Joanna E. Gullam

An Early Pregnancy HbA1c ≥5.9% (41 mmol/mol) Is Optimal for Detecting Diabetes and Identifies Women at Increased Risk of Adverse Pregnancy Outcomes

OBJECTIVE Pregnant women with undiagnosed diabetes are a high-risk group that may benefit from early intervention. Extrapolating from nonpregnancy data, HbA1c ≥6.5% (48 mmol/mol) is recommended to define diabetes in pregnancy. Our aims were to determine the optimal HbA1c threshold for detecting diabetes in early pregnancy as defined by an early oral glucose tolerance test (OGTT) at <20 weeks’ gestation and to examine pregnancy outcomes relating to this threshold. RESEARCH DESIGN AND METHODS During 2008–2010 in Christchurch, New Zealand, women were offered an HbA1c measurement with their first antenatal bloods. Pregnancy outcome data were collected. A subset completed an early OGTT, and HbA1c performance was assessed using World Health Organization criteria. RESULTS HbA1c was measured at a median 47 days’ gestation in 16,122 women. Of those invited, 974/4,201 (23%) undertook an early OGTT. In this subset, HbA1c ≥5.9% (41 mmol/mol) captured all 15 cases of diabetes, 7 with HbA1c <6.5% (<48 mmol/mol). This HbA1c threshold was also 98.4% (95% CI 97–99.9%) specific for gestational diabetes mellitus (GDM) before 20 weeks (positive predictive value = 52.9%). In the total cohort, excluding women referred for GDM management, women with HbA1c of 5.9–6.4% (41–46 mmol/mol; n = 200) had poorer pregnancy outcomes than those with HbA1c <5.9% (<41 mmol/mol; n = 8,174): relative risk (95% CI) of major congenital anomaly was 2.67 (1.28–5.53), preeclampsia was 2.42 (1.34–4.38), shoulder dystocia was 2.47 (1.05–5.85), and perinatal death was 3.96 (1.54–10.16). CONCLUSIONS HbA1c measurements were readily performed in contrast to the low uptake of early OGTTs. HbA1c ≥5.9% (≥41 mmol/mol) identified all women with diabetes and a group at significantly increased risk of adverse pregnancy outcomes.

Multiple mechanisms involved in oxytocin-induced modulation of myometrial contractility

AbstractOxytocin is a small peptide hormone with multiple sites of action in human body. It regulates a large number of reproduction-related processes in all species. Particularly important is its ability to stimulate uterine contractility. This is achieved by multiple mechanisms involving sarcoplasmic reticulum Ca2+ release and sensitization of the contractile apparatus to Ca2+. In this paper, we review the data published by us and other groups on oxytocin-induced modulation of uterine contractility. We conclude that sensitization of contractile apparatus to Ca2+ is the most relevant physiological effect of oxytocin on human myometrium.

Control of uterine Ca2+ by membrane voltage: toward understanding the excitation-contraction coupling in human myometrium.

Abstract:u2002 Myometrial contractility is a complex and dynamic physiological process that changes substantially during pregnancy and culminates in childbirth. Uterine contractions are initiated by transient rises in cytoplasmic Ca2+ concentration ([Ca2+]i), which in turn are triggered and controlled by myometrial action potentials. The sequence of events between the action potential generation and the contraction initiation is referred to as excitation–contraction coupling. Hormones and other physiologically active substances affect myometrial contractility by modulating different steps in the excitation–contraction coupling process. It is therefore imperative that we understand that process to understand the regulation of myometrial contractility. The complex action potentials generated by human myometrium result from the activity of many ion channels, transporters, and pumps. Two types of myometrial action potential waveform have been described in the literature: a plateau type and a spike type. Parameters of the myometrial [Ca2+]i transients and contractions differ depending on the type of action potential that triggers them. Some aspects of the excitation–contraction coupling are unique to human myometrium and cannot be found in animal models; some others are common between many species. This article reviews the current state and discusses future directions of physiological research on human myometrial excitation–contraction coupling.

Delayed versus Immediate Cord Clamping in Preterm Infants

Background The preferred timing of umbilical‐cord clamping in preterm infants is unclear. Methods We randomly assigned fetuses from women who were expected to deliver before 30 weeks of gestation to either immediate clamping of the umbilical cord (≤10 seconds after delivery) or delayed clamping (≥60 seconds after delivery). The primary composite outcome was death or major morbidity (defined as severe brain injury on postnatal ultrasonography, severe retinopathy of prematurity, necrotizing enterocolitis, or late‐onset sepsis) by 36 weeks of postmenstrual age. Analyses were performed on an intention‐to‐treat basis, accounting for multiple births. Results Of 1634 fetuses that underwent randomization, 1566 were born alive before 30 weeks of gestation; of these, 782 were assigned to immediate cord clamping and 784 to delayed cord clamping. The median time between delivery and cord clamping was 5 seconds and 60 seconds in the respective groups. Complete data on the primary outcome were available for 1497 infants (95.6%). There was no significant difference in the incidence of the primary outcome between infants assigned to delayed clamping (37.0%) and those assigned to immediate clamping (37.2%) (relative risk, 1.00; 95% confidence interval, 0.88 to 1.13; P=0.96). The mortality was 6.4% in the delayed‐clamping group and 9.0% in the immediate‐clamping group (P=0.03 in unadjusted analyses; P=0.39 after post hoc adjustment for multiple secondary outcomes). There were no significant differences between the two groups in the incidences of chronic lung disease or other major morbidities. Conclusions Among preterm infants, delayed cord clamping did not result in a lower incidence of the combined outcome of death or major morbidity at 36 weeks of gestation than immediate cord clamping. (Funded by the Australian National Health and Medical Research Council [NHMRC] and the NHMRC Clinical Trials Centre; APTS Australian and New Zealand Clinical Trials Registry number, ACTRN12610000633088.)

Response to Comment on Hughes et al. An Early Pregnancy HbA1c ≥5.9% (41 mmol/mol) Is Optimal for Detecting Diabetes and Identifies Women at Increased Risk of Adverse Pregnancy Outcomes. Diabetes Care 2014;37:2953–2959

We appreciate the opportunity to respond to the comments made by Anderson et al. (1) on our recent article (2). We agree, as highlighted under our study limitations, that the low participation rate in the oral glucose tolerance test (OGTT) could affect the validity of the HbA1c sensitivity and specificity calculations. As women with lower HbA1c (particularly <5.6% [38 mmol/mol]) were least likely to consent to an early OGTT, it is possible that the optimal HbA1c threshold for identifying women with undiagnosed preexisting diabetes (not gestational diabetes mellitus [GDM]) is in fact lower than 5.9% (41 mmol/mol) and we invite others …

Phase-plot analysis of the oxytocin effect on human myometrial contractility.

OBJECTIVEnAnalysis of uterine contractility in vitro is usually confined to measuring a few traditional parameters of uterine contractility, such as contraction amplitude, frequency and area under the curve. In this paper, we describe parameters that provide additional information obtained from the traces of force and its first derivative. We propose an improved contractility index which is less dependent on variability between samples.nnnSTUDY DESIGNnStandard organ bath recording of myometrial contractions in the presence or absence of oxytocin on samples of human myometrium obtained from 26 patients at Caesarean section. The parameters were obtained from the plots of first derivative vs. contractile force (phase portrait plot).nnnRESULTS AND CONCLUSIONSnOxytocin (1nM) significantly increased the contraction amplitude (Fmax), area under the curve, maximum rate of contraction (CVmax), decreased the maximum rate of relaxation (RVmax) and had no statistically significant effect on the duration of contraction (measured as full width at half amplitude, W50). In addition to the above effects, 10nM oxytocin increased the contraction duration (P=0.0036, n=24). The fraction of force developed at the time of CVmax showed no change at any concentration of oxytocin, while the fraction of force remaining at RVmax was decreased in a dose dependent manner. The least variable (i.e. showing lowest P values in paired Students t-Test) parameters were the Fmax and CVmax/RVmax. When non-paired t-Test was applied, P value of the CVmax/RVmax remained low, while the variability of Fmax increased reflecting the sample-to-sample variations. The product of the Fmax and CVmax/RVmax, which we propose as uterine contractility index (CI) showed low P values in both paired and non-paired t-Tests. We conclude that the phase plot analysis provides useful additional information on contraction/relaxation properties of human myometrium and the CI is suitable for characterising the contractility of uterine samples with different connective tissue content.

The management of preterm labour

Preterm labour is the onset of regular uterine contractions associated with progressive cervical change between viability and 37 completed weeks of gestation. The incidence is between 5% and 10% in most developed nations. In the US, the incidence has increased from 9% to 12% in the past two decades. Preterm delivery can be associated with immediate and long-term neonatal complications. Long-term morbidity includes cerebral palsy, neurodevelopmental delay and chronic lung disease. The neonatal outcome is dependent on the gestational age at delivery and associated features such as infection. The lower the gestational age, the higher the risk of mortality and morbidity. The management of preterm labour involves identification of high-risk women, prevention and treatment.nnThe identification of women at high risk of preterm delivery remains a major challenge. Scoring systems based on socioeconomic status, obstetric or medical history and antenatal events in the index pregnancy have shown a suboptimal correlation with subsequent preterm birth.1 This is primarily because the single greatest risk factor is a history of preterm labour, so delivery cannot be reliably predicted in the first pregnancy. The risk of preterm delivery after one and two previous preterm deliveries has been given as 15% and 41%, respectively1; however, such figures are difficult to apply to individuals as the risk is dependent on the cause and the gestational age of the previous preterm delivery.nnInvestigations such as fetal fibronectin or cervical ultrasound can be used to identify women at high risk. A positive swab for vaginal fetal fibronectin taken in the late second or early third trimester increases the likelihood of delivery before 34 weeks by a factor of 4.2 Likewise, a negative swab reduces the likelihood of delivery to 0.78. Such results from meta-analysis include women both at high risk and at low risk. …

C-Type Natriuretic Peptide in Complicated Pregnancy: Increased Secretion Precedes Adverse Events

CONTEXTnC-type natriuretic peptide (CNP), a vasoactive product of the endothelium, is markedly increased during placentation in ovine pregnancy and is further stimulated by nutrient restriction. Whether CNP products change in human pregnancy is unknown.nnnOBJECTIVESnThe objective of the study was to compare serial changes in maternal plasma CNP peptides during normal pregnancy with changes in pregnancy complicated by adverse events and relate these to fetal growth and placental CNP content.nnnDESIGNnThis was a prospective observational study undertaken in a tertiary care center.nnnMETHODSnWe studied changes in maternal plasma aminoterminal proCNP (NTproCNP) and CNP at monthly intervals, fetal growth, and placental and umbilical plasma CNP peptides in 51 women, 28 of whom experienced an adverse event and 23 were uneventful. Age matched healthy nonpregnant women served as a reference range for NTproCNP.nnnRESULTSnCompared with nonpregnant women, maternal plasma NTproCNP in an uneventful pregnancy was significantly reduced from first sampling (16 wk gestation) until 36 weeks. In contrast, in complicated pregnancy, levels did not decline and were significantly higher (P < .001 by ANOVA) than in normal pregnancy from 20 weeks. Highest values occurred in women later developing hypertension and fetal growth disorders. Placental concentration of NTproCNP was unrelated to maternal NTproCNP but strongly correlated with cord plasma levels.nnnCONCLUSIONSnMaternal NTproCNP is significantly raised in women who later exhibit a range of obstetric adverse events. Lack of association with placental concentrations suggests that these changes represent an adaptive response within the maternal circulation to a threatened nutrient supply to the fetus.

Universal HbA1c Measurement in Early Pregnancy to Detect Type 2 Diabetes Reduces Ethnic Disparities in Antenatal Diabetes Screening: A Population-Based Observational Study

In response to the type 2 diabetes epidemic, measuring HbA1c with the first-antenatal blood screen was recently recommended in NZ. This would enable prompt treatment of women with unrecognised type 2 diabetes, who may otherwise go undetected until the gestational diabetes (GDM) screen. We compare inter-ethnic antenatal screening practices to examine whether the HbA1c test would be accessed by ethnicities most at risk of diabetes, and we determined the prevalence of unrecognised type 2 diabetes and prediabetes in our pregnant population. This is an observational study of pregnancies in Christchurch NZ during 2008–2010. Utilising electronic databases, we matched maternal characteristics to first-antenatal bloods, HbA1c, and GDM screens (glucose challenge tests and oral glucose tolerance tests). Overall uptake of the first-antenatal bloods versus GDM screening was 83.1% and 53.8% respectively in 11,580 pregnancies. GDM screening was lowest in Māori 39.3%, incidence proportion ratio (IPR) 0.77 (0.71, 0.84) compared with Europeans. By including HbA1c with the first-antenatal bloods, the number screened for diabetes increases by 28.5% in Europeans, 40.0% in Māori, 28.1% in Pacific People, and 26.7% in ‘Others’ (majority of Asian descent). The combined prevalence of unrecognised type 2 diabetes and prediabetes by NZ criteria, HbA1c ≥5.9% (41mmol/mol), was 2.1% in Europeans, Māori 4.7% IPR 2.59 (1.71, 3.93), Pacific People 9.5% IPR 4.76 (3.10, 7.30), and ‘Others’ 6.2% IPR 2.99 (2.19, 4.07). Applying these prevalence data to 2013 NZ national births data, routine antenatal HbA1c testing could have identified type 2 diabetes in 0.44% and prediabetes in 3.96% of women. Routine HbA1c measurement in early pregnancy is an ideal screening opportunity, particularly benefitting vulnerable groups, reducing ethnic disparities in antenatal diabetes screening. This approach is likely to have world-wide relevance and applicability. Further research is underway to establish whether, as for type 2 diabetes, prompt treatment of prediabetes improves pregnancy and neonatal outcomes.

Evaluation of the NZ guidelines for screening for persistent postpartum hyperglycaemia following gestational diabetes

Recent New Zealand guidelines recommend annual glycated haemoglobin (HbA1c) measurements from three months postpartum, replacing the glucose tolerance test (GTT) at six weeks, to screen for persistent hyperglycaemia following gestational diabetes. Data suggest that this screening approach may miss cases of type 2 diabetes, but are they detected at subsequent screening and will screening rates improve?