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International Journal of Molecular... Dec 2022Human placental lactogen (hPL) is a placental hormone which appears to have key metabolic functions in pregnancy. Preclinical studies have putatively linked hPL to... (Meta-Analysis)
Meta-Analysis Review
Human placental lactogen (hPL) is a placental hormone which appears to have key metabolic functions in pregnancy. Preclinical studies have putatively linked hPL to maternal and fetal outcomes, yet-despite human observational data spanning several decades-evidence on the role and importance of this hormone remains disparate and conflicting. We aimed to explore (via systematic review and meta-analysis) the relationship between hPL levels, maternal pre-existing and gestational metabolic conditions, and fetal growth. MEDLINE via OVID, CINAHL plus, and Embase were searched from inception through 9 May 2022. Eligible studies included women who were pregnant or up to 12 months post-partum, and reported at least one endogenous maternal serum hPL level during pregnancy in relation to pre-specified metabolic outcomes. Two independent reviewers extracted data. Meta-analysis was conducted where possible; for other outcomes narrative synthesis was performed. 35 studies met eligibility criteria. No relationship was noted between hPL and gestational diabetes status. In type 1 diabetes mellitus, hPL levels appeared lower in early pregnancy (possibly reflecting delayed placental development) and higher in late pregnancy (possibly reflecting increased placental mass). Limited data were found in other pre-existing metabolic conditions. Levels of hPL appear to be positively related to placental mass and infant birthweight in pregnancies affected by maternal diabetes. The relationship between hPL, a purported pregnancy metabolic hormone, and maternal metabolism in human pregnancy is complex and remains unclear. This antenatal biomarker may offer value, but future studies in well-defined contemporary populations are required.
Topics: Pregnancy; Female; Humans; Placental Lactogen; Placenta; Placental Hormones; Fetal Development; Biomarkers
PubMed: 36555258
DOI: 10.3390/ijms232415621 -
Cureus Jan 2024Gestational diabetes mellitus (GDM) is one of the most common endocrine disorders to occur during pregnancy due to the increase in circulating human placental lactogen... (Review)
Review
Gestational diabetes mellitus (GDM) is one of the most common endocrine disorders to occur during pregnancy due to the increase in circulating human placental lactogen (hPL) and possible beta-cell sensitivity. While GDM can be managed either with diet and exercise or pharmacological interventions, it is associated with significant maternal and neonatal complications. Maternal complications include short- and long-term conditions such as pre-eclampsia, preterm birth, arrest of labor, future development of type 2 diabetes mellitus (T2DM), and cardiovascular disorders. Neonates can develop hypoglycemia and hypocalcemia and have a large gestational age (LGA). New research has also highlighted another possible long-term complication for both mothers and offspring, which is the development of cancer. Cancer has various types of progression, but most cause systemic symptoms leading to a reduced quality of life. Cancer can be terminal and can affect the majority of the population; thus, significant effort is being employed to try and reduce its occurrence. This systematic review was conducted with adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using PubMed, ScienceDirect, and ProQuest databases. Initially, 136,019 publications were identified. Through the screening process, a total of 27 publications were finalized within the scope of this paper. Most studies observing maternal cancer with a history of GDM found that there was an association between the increased risk of cancer and GDM. Specifically, these studies identified the association of GDM with breast, ovarian, cervical, and uterine cancer, as well as other non-reproductive organs such as the thyroid and pancreas. Cancer development in the offspring also presented an association with mothers who developed GDM. The most prevalent cancer evaluated was leukemia, and it was specifically associated with a maternal history of GDM. With the consistent rise in the incidence of cancer, any attempts to reduce its development are imperative to assess. While GDM is essentially a temporary condition that resolves following pregnancy in most patients, the possibility of contributing to future conditions years after its occurrence creates a sense of urgency and necessity to reduce the incidence of GDM. Researchers should be able to identify other unknown biomarkers that contribute to the development of cancer in mothers who experienced GDM as well as their infants.
PubMed: 38435884
DOI: 10.7759/cureus.53328 -
The Cochrane Database of Systematic... Nov 2015Down's syndrome occurs when a person has three, rather than two copies of chromosome 21; or the specific area of chromosome 21 implicated in causing Down's syndrome. It... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Down's syndrome occurs when a person has three, rather than two copies of chromosome 21; or the specific area of chromosome 21 implicated in causing Down's syndrome. It is the commonest congenital cause of mental disability and also leads to numerous metabolic and structural problems. It can be life-threatening, or lead to considerable ill health, although some individuals have only mild problems and can lead relatively normal lives. Having a baby with Down's syndrome is likely to have a significant impact on family life.Noninvasive screening based on biochemical analysis of maternal serum or urine, or fetal ultrasound measurements, allows estimates of the risk of a pregnancy being affected and provides information to guide decisions about definitive testing. However, no test can predict the severity of problems a person with Down's syndrome will have.
OBJECTIVES
The aim of this review was to estimate and compare the accuracy of first trimester serum markers for the detection of Down's syndrome in the antenatal period, both as individual markers and as combinations of markers. Accuracy is described by the proportion of fetuses with Down's syndrome detected by screening before birth (sensitivity or detection rate) and the proportion of women with a low risk (normal) screening test result who subsequently had a baby unaffected by Down's syndrome (specificity).
SEARCH METHODS
We conducted a sensitive and comprehensive literature search of MEDLINE (1980 to 25 August 2011), Embase (1980 to 25 August 2011), BIOSIS via EDINA (1985 to 25 August 2011), CINAHL via OVID (1982 to 25 August 2011), The Database of Abstracts of Reviews of Effectiveness (The Cochrane Library 25 August 2011), MEDION (25 August 2011), The Database of Systematic Reviews and Meta-Analyses in Laboratory Medicine (25 August 2011), The National Research Register (Archived 2007), Health Services Research Projects in Progress database (25 August 2011). We did forward citation searching ISI citation indices, Google Scholar and PubMed 'related articles'. We did not apply a diagnostic test search filter. We also searched reference lists and published review articles.
SELECTION CRITERIA
We included studies in which all women from a given population had one or more index test(s) compared to a reference standard (either chromosomal verification or macroscopic postnatal inspection). Both consecutive series and diagnostic case-control study designs were included. Randomised trials where individuals were randomised to different screening strategies and all verified using a reference standard were also eligible for inclusion. Studies in which test strategies were compared head-to-head either in the same women, or between randomised groups were identified for inclusion in separate comparisons of test strategies. We excluded studies if they included less than five Down's syndrome cases, or more than 20% of participants were not followed up.
DATA COLLECTION AND ANALYSIS
We extracted data as test positive or test negative results for Down's and non-Down's pregnancies allowing estimation of detection rates (sensitivity) and false positive rates (1-specificity). We performed quality assessment according to QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria. We used hierarchical summary ROC meta-analytical methods or random-effects logistic regression methods to analyse test performance and compare test accuracy as appropriate. Analyses of studies allowing direct and indirect comparisons between tests were undertaken.
MAIN RESULTS
We included 56 studies (reported in 68 publications) involving 204,759 pregnancies (including 2113 with Down's syndrome). Studies were generally of good quality, although differential verification was common with invasive testing of only high-risk pregnancies. We evaluated 78 test combinations formed from combinations of 18 different tests, with or without maternal age; ADAM12 (a disintegrin and metalloprotease), AFP (alpha-fetoprotein), inhibin, PAPP-A (pregnancy-associated plasma protein A, ITA (invasive trophoblast antigen), free βhCG (beta human chorionic gonadotrophin), PlGF (placental growth factor), SP1 (Schwangerschafts protein 1), total hCG, progesterone, uE3 (unconjugated oestriol), GHBP (growth hormone binding protein), PGH (placental growth hormone), hyperglycosylated hCG, ProMBP (proform of eosinophil major basic protein), hPL (human placental lactogen), (free αhCG, and free ßhCG to AFP ratio. Direct comparisons between two or more tests were made in 27 studies.Meta-analysis of the nine best performing or frequently evaluated test combinations showed that a test strategy involving maternal age and a double marker combination of PAPP-A and free ßhCG significantly outperformed the individual markers (with or without maternal age) detecting about seven out of every 10 Down's syndrome pregnancies at a 5% false positive rate (FPR). Limited evidence suggested that marker combinations involving PAPP-A may be more sensitive than those without PAPP-A.
AUTHORS' CONCLUSIONS
Tests involving two markers in combination with maternal age, specifically PAPP-A, free βhCG and maternal age are significantly better than those involving single markers with and without age. They detect seven out of 10 Down's affected pregnancies for a fixed 5% FPR. The addition of further markers (triple tests) has not been shown to be statistically superior; the studies included are small with limited power to detect a difference.The screening blood tests themselves have no adverse effects for the woman, over and above the risks of a routine blood test. However some women who have a 'high risk' screening test result, and are given amniocentesis or chorionic villus sampling (CVS) have a risk of miscarrying a baby unaffected by Down's. Parents will need to weigh up this risk when deciding whether or not to have an amniocentesis or CVS following a 'high risk' screening test result.
Topics: ADAM Proteins; ADAM12 Protein; Biomarkers; Chorionic Gonadotropin, beta Subunit, Human; Down Syndrome; Female; Humans; Maternal Age; Membrane Proteins; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy-Associated Plasma Protein-A; Prenatal Diagnosis; alpha-Fetoproteins
PubMed: 26617074
DOI: 10.1002/14651858.CD011975 -
The Cochrane Database of Systematic... Nov 2015The placenta has an essential role in determining the outcome of pregnancy. Consequently, biochemical measurement of placentally-derived factors has been suggested as a... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The placenta has an essential role in determining the outcome of pregnancy. Consequently, biochemical measurement of placentally-derived factors has been suggested as a means to improve fetal and maternal outcome of pregnancy.
OBJECTIVES
To assess whether clinicians' knowledge of the results of biochemical tests of placental function is associated with improvement in fetal or maternal outcome of pregnancy.
SEARCH METHODS
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2015) and reference lists of retrieved studies.
SELECTION CRITERIA
Randomised, cluster-randomised or quasi-randomised controlled trials assessing the merits of the use of biochemical tests of placental function to improve pregnancy outcome.Studies were eligible if they compared women who had placental function tests and the results were available to their clinicians with women who either did not have the tests, or the tests were done but the results were not available to the clinicians. The placental function tests were any biochemical test of placental function carried out using the woman's maternal biofluid, either alone or in combination with other placental function test/s.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trials for inclusion, extracted data and assessed trial quality. Authors of published trials were contacted for further information.
MAIN RESULTS
Three trials were included, two quasi-randomised controlled trials and one randomised controlled trial. One trial was deemed to be at low risk of bias while the other two were at high risk of bias. Different biochemical analytes were measured - oestrogen was measured in one trial and the other two measured human placental lactogen (hPL). One trial did not contribute outcome data, therefore, the results of this review are based on two trials with 740 participants.There was no evidence of a difference in the incidence of death of a baby (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.36 to 2.13, two trials, 740 participants (very low quality evidence)) or the frequency of a small-for-gestational-age infant (RR 0.44, 95% CI 0.16 to 1.19, one trial, 118 participants (low quality evidence)).In terms of this review's secondary outcomes, there was no evidence of a clear difference between women who had biochemical tests of placental function compared with standard antenatal care for the incidence of stillbirth (RR 0.56, 95% CI 0.16 to 1.88, two trials, 740 participants (very low quality evidence)) or neonatal death (RR 1.62, 95% CI 0.39 to 6.74, two trials, 740 participants, very low quality evidence)) although the directions of any potential effect were in opposing directions. There was no evidence of a difference between groups in elective delivery (RR 0.98, 95% CI 0.84 to 1.14, two trials, 740 participants (low quality evidence)), caesarean section (one trial, RR 0.48, 95% CI 0.15 to 1.52, one trial, 118 participants (low quality evidence)), change in anxiety score (mean difference -2.40, 95% CI -4.78 to -0.02, one trial, 118 participants), admissions to neonatal intensive care (RR 0.32, 95% CI 0.03 to 3.01, one trial, 118 participants), and preterm birth before 37 weeks' gestation (RR 2.90, 95% CI 0.12 to 69.81, one trial, 118 participants). One trial (118 participants) reported that there were no cases of serious neonatal morbidity. Maternal death was not reported.A number of this review's secondary outcomes relating to the baby were not reported in the included studies, namely: umbilical artery pH < 7.0, neonatal intensive care for more than seven days, very preterm birth (< 32 weeks' gestation), need for ventilation, organ failure, fetal abnormality, neurodevelopment in childhood (cerebral palsy, neurodevelopmental delay). Similarly, a number of this review's maternal secondary outcomes were not reported in the included studies (admission to intensive care, high dependency unit admission, hospital admission for > seven days, pre-eclampsia, eclampsia, and women's perception of care).
AUTHORS' CONCLUSIONS
There is insufficient evidence to support the use of biochemical tests of placental function to reduce perinatal mortality or increase identification of small-for-gestational-age infants. However, we were only able to include data from two studies that measured oestrogens and hPL. The quality of the evidence was low or very low.Two of the trials were performed in the 1970s on women with a variety of antenatal complications and this evidence cannot be generalised to women at low-risk of complications or groups of women with specific pregnancy complications (e.g. fetal growth restriction). Furthermore, outcomes described in the 1970s may not reflect what would be expected at present. For example, neonatal mortality rates have fallen substantially, such that an infant delivered at 28 weeks would have a greater chance of survival were those studies repeated; this may affect the primary outcome of the meta-analysis.With data from just two studies (740 women), this review is underpowered to detect a difference in the incidence of death of a baby or the frequency of a small-for-gestational-age infant as these have a background incidence of approximately 0.75% and 10% of pregnancies respectively. Similarly, this review is underpowered to detect differences between serious and/or rare adverse events such as severe neonatal morbidity. Two of the three included studies were quasi-randomised, with significant risk of bias from group allocation. Additionally, there may be performance bias as in one of the two studies contributing data, participants receiving standard care did not have venepuncture, so clinicians treating participants could identify which arm of the study they were in. Future studies should consider more robust randomisation methods and concealment of group allocation and should be adequately powered to detect differences in rare adverse events.The studies identified in this review examined two different analytes: oestrogens and hPL. There are many other placental products that could be employed as surrogates of placental function, including: placental growth factor (PlGF), human chorionic gonadotrophin (hCG), plasma protein A (PAPP-A), placental protein 13 (PP-13), pregnancy-specific glycoproteins and progesterone metabolites and further studies should be encouraged to investigate these other placental products. Future randomised controlled trials should test analytes identified as having the best predictive reliability for placental dysfunction leading to small-for-gestational-age infants and perinatal mortality.
Topics: Biomarkers; Female; Humans; Infant, Newborn; Infant, Small for Gestational Age; Perinatal Death; Placenta; Placental Function Tests; Pregnancy; Pregnancy Outcome; Randomized Controlled Trials as Topic; Stillbirth
PubMed: 26602956
DOI: 10.1002/14651858.CD011202.pub2 -
The Cochrane Database of Systematic... May 2019Stillbirth affects 2.6 million pregnancies worldwide each year. Whilst the majority of cases occur in low- and middle-income countries, stillbirth remains an important... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Stillbirth affects 2.6 million pregnancies worldwide each year. Whilst the majority of cases occur in low- and middle-income countries, stillbirth remains an important clinical issue for high-income countries (HICs) - with both the UK and the USA reporting rates above the mean for HICs. In HICs, the most frequently reported association with stillbirth is placental dysfunction. Placental dysfunction may be evident clinically as fetal growth restriction (FGR) and small-for-dates infants. It can be caused by placental abruption or hypertensive disorders of pregnancy and many other disorders and factorsPlacental abnormalities are noted in 11% to 65% of stillbirths. Identification of FGA is difficult in utero. Small-for-gestational age (SGA), as assessed after birth, is the most commonly used surrogate measure for this outcome. The degree of SGA is associated with the likelihood of FGR; 30% of infants with a birthweight < 10th centile are thought to be FGR, while 70% of infants with a birthweight < 3rd centile are thought to be FGR. Critically, SGA is the most significant antenatal risk factor for a stillborn infant. Correct identification of SGA infants is associated with a reduction in the perinatal mortality rate. However, currently used tests, such as measurement of symphysis-fundal height, have a low reported sensitivity and specificity for the identification of SGA infants.
OBJECTIVES
The primary objective was to assess and compare the diagnostic accuracy of ultrasound assessment of fetal growth by estimated fetal weight (EFW) and placental biomarkers alone and in any combination used after 24 weeks of pregnancy in the identification of placental dysfunction as evidenced by either stillbirth, or birth of a SGA infant. Secondary objectives were to investigate the effect of clinical and methodological factors on test performance.
SEARCH METHODS
We developed full search strategies with no language or date restrictions. The following sources were searched: MEDLINE, MEDLINE In Process and Embase via Ovid, Cochrane (Wiley) CENTRAL, Science Citation Index (Web of Science), CINAHL (EBSCO) with search strategies adapted for each database as required; ISRCTN Registry, UK Clinical Trials Gateway, WHO International Clinical Trials Portal and ClinicalTrials.gov for ongoing studies; specialist abstract and conference proceeding resources (British Library's ZETOC and Web of Science Conference Proceedings Citation Index). Search last conducted in Ocober 2016.
SELECTION CRITERIA
We included studies of pregnant women of any age with a gestation of at least 24 weeks if relevant outcomes of pregnancy (live birth/stillbirth; SGA infant) were assessed. Studies were included irrespective of whether pregnant women were deemed to be low or high risk for complications or were of mixed populations (low and high risk). Pregnancies complicated by fetal abnormalities and multi-fetal pregnancies were excluded as they have a higher risk of stillbirth from non-placental causes. With regard to biochemical tests, we included assays performed using any technique and at any threshold used to determine test positivity.
DATA COLLECTION AND ANALYSIS
We extracted the numbers of true positive, false positive, false negative, and true negative test results from each study. We assessed risk of bias and applicability using the QUADAS-2 tool. Meta-analyses were performed using the hierarchical summary ROC model to estimate and compare test accuracy.
MAIN RESULTS
We included 91 studies that evaluated seven tests - blood tests for human placental lactogen (hPL), oestriol, placental growth factor (PlGF) and uric acid, ultrasound EFW and placental grading and urinary oestriol - in a total of 175,426 pregnant women, in which 15,471 pregnancies ended in the birth of a small baby and 740 pregnancies which ended in stillbirth. The quality of included studies was variable with most domains at low risk of bias although 59% of studies were deemed to be of unclear risk of bias for the reference standard domain. Fifty-three per cent of studies were of high concern for applicability due to inclusion of only high- or low-risk women.Using all available data for SGA (86 studies; 159,490 pregnancies involving 15,471 SGA infants), there was evidence of a difference in accuracy (P < 0.0001) between the seven tests for detecting pregnancies that are SGA at birth. Ultrasound EFW was the most accurate test for detecting SGA at birth with a diagnostic odds ratio (DOR) of 21.3 (95% CI 13.1 to 34.6); hPL was the most accurate biochemical test with a DOR of 4.78 (95% CI 3.21 to 7.13). In a hypothetical cohort of 1000 pregnant women, at the median specificity of 0.88 and median prevalence of 19%, EFW, hPL, oestriol, urinary oestriol, uric acid, PlGF and placental grading will miss 50 (95% CI 32 to 68), 116 (97 to 133), 124 (108 to 137), 127 (95 to 152), 139 (118 to 154), 144 (118 to 161), and 144 (122 to 161) SGA infants, respectively. For the detection of pregnancies ending in stillbirth (21 studies; 100,687 pregnancies involving 740 stillbirths), in an indirect comparison of the four biochemical tests, PlGF was the most accurate test with a DOR of 49.2 (95% CI 12.7 to 191). In a hypothetical cohort of 1000 pregnant women, at the median specificity of 0.78 and median prevalence of 1.7%, PlGF, hPL, urinary oestriol and uric acid will miss 2 (95% CI 0 to 4), 4 (2 to 8), 6 (6 to 7) and 8 (3 to 13) stillbirths, respectively. No studies assessed the accuracy of ultrasound EFW for detection of pregnancy ending in stillbirth.
AUTHORS' CONCLUSIONS
Biochemical markers of placental dysfunction used alone have insufficient accuracy to identify pregnancies ending in SGA or stillbirth. Studies combining U and placental biomarkers are needed to determine whether this approach improves diagnostic accuracy over the use of ultrasound estimation of fetal size or biochemical markers of placental dysfunction used alone. Many of the studies included in this review were carried out between 1974 and 2016. Studies of placental substances were mostly carried out before 1991 and after 2013; earlier studies may not reflect developments in test technology.
Topics: Female; Fetal Development; Fetal Growth Retardation; Humans; Infant, Newborn; Infant, Small for Gestational Age; Perinatal Mortality; Placenta; Pregnancy; Pregnancy Outcome; Stillbirth; Ultrasonography, Prenatal
PubMed: 31087568
DOI: 10.1002/14651858.CD012245.pub2