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

BACKGROUND: 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? AIMS: Our aim was to evaluate the effectiveness of HbA1c monitoring in improving screening rates following gestational diabetes and in detecting postpartum hyperglycaemia. MATERIALS AND METHODS: During 2015 in Christchurch, all women with gestational diabetes were offered HbA1c and GTT measurements at three months postpartum and subsequent annual HbA1c measurements were recommended. Data from electronic hospital records were collected for a minimum 18 months postpartum. RESULTS: Of the cohort of 333 women, 218 (65%) completed both HbA1c and GTT at three months postpartum, 74 (22%) HbA1c only, 16 (5%) GTT only, 25 (8%) no screening; 184 (55%) had subsequent HbA1c tests. Diabetes was detected by GTT in five (2%) women and by HbA1c in only one out of five (20%); the disagreement between tests resolved in three out of four (75%) women with subsequent testing. Prediabetes was detected by GTT in 30 (14%) women; however, HbA1c only detected five out of 30 (17%) and subsequent HbA1c testing identified a further two out of 30 with prediabetes. CONCLUSIONS: HbA1c measurement at three months postpartum had a good uptake. However, most cases of diabetes were identified by subsequent HbA1c testing, the uptake of which was suboptimal. The importance of annual HbA1c monitoring following gestational diabetes needs greater emphasis.

Antenatal haemoglobin A1c centiles: does one size fit all?

BACKGROUND: In New Zealand, haemoglobin A1c measurements are routinely offered at booking, preferably before 20 weeks gestation, to detect pre-existing hyperglycaemia. A haemoglobin A1c <5.9% (41 mmol/mol) is considered normal based on the reference range for the non-pregnant population. AIMS: To determine pregnancy-specific haemoglobin A1c centiles by gestation and ethnicity. MATERIALS AND METHODS: This is a population-based observational study of pregnancies uncomplicated by diabetes (pre-existing or gestational) with ≥1 haemoglobin A1c measurement. Haemoglobin A1c centiles were calculated from data extracted from electronic laboratory and clinical records for pregnancies during 2008-2010. RESULTS: Included were 6800 pregnancies, European 80% (5462), Maori 6% (415), Pacific Islander 3% (196) and 11% (727) 'Others' (mostly Asian). Haemoglobin A1c levels fell with increasing gestation, reaching a nadir at 24 weeks, a trend verified by longitudinal data from 112 women. The 97.5th centile for haemoglobin A1c in European women was 5.76% (39.5 mmol/mol) at 8+0  weeks, 5.70% (38.8 mmol/mol) at 16+0  weeks, and 5.65% (38.3 mmol/mol) at 24+0  weeks. Non-European women had both higher plasma glucose levels (although within the range considered normal) and higher mean haemoglobin A1c levels compared with Europeans; mean (SD) difference in haemoglobin A1c in Maori +0.13% (0.05) (+1.4 mmol/mol (0.5)), Pacific +0.20% (0.03) (+2.2 mmol/mol (0.3)), 'Others' +0.10% (0.03) (+1.1 mmol/mol (0.3)). CONCLUSIONS: The New Zealand haemoglobin A1c cut-point ≥5.9% (41 mmol/mol) for identifying hyperglycaemia in early pregnancy is greater than the 97.5th centile in European and 'Other' women. Utilising population haemoglobin A1c centiles adjusted by gestation may thus better guide management decisions.

Characterization of the tissue-level Ca2+ signals in spontaneously contracting human myometrium.

In the labouring uterus, millions of myocytes forming the complex geometrical structure of myometrium contract in synchrony to increase intrauterine pressure, dilate the cervix and eventually expel the foetus through the birth canal. The mechanisms underlying the precise coordination of contractions in human myometrium are not completely understood. In the present study, we have characterized the spatio-temporal properties of tissue-level [Ca(2+)](i) transients in thin slices of intact human myometrium. We found that the waveform of [Ca(2+)](i) transients and isotonic contractions recorded from thin slices was similar to the waveform of isometric contractions recorded from the larger strips in traditional organ bath experiments, suggesting that the spatio-temporal information obtained from thin slices is representative of the whole tissue. By comparing the time course of [Ca(2+)](i) transients in individual cells to that recorded from the bundles of myocytes we found that the majority of myocytes produce rapidly propagating long-lasting [Ca(2+)](i) transients accompanied by contractions. We also found a small number of cells showing desynchronized [Ca(2+)](i) oscillations that did not trigger contractions. The [Ca(2+)](i) oscillations in these cells were insensitive to nifedipine, but readily inhibited by the T-type Ca(2+) channel inhibitor NNC55-0396. In conclusion, our data suggest that the spread of [Ca(2+)](i) signals in human myometrium is achieved via propagation of long-lasting action potentials. The propagation was fast when action potentials propagated along bundles of myocytes and slower when propagating between the bundles of uterine myocytes.

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

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 Ca(2+) concentration ([Ca(2+)](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 [Ca(2+)](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.

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.

C-type natriuretic peptide in complicated pregnancy: increased secretion precedes adverse events.

CONTEXT: C-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. OBJECTIVES: The 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. DESIGN: This was a prospective observational study undertaken in a tertiary care center. METHODS: We 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. RESULTS: Compared 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. CONCLUSIONS: Maternal 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.

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

OBJECTIVE: Analysis 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. STUDY DESIGN: Standard 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). RESULTS AND CONCLUSIONS: Oxytocin (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 Student's 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.