log-linear regression of concentration versus gestational age. RESULTS: Serum ADAM12 levels in women who developed preeclampsia during pregnancy had a mean log MoM of -0.066, which was significantly lower than the mean log MoM of -0.001 for ADAM12 levels observed in serum samples from women with normal pregnancy (P = .008). The mean log MoM was even lower in serum derived from preeclamptic women whose infant's weight at birth was less than 2,500 g (n = 27, mean log MoM of -0.120, P = .053). CONCLUSION: The maternal serum levels of ADAM12 are significantly lower during the first trimester in women who later develop preeclampsia during pregnancy when compared with levels in women with normal pregnancies. Because the secreted form of ADAM12 cleaves insulin-like growth factor binding protein (IGFBP)-3 and IGFBP-5, the IGF axis may play a role in preeclampsia. ADAM12 may be a useful early marker for preeclampsia. LEVEL OF EVIDENCE: II-2.

Obesity-related complications in Danish single cephalic term pregnancies.

OBJECTIVE: Our objective was to investigate the relationship between prepregnancy and obstetric body mass index (BMI) as well as fetal complications in a large, unselected cohort of Danish women with single cephalic pregnancies. METHODS: A cohort of 8,092 women from the Copenhagen First Trimester Study with a registered prepregnancy BMI and a single cephalic term delivery were stratified into 3 BMI groups: normal weight (BMI < 25 kg/m(2)), overweight (BMI 25-29.9 kg/m(2)), and obese (BMI >/= 30 kg/m(2)). The effects of BMI and parity on the outcome were analyzed using multivariate logistic regression analyses. RESULTS: Overweight women had an odds ratio (OR) of 3.4 for diabetes, 1.9 for hypertension, 1.7 for preeclampsia, and 1.5 for cesarean delivery. The corresponding figures for obese women were 15.3, 4.8, 2.7, and 1.7, respectively. No relationship was found between BMI and vacuum extraction. Obese women had an increased risk of delivering macrosomic but also low birth weight children. No differences existed among the 3 weight groups with regard to neonatal morbidity estimated by Apgar score, umbilical cord pH, or admittance to a neonatal intensive care unit. Nulliparous women had an increased incidence of preeclampsia (OR 2.8), hypertension (OR 1.9), emergency cesarean delivery (OR 3.4), vacuum extraction (OR 5.6), and perineal rupture (OR 1.7) but a lower frequency of elective cesarean delivery (OR 0.25). CONCLUSION: The rate of complications during pregnancy and delivery increases with an increasing prepregnancy BMI in women with single cephalic term pregnancies, particularly in nulliparous women.

Combined first- and second-trimester screening for Down syndrome: an evaluation of proMBP as a marker.

OBJECTIVES: To estimate the screening performance of different combinations of first- and second-trimester markers, including a new marker, the proform of eosinophil major basic protein (proMBP). METHODS: The population comprised 195 singleton pregnancies with a normal outcome enrolled in the Copenhagen First Trimester Study, in which a serum sample was available from both the first and the second trimester. The performance of different marker combinations was estimated by receiver-operator-characteristics (ROC) analysis using a Monte Carlo simulation and distributions of log(10)MoM markers and their correlations, derived from our normal material and Down syndrome cases from the literature. RESULTS: Using a fixed screen-positive rate (SPR) of 5%, the first-trimester combined test [nuchal translucency (NT), PAPP-A and free beta-hCG] yielded a detection rate (DR) of 76%, and the integrated test (NT, PAPP-A, AFP, hCG, uE3 and inhibin A) yielded a DR of 86%. With a DR of 90%, the best combination was the first-trimester beta-hCG and NT with the second-trimester proMBP and AFP. ProMBP combined with the triple test increased the DR from 62 to 83%, whereas the addition of inhibin A only increased the DR to 69%. CONCLUSION: These results suggest that proMBP may be an important new marker in Down syndrome screening and, in particular, a good substitute for inhibin A.

Gender impact on first trimester markers in Down syndrome screening.

The influence of fetal gender on the level in the first trimester of the serological markers alpha-fetoprotein (AFP), pregnancy-associated plasma protein-A (PAPP-A) and free beta human chorionic gonadotropin (betahCG) and on nuchal translucency is described for 2637 singleton pregnancies with normal outcome. Mean log MoM values for pregnancies with female and male fetuses were calculated using regression of log marker values on gestational age expressed as crown rump length and on maternal weight. A pronounced gender impact was found for free betahCG, being 16% higher for female than for male fetuses.