Diagnostic yield of exome sequencing in isolated fetal growth restriction: Systematic review and meta-analysis.

The aim of this study was to determine the diagnostic yield of exome sequencing (ES) above that of chromosomal microarray analysis (CMA) or karyotyping in fetuses with isolated fetal growth restriction (FGR). This was a systematic review conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Selected studies included those with (a) only fetuses with FGR in the absence of fetal structural anomalies and (b) negative CMA or karyotyping results. Only positive variants classified as likely pathogenic or pathogenic determined as causative of the fetal phenotype were considered. A negative CMA or karyotype result was treated as the reference standard. Eight studies with data on ES diagnostic yield, including 146 fetuses with isolated FGR, were identified. Overall, a pathogenic variant determined as potentially causative of the fetal phenotype was found in 17 cases, resulting in a 12% (95% CI: 7%-18%) incremental performance pool of ES. The vast majority were studied before 32 weeks'gestation. In conclusion, a monogenic disorder was prenatally found in association with apparently isolated FGR in 12% of these fetuses.

Third-trimester uterine artery Doppler for prediction of adverse outcome in late small-and adequate for-gestational-age fetuses.

Fetal growth restriction includes all those fetuses that do not reach their own growth potential due to placental insufficiency and therefore at higher risk of adverse perinatal outcomes. Identification and follow-up of these fetuses is essential to decrease this additional risk. Although estimated fetal weight under the 3rd centile and pathological cerebroplacental ratio are the most accepted predictive criteria, some evidence suggests that abnormal uterine artery Doppler may be a useful prognostic parameter in late-onset growth restriction fetuses at the moment of diagnosis. However, its prediction capacity as a standalone parameter is limited. In that context, integrated models of biometric and hemodynamic ultrasound parameters including uterine Doppler have been proposed as an effective approach to stratify the risk and improve perinatal outcomes. Moreover, an association of abnormal uterine artery Doppler and histological findings of placental underperfusion due to vascular obstruction has been described. Finally, it has also been suggested that the evaluation of uterine artery Doppler at third trimester in appropriate-for-gestational-age fetuses could identify cases of subclinical placental insufficiency, but further evidence is needed to define such predictive strategies.

Death and severe morbidity in isolated periviable small-for-gestational-age fetuses.

OBJECTIVE: This study aims to predict perinatal death or severe sequelae in isolated small-for-gestational-age fetuses, diagnosed at a periviable gestational age, based on ultrasound and Doppler parameters at diagnosis. DESIGN: Observational study. SETTING: A tertiary perinatal centre. POPULATION: A cohort of singleton non-malformed fetuses suspected to be small for gestational age (estimated fetal weight, EFW, <10th centile) diagnosed at 22.0-25.6 weeks of gestation. The following parameters were recorded at diagnosis: severe smallness (<3rd centile); absent or reversed end-diastolic velocity in umbilical artery; abnormal middle cerebral artery Doppler; abnormal cerebroplacental ratio; abnormal uterine artery Doppler; and absent or reversed end-diastolic velocity in the ductus venosus. METHODS: Logistic regression analysis. MAIN OUTCOME MEASURES: Predictive performance of EFW and Doppler parameters for short-term adverse outcome of perinatal morbimortality and composite serious adverse outcomes (death, neurological impairment or severe bronchopulmonary dysplasia). RESULTS: A total of 155 pregnancies were included. There were 13 (8.4%) intrauterine and 11 (7.7%) neonatal deaths. A short-term adverse perinatal outcome occurred in 40 (25.8%) pregnancies. There were 31 (20%) cases of serious adverse outcomes. For the prediction of serious adverse outcomes, the combination of absent or reversed end-diastolic velocity in the umbilical artery and impaired middle cerebral artery detected by Doppler evaluation achieved a detection rate of 87%, with a false-positive rate of 14% (accuracy 86%). CONCLUSION: In periviable isolated small-for-gestational-age fetuses, a Doppler evaluation of the umbilical and fetal brain circulation can accurately predict short-term adverse perinatal complications and serious adverse outcomes.

Angiogenic factors assessment in pre-eclampsia high-risk population for the prediction of small-for-gestational age neonates: A prospective longitudinal study.

OBJECTIVE: The authors aimed to compare cross-sectional versus longitudinal models for prediction of small-for-gestational age (SGA) neonates among pregnancies with high risk of early pre-eclampsia (PE). METHODS: A prospective longitudinal study was performed in Hospital Universitari Dexeus, Barcelona. The study population included 390 pregnancies with a high risk of early PE according to the first trimester algorithm. Cross-sectional models combining first trimester risk plus placental growth factor and FMS-like tyrosine kinase 1/placental growth factor ratio, respectively, were created at 19-22, 24-26, and 27-30 weeks and compared with a model assessing longitudinal changes of these parameters. Models adding mean uterine artery pulsatility index and abdominal circumference were evaluated. SGA neonates were defined as having a birth weight less than the tenth centile. RESULTS: The predictive performance of a model assessing longitudinal changes of angiogenic factors was similar to that of single evaluations at the second and early third trimesters. The performance of the models combining angiogenic factors with mean uterine artery pulsatility index and abdominal circumference was better than those using only biochemical markers. However, the longitudinal evaluation of biochemical and biophysical parameters did not perform better than cross-sectional evaluations. CONCLUSIONS: Evaluation of angiogenic factors are useful for prediction of SGA neonates in a high-risk population for early PE. However, longitudinal models do not increase their predictive capacity.

Novel glycoproteins identify preclinical atherosclerosis among women with previous preeclampsia regardless of type 1 diabetes status.

BACKGROUND AND AIMS: Information regarding inflammation and cardiovascular disease (CVD) risk in type 1 diabetes (T1D) or preeclampsia (PE) is scarce. We assessed differences in inflammation markers according to the presence of both conditions and their association with atherosclerosis. METHODS AND RESULTS: We recruited 112 women without CVD and last pregnancy ≥5 years previously (n = 28 per group): a)T1D and PE; b)T1D without PE; c)PE without T1D; and d)Controls (without T1D or PE). Groups were matched by several CVD risk factors, and diabetes duration and retinopathy in T1D. Carotid intima-media thickness (IMT) and plaque presence (IMT ≥1.5 mm) were assessed by ultrasonography. Inflammatory markers included classical variables (leucocytes and high-sensitivity C-reactive protein [hsCRP]) and glycoproteins by nuclear magnetic resonance (1H-NMR) spectroscopy (GlycA, GlycB, GlycF and the height/width [H/W] ratios of GlycA and GlycB). The age of the participants was 44.9 ± 7.8 years, and 20.5% harbored plaque. There were no differences in inflammatory markers among the four study groups. Overall, in multivariate-adjusted models, all 1H-NMR-glycoproteins (except GlycB) were positively associated with IMT measures (IMT of bulb and maximum-IMT of any carotid segment; p < 0.05). After dividing the sample according to PE status, previous findings remained largely unchanged. Furthermore, GlycF was independently associated with carotid plaque only in PE group (OR 5.08 [1.03-25.01] per 0.1 log-increments, p = 0.046). Neither leucocytes nor hsCRP were related to atherosclerosis. Regarding T1D status, non-uniform results were observed. CONCLUSIONS: High 1H-NMR-glycoprotein concentrations have a negative impact on carotid atherosclerosis among women with preeclampsia, regardless of T1D status.

Doppler studies of placental function.

Placental-associated diseases account for most cases of adverse perinatal outcome in developing countries. Doppler evaluation has been incorporated as a predictive parameter at early pregnancy for high-risk placental disease, in the diagnosis and management of those fetuses with impaired intrauterine growth and for the evaluation of fetal wellbeing in those high-risk pregnancies. Uterine Doppler at second trimester predicts most instances of early-onset preeclampsia and intrauterine growth restriction. However, the growing evidence of an effective early propylactic strategy, has turned Uterine Doppler an essential parameter to be included in first trimester predictive algorithms. Umbilical artery Doppler helps in the identification of small-for-gestational-age fetuses at higher risk, and is one of the essential vessels in the assessment of fetal hypoxia impairment, especially in the early cases. It helps in the decision timing for ending the pregnancy improving thus perinatal outcomes. Moreover, in high-risk pregnancies, umbilical artery Doppler has demonstrated to reduce the risk of perinatal deaths and the risk of obstetric interventions. On the other hand, middle cerebral artery Doppler reflects fetal adaptation to hypoxia, and with the cerebroplacental ratio, they improve the detection of fetuses a high risk of adverse perinatal outcome, mostly of those late small fetuses, where most instances of adverse outcome occur in fetuses with normal umbilical artery. Ductus venosous Doppler waveform is a surrogate parameter of the fetal base-acid status. Its use has demonstrated to improve perinatal outcomes, mainly reducing the risk of fetal intrauterine death. Alone or in combination with computerized CTG, it helps tailoring the best moment to end the pregnancy among early cases.

How to define late fetal growth restriction.

A fraction of third-trimester small fetuses does not achieve their endowed growth potential mainly due to placental insufficiency, usually not evident in terms of impaired umbilical artery Doppler, but severe enough to increase the risk of perinatal adverse outcomes and long-term complications. The identification of those fetuses at higher-risk helps to optimize their follow-up and to decrease the risk of intrauterine demise. Several parameters can help in the identification of those fetuses at higher risk, defined as fetal growth restricted (FGR) fetuses. Severe smallness and the cerebroplacental ratio are the most consistent parameters; regarding uterine artery Doppler, although some evidence in favour has been published, there is currently no consensus about its use. Thirty-two weeks of gestation is the accepted cut-off to define late FGR. The differentiation with early FGR is necessary as these two entities have different clinical maternal manifestations, and different associated short-term and long-term neonatal outcomes. The use of angiogenic factors is promising but more research is needed on this field.

Placental growth factor testing in the management of late preterm preeclampsia without severe features: a multicenter, randomized, controlled trial.

BACKGROUND: In women with late preterm preeclampsia, the optimal time for delivery remains a controversial topic, because of the fine balance between the maternal benefits from early delivery and the risks for prematurity. It remains challenging to define prognostic markers to identify women at highest risk for complications, in which case a selective, planned delivery may reduce the adverse maternal and perinatal outcomes. OBJECTIVE: This trial aimed to determine whether using an algorithm based on the maternal levels of placental growth factor in women with late preterm preeclampsia to evaluate the best time for delivery reduced the progression to preeclampsia with severe features without increasing the adverse perinatal outcomes. STUDY DESIGN: This parallel-group, open-label, multicenter, randomized controlled trial was conducted at 7 maternity units across Spain. We compared selective planned deliveries based on maternal levels of placental growth factor at admission (revealed group) and expectant management under usual care (concealed group) with individual randomization in singleton pregnancies with late preterm preeclampsia from 34 to 36+6 weeks' gestation. The coprimary maternal outcome was the progression to preeclampsia with severe features. The coprimary neonatal outcome was morbidity at infant hospital discharge with a noninferiority hypothesis (noninferiority margin of 10% difference in incidence). Analyses were conducted according to intention-to-treat. RESULTS: Between January 1, 2016, and December 31, 2019, 178 women were recruited. Of those women, 88 were assigned to the revealed group and 90 were assigned to the concealed group. The data analysis was performed before the completion of the required sample size. The proportion of women with progression to preeclampsia with severe features was significantly lower in the revealed group than in the concealed group (adjusted relative risk, 0.5; 95% confidence interval, 0.33-0.76; P=.001). The proportion of infants with neonatal morbidity was not significantly different between groups (adjusted relative risk, 0.77; 95% confidence interval, 0.39-1.53; P=.45). CONCLUSION: There is evidence to suggest that the use of an algorithm based on placental growth factor levels in women with late preterm preeclampsia leads to a lower rate of progression to preeclampsia with severe features and reduces maternal complications without worsening the neonatal outcomes. This trade-off should be discussed with women with late preterm preeclampsia to allow shared decision making about the timing of delivery.

Nuclear magnetic resonance lipoproteins are associated with carotid atherosclerosis in type 1 diabetes and pre-eclampsia.

AIMS: Persistence of lipoprotein abnormalities in type 1 diabetes (T1D) and/or pre-eclampsia could be associated with cardiovascular disease (CVD). We assessed differences in the advanced lipoprotein profiles according to the presence of both conditions and their differential association with atherosclerosis. MATERIAL AND METHODS: We recruited 112 women without CVD and last pregnancy ≥5 years previously, divided into four groups (n = 28 per group): (a) T1D and previous pre-eclampsia; (b) T1D without pre-eclampsia; (c) pre-eclampsia without T1D; and (d) controls (without T1D/pre-eclampsia). Groups were matched by several risk factors, and diabetes duration and retinopathy in T1D. Carotid intima-media thickness (IMT) and the presence of plaque (IMT ≥1.5 mm) were assessed by ultrasonography. The lipoprotein profile was evaluated by nuclear magnetic resonance (NMR) spectroscopy. RESULTS: The participants were 44.9 ± 7.8 years old. Carotid plaque presence was 20.5%, with a higher prevalence in T1D and/or pre-eclampsia vs controls (P < .05). High-density lipoprotein (HDL)-related variables differed among groups, mainly driven by an increase in T1D (P < .05), whereas triglyceride-related variables were increased in pre-eclampsia [medium very low-density lipoprotein (VLDL) particles and triglyceride enrichment in HDL and low-density lipoprotein (LDL)]. Overall, in multivariate-adjusted models, LDL-related variables were the most strongly associated with atherosclerosis (P < .05). In age- and statin-adjusted models, previous pre-eclampsia showed an independent association with triglyceride-related variables (plaque: medium-VLDL-particles, OR 1.550 [1.013-2.374]; HDL-cholesterol/HDL-triglycerides ratio, OR 0.411 [0.175-0.967]). Regarding T1D, HDL-parameters were also differentially associated (maximum-IMT: HDL-cholesterol/HDL-particles ratio, ß = -.258, P = .036). CONCLUSIONS: NMR lipoproteins were differentially and independently associated with atherosclerosis in T1D/pre-eclampsia. Further studies are needed to ascertain the role of NMR parameters as CVD biomarkers in this high-risk population.

Nuclear magnetic resonance-based metabolomic analysis in the assessment of preclinical atherosclerosis in type 1 diabetes and preeclampsia.

AIMS: Evaluate the role of plasma metabolomics in atherosclerosis according to the presence of type 1 diabetes (T1D) or previous preeclampsia. METHODS: We recruited 105 women without cardiovascular disease and last pregnancy ≥5 years previously, divided according to the presence of T1D or previous preeclampsia. Preclinical atherosclerosis was defined as the presence of carotid plaque (intima-media thickness ≥1.5 mm) assessed by ultrasonography. Metabolomics were evaluated by nuclear magnetic resonance (NMR). Bivariate and multivariate-adjusted differences in NMR-metabolomics were evaluated. RESULTS: The participants were 44.9 ± 8.1 years-old; 20% harbored plaques. There were significant differences in lipidic-, energetic- and nitrogen-related metabolites according to the presence of T1D/preeclampsia (p < 0.05). In multivariate-adjusted models (by age, statins, blood pressure and T1D/preeclampsia), only lipidomic-related metabolites were associated with atherosclerosis in the whole sample. However, stronger associations were observed in women with previous preeclampsia (vs. without; per 0.5 mmol/L increments); phosphatidylcholine, OR 4.08 (1.32-27.22); free cholesterol, 5.18 (1.22-21.97); saturated fatty acids, OR 2.99 (1.37-6.48); w-7, OR 2.29 (1.15-4.56); and w-9 fatty acids, OR 1.49 (1.00-2.23). CONCLUSIONS: NMR-metabolomics showed a differential pattern according to the presence of T1D/preeclampsia in relation to preclinical atherosclerosis. Since most of these metabolites mirror lifestyle factors, they could help tailor dietetic advice in high-risk women.

"Screening for small-for-gestational age neonates at early third trimester in a high-risk population for preeclampsia".

BACKGROUND: Strategies to improve prenatal detection of small-for-gestational age (SGA) neonates are necessary because its association with poorer perinatal outcome. This study evaluated, in pregnancies with first trimester high risk of early preeclampsia, the performance of a third trimester screening for SGA combining biophysical and biochemical markers. METHODS: This is a prospective longitudinal study on 378 singleton pregnancies identified at high risk of early preeclampsia according to a first trimester multiparametric algorithm with the cutoff corresponding to 15% false positive rate. This cohort included 50 cases that delivered SGA neonates with birthweight < 10th centile (13.2%) and 328 cases with normal birthweight (86.8%). At 27-30 weeks' gestation, maternal weight, blood pressure, estimated fetal weight, mean uterine artery pulsatility index and maternal biochemical markers (placental growth factor and soluble FMS-Like Tyrosine Kinase-1) were assessed. Different predictive models were created to evaluate their performance to predict SGA neonates. RESULTS: For a 15% FPR, a model that combines maternal characteristics, estimated fetal weight, mean uterine artery pulsatility index and placental growth factor achieved a detection rate (DR) of 56% with a negative predictive value of 92.2%. The area under receiver operating characteristic curve (AUC) was 0.79 (95% confidence interval (CI), 0.72-0.86). The DR of a model including maternal characteristics, estimated fetal weight and mean uterine artery pulsatility index was 54% (AUC, 0.77 (95% CI, 0.70-0.84)). The DR of a model that includes maternal characteristics and placental growth factor achieved a similar performance (DR 56%, AUC 0.75, 95% CI (0.67-0.83)). CONCLUSIONS: The performance of screening for SGA neonates at early third trimester combining biophysical and biochemical markers in a high-risk population is poor. However, a high negative predictive value could help in reducing maternal anxiety, avoid iatrogenic interventions and propose a specific plan for higher risk patients.

Coronavirus Disease 2019 in Pregnancy: A Clinical Management Protocol and Considerations for Practice.

The coronavirus disease 2019 (COVID-19) pandemic has represented a major impact to health systems and societies worldwide. The generation of knowledge about the disease has occurred almost as fast as its global expansion. The mother and fetus do not seem to be at particularly high risk. Nevertheless, obstetrics and maternal-fetal medicine practice have suffered profound changes to adapt to the pandemic. In addition, there are aspects specific to COVID-19 and gestation that should be known by specialists in order to correctly diagnose the disease, classify the severity, distinguish specific signs of COVID-19 from those of obstetric complications, and take the most appropriate management decisions. In this review we present in a highly concise manner an evidence-based protocol for the management of COVID-19 in pregnancy. We briefly contemplate all relevant aspects that we believe a specialist in obstetrics and maternal medicine should know, ranging from basic concepts about the disease and protection measures in the obstetric setting to more specific aspects related to maternal-fetal management and childbirth.

A new model for screening for early-onset preeclampsia.

BACKGROUND: Early identification of women with an increased risk for preeclampsia is of utmost importance to minimize adverse perinatal events. Models developed until now (mainly multiparametric algorithms) are thought to be overfitted to the derivation population, which may affect their reliability when applied to other populations. Options allowing adaptation to a variety of populations are needed. OBJECTIVE: The objective of the study was to assess the performance of a first-trimester multivariate Gaussian distribution model including maternal characteristics and biophysical/biochemical parameters for screening of early-onset preeclampsia (delivery <34 weeks of gestation) in a routine care low-risk setting. STUDY DESIGN: Early-onset preeclampsia screening was undertaken in a prospective cohort of singleton pregnancies undergoing routine first-trimester screening (8 weeks 0/7 days to 13 weeks 6/7 days of gestation), mainly using a 2-step scheme, at 2 hospitals from March 2014 to September 2017. A multivariate Gaussian distribution model including maternal characteristics (a priori risk), serum pregnancy-associated plasma protein-A and placental growth factor assessed at 8 weeks 0/7 days to 13 weeks 6/7 days and mean arterial pressure and uterine artery pulsatility index measured at 11.0-13.6 weeks was used. RESULTS: A total of 7908 pregnancies underwent examination, of which 6893 were included in the analysis. Incidence of global preeclampsia was 2.3% (n = 161), while of early-onset preeclampsia was 0.2% (n = 17). The combination of maternal characteristics, biophysical parameters, and placental growth factor showed the best detection rate, which was 59% for a 5% false-positive rate and 94% for a 10% false-positive rate (area under the curve, 0.96, 95% confidence interval, 0.94-0.98). The addition of placental growth factor to biophysical markers significantly improved the detection rate from 59% to 94%. CONCLUSION: The multivariate Gaussian distribution model including maternal factors, early placental growth factor determination (at 8 weeks 0/7 days to 13 weeks 6/7 days), and biophysical variables (mean arterial pressure and uterine artery pulsatility index) at 11 weeks 0/7 days to 13 weeks 6/7 days is a feasible tool for early-onset preeclampsia screening in the routine care setting. Performance of this model should be compared with predicting models based on regression analysis.

Genetic syndromes associated with isolated fetal growth restriction.

Early onset fetal growth restriction (FGR) may be due to impaired placentation, environmental or toxic exposure, congenital infections or genetic abnormalities. Remarkable research, mainly based on retrospective series, has been published on the diverse genetic causes. Those have become more and more relevant with the improvement in the accuracy of the analysis techniques and the rising of breakthrough genomewide methods such as the whole genome sequencing. However, no publication has presented an integrated view of management of those fetuses with an early and severe affection. In this review, we explored to which extent genetic syndromes can cause FGR fetuses without structural defects. The most common chromosomal abnormalities (Triploidies and Trisomy 18), submicroscopic chromosomal anomalies (22q11.2 microduplication syndrome) and single gene disorders (often associated with mild ultrasound findings) related to early and severe FGR had been analysed. Finally, we addressed the impact of epigenetic marks on fetal growth, a matter of growing importance. At the end of this review, we should be able to provide an adequate counseling to parents in terms of diagnosis, prognosis and management of those pregnancies.

Preeclampsia Is Associated With Increased Preclinical Carotid Atherosclerosis in Women With Type 1 Diabetes.

PURPOSE: Although preeclampsia (PE) is a well-established cardiovascular risk factor (CVRF) in the general population, its role in type 1 diabetes (T1D) has been scarcely studied. We assessed the association between PE and preclinical atherosclerosis in T1D. METHODS: We recruited 112 women without cardiovascular disease and last pregnancy ≥5 years before: (1) T1D and previous PE (T1D+/PE+; n = 28); (2) T1D without preeclampsia (T1D+/PE-; n = 28); (3) previous PE without T1D (T1D-/PE+; n = 28); and (4) controls (without T1D or PE; T1D-/PE-; n = 28). Groups were matched by age, several CVRFs, and diabetes duration and retinopathy (in T1D participants). Carotid intima-media thickness (IMT) and the presence of plaque (IMT ≥ 1.5 mm) were assessed by standardized ultrasonography protocol. RESULTS: Mean age of the participants was 44.9 ± 7.8 years (14.3% hypertension and 21.4% active smokers). Groups including T1D (T1D+/PE+ and T1D+/PE-) more frequently presented hypertension and statin treatment (23.2% vs 5.4% and 37.5% vs 8.9%; respectively; P < 0.01), without differences in other CVRFs. Carotid plaques were observed in 20.5%. In multivariate models adjusted for age, CVRF, and statins, both T1D and PE showed a similar impact on the presence of plaque, with odds ratios (95% confidence interval), 5.45 (1.36-21.9) and 4.24 (1.04-17.3), respectively. Both entities showed an additive effect when combined, both in common carotid-IMT (T1D+/PE- or T1D-/PE+, ß = 0.198; T1D+/PE+, ß = 0.297) and in the presence of plaque (8.53 [1.07-68.2] and 28.1 [2.67-296.4], respectively). CONCLUSIONS: Previous PE was independently associated with preclinical atherosclerosis in T1D. Further studies are needed to ascertain its usefulness for stratifying risk in T1D women.

Strategies for the prediction of late preeclampsia.

Objectives: To evaluate different strategies for the prediction of late preeclampsia. Methods: A retrospective study was undertaken. A predictive model including maternal parameters (maternal age, maternal BMI, maternal history of preeclampsia or intrauterine growth restriction (PE/IUGR) or maternal chronic disease, and maternal arterial pressure) and mean pulsatility index (PI) of uterine Doppler was created. It was evaluated as an independent model in each trimester, considering 11-13.6 weeks, 20-22.6 weeks and 32-33.6 weeks consequently, and as an integrated model. Results: In the group of late preeclampsia, patients were more obese and had higher incidence of chronic hypertension. Uterine artery pulsatility index (UtA PI) and mean blood pressure were increased in all three trimesters. When evaluating all three models independently, third trimester model performed better than the other two with a sensitivity of 79% and specificity of 82%. The area under the receiver-operating characteristic (ROC) curve (AUC) was 0.86. The integration of all three determinations did not improve third trimester's model. Conclusion: Prediction of late preeclampsia at third trimester seems to be possible if maternal characteristics, blood pressure and UtA Doppler are included.

Osteocalcin Serum Levels in Gestational Diabetes Mellitus and Their Intrinsic and Extrinsic Determinants: Systematic Review and Meta-Analysis.

BACKGROUND: Undercarboxylated osteocalcin (ucOC) increases insulin release and insulin resistance in mice. In humans, evidence is scarce but a correlation of ucOC and total osteocalcin (tOC) with glycemic status markers has been demonstrated. The relationship of ucOC and tOC with gestational diabetes mellitus (GDM) has been even less characterized. OBJECTIVE: To assess the mean difference of tOC and ucOC serum concentrations among nondiabetic pregnant women and women diagnosed as GDM in the second trimester of pregnancy and to determine the possible intrinsic and extrinsic contributors to this difference. METHODS: A systematic search was performed to identify relevant studies published in English and Spanish using PubMed, SCOPUS, ISI Web of Knowledge, and PROSPERO database for meta-analysis. Observational studies measuring mean serum levels of osteocalcin among GDM, with at least 10 subjects analyzed in each group were selected. Mean difference (MD) by random effects model was used. Heterogeneity between studies was assessed using Cochran's Q, H, and I 2 statistics. RESULTS: From 38 selected studies, 5 were retained for analysis for a total of 1119 pregnant women. Serum concentrations of tOC were not significantly different among women with GDM and nondiabetic pregnant controls (MD: 1.56; 95% CI: -0.70 to 3.82; p = 0.175). Meanwhile, ucOC serum levels were significantly higher among women with GDM (MD: 1.17; 95% CI: 0.24 to 2.11; p = 0.013). The only factor influencing tOC was the UV index, showing a reduction in mean difference between GDM and controls when exposed to higher concentrations of UV rays. CONCLUSIONS: This meta-analysis provides evidence to support the use of ucOC as a potential marker for GDM rather than tOC, yielding very little variability among studies and no difference among methods or brands used for its analysis.