Safe threshold of capillary blood glucose for predicting early future neonatal hypoglycaemia in babies born to mothers with gestational diabetes mellitus, an observational, retrospective cohort study

It is estimated that 17% of live births around the world are affected by hyperglycaemia in pregnancy, 84% of which have gestational diabetes mellitus (GDM) [1]. GDM is one of the commonest medical problems of pregnancy with increasing incidence worldwide [2]. Untreated, GDM is associated with maternal and neonatal complications [3]. One such complication, neonatal hypoglycaemia, mostly occurs within the first 24-h after birth as babies complete their metabolic transition over the first few days of life [4‐6]. One observational study found that heel-prick plasma glucose concentrations of 2.6 mmol/L approximated the 10th percentile in the first 48-h but 39% of infants had ≥ 1 episode below this threshold [4]. Rarely, hypoglycaemia can bring about serious and long-lasting neurological sequelae if prolonged or recurrent [7] and there is particular concern for babies with mothers who had co-morbidities such as GDM.

Unfortunately, hypoglycaemia can be asymptomatic or accompanied by nonspecific symptoms. Therefore, screening programmes have been developed for early detection and management of hypoglycaemia and widely adopted amongst neonatologists. However, one of the limitations of such programmes is that asymptomatic euglycemic babies included in high-risk categories can experience excessive blood sampling, prolonged hospital admissions, and family separation [8, 9].

In 2017, the British Association of Perinatal Medicine (BAPM) published a framework for practice for the identification and management of neonatal hypoglycaemia in the full-term babies [10]. The BAPM framework was released in response to concerns about variable practice across the UK in the detection and management of hypoglycaemia. These pragmatic guidelines recommended a care pathway that includes early feeding and blood glucose (BG) monitoring, and regular assessment of clinical condition and feeding for 24 h for babies born to mothers with diabetes.

The adoption of the World Health Organisation (WHO) / International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria to diagnose GDM has resulted in more women being diagnosed with GDM, with consequently more babies monitored on a high-risk pathway for hypoglycaemia. Monitoring increases workload for midwives, requires in-patient stay for the woman for at least 24-h, and requires heel-prick testing timed before feeds for the baby.

In response to queries from mothers in our hospital about the need for inpatient monitoring, we sought to determine whether in our local population, the risk of neonatal hypoglycaemia could be predicted in babies born to women with GDM, and whether a group of babies could be identified as low-risk and potentially safe to go home earlier.

This was an observational retrospective cohort study using routinely collected clinical data conducted in a teaching hospital in South East England, delivering approximately 7,500 babies per year. Any incidences of hospital re-admission were reviewed up to 6 weeks post-partum. Data analysis occurred between February 2019 and March 2020 and validation data analysis between August and September 2020.

We included singleton, liveborn, term babies (≥ 37 completed weeks) born to mothers with GDM born between August-December 2018 with at least one BG reading documented in the first 24-h of life. GDM was diagnosed following National Institute for Health and Care Excellence (NICE) [11] 2015 clinical risk factor screening criteria, with IADPSG diagnostic criteria for the 75 g oral glucose tolerance test (OGTT). We excluded babies with major congenital abnormalities, those requiring immediate neonatal intensive care unit (NICU) admission, and babies in whom hypoglycaemia monitoring would be recommended for another reason (e.g. fetal growth restriction, birthweight for gestational age < 2^nd centile, beta-blocker therapy during pregnancy, neonatal sepsis).

We assessed the risk of neonatal hypoglycaemia in relation to: maternal characteristics (age, Body Mass Index (BMI), parity, non-white ethnic group), treatments for diabetes during pregnancy (diet, metformin, insulin), use of insulin infusion during labour, birthweight for gestational age and gender according to The International Fetal and Newborn Growth Consortium for the 21^st Century [12] criteria, time to first feed, mode of feeding (artificial or breast), and first capillary BG.

From 6/8/18 to 31/12/18, 168 babies were born to 163 mothers with GDM. Of these, we excluded 62 babies: 11 preterm, 11 admitted to NICU with suspected sepsis, 10 twins, 3 with respiratory distress, one stillbirth, 8 born to mothers taking beta-blockers, two with birth weight < 2nd centile and, and 16 without a documented BG. Thus, 106 babies were included in the analysis (Fig. 1).

Characteristics of babies and their mothers are reported in Table 1. Of note, half the mothers were obese (n = 56, 52%), with just under half needing pharmacologic treatment for their GDM (n = 49, 46%). The majority of deliveries were vaginal (n = 75, 69%). One woman developed pre-eclampsia; 46 had blood loss > 500 mL at delivery (23 vaginal deliveries, 23 Caesarean sections), and 7 women developed peripartum sepsis.

The mean gestational age at birth was 39.3 weeks and mean birth weight was 3455 g (Standard Deviation (SD) 486 g). The first feed was breastmilk for 93% of babies.

All 106 babies had a BG measurement before their second feed. After the first BG, 38 babies had one further measurement (two measurements in total), 20 babies had two further measurements, and 12 babies had more than three further BG measurements.

We demonstrate in babies born to mothers with GDM, maternal, neonatal, birth or early feeding characteristics are unreliable predictors of neonatal hypoglycaemia. However, by using the threshold of 2.6 mmol/L at the first neonatal BG, all babies that subsequently developed neonatal (clinical or biochemical) hypoglycaemia in the first 24-h of life were identified. The BAPM recommends a threshold of intervention for hypoglycaemia at < 2.0 mmol/L. Whilst our data do not challenge this, as a screening test to identify newborns at low risk, 2.6 mmol/L appears to perform well in our babies. We used a pragmatic definition of neonatal hypoglycaemia as we aimed to capture clinically relevant events that would be best managed in hospital. We have adopted this approach both to allow for the well-recognised variability in the handheld capillary BG meters particularly at low readings and recognising the likely minimal long-term effects of very transient episodes of hypoglycaemia in otherwise well newborns. This study suggests that effective feeding can be challenging to establish, and additional support may be required for women with underlying psychiatric conditions.

The BAPM framework recommends interventions to raise BG in babies with a “BG < 1.0 mmol/L; a single value of < 2.5 mmol/L in a baby with abnormal clinical signs; or a value of < 2.0 mmol/L and remaining < 2.0 mmol/L at next measurement in a baby with risk factors for metabolic adaptation.” The BAPM screening guideline is the same for all babies at risk of hypoglycaemia regardless of the underlying metabolic condition. Our study demonstrates that there may be a group of babies born to mothers with GDM who are at lower risk of developing clinically significant hypoglycaemia. If the threshold of 2.6 mmol/L for the first BG had been used as a screening test in these babies, it had a sensitivity of 100% (95% CI 74-100%) to correctly identify the babies at risk of subsequent hypoglycaemia, and specificity of 69% (59–79%). This suggests that if babies have a first BG > 2.6 mmol/L, they would not require a second BG prior to third feed as recommended by BAPM unless they developed signs of hypoglycaemia.

The Coronavirus disease (COVID-19) pandemic has resulted in many maternity units in the UK adopting a model of care aiming for earlier discharge of women and babies to minimise exposure to the virus. All mothers should be given education on the signs of poor feeding and possible hypoglycaemia in their newborn. The decision on whether mothers can go home to continue this monitoring or need a full 24-h inpatient monitoring needs to be carefully considered. For mothers with physical or mental conditions impairing their ability to feed may need close inpatient observation. This study could help guide which babies born to mothers with GDM could be safely managed in the community, reducing the time spent in hospitals for women and babies who would otherwise be able to go home.

The IADPSG criteria for GDM were based on the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study [13], which demonstrated linear increases between worsening hyperglycaemia at the 28-week OGTT, with the risks of birth weight > 90^th centile, primary Caesarean-section, and cord blood serum Connecting-peptide (C-peptide). A linear relationship with clinical neonatal hypoglycaemia was weak, and the impact of changing to these criteria on neonatal inpatient monitoring is significant. A number of studies have reported higher rates of hypoglycaemia and intravenous dextrose use in babies born to insulin-treated women compared to women treated by metformin or diet [14‐16]. Conversely, other groups have demonstrated that there is no real difference between maternal treatment modalities [5, 6]. Our study supports these findings, namely that the risk of neonatal hypoglycaemia is not predictable from maternal background characteristics, medication requirement for GDM, or the birthweight (excluding babies born < 2^nd centile).

Acknowledging the limitation of the small sample size, and known inaccuracies of handheld glucometer, we demonstrate that whilst maternal characteristics of women did not predict which babies developed neonatal hypoglycaemia, if the first neonatal BG is > 2.6 mmol/L, the baby was subsequently at low-risk of biochemical or clinical hypoglycaemia. If a strategy of no further testing were adopted for babies in our unit with this threshold, this could reduce the need for further capillary tests and monitoring for around two-thirds of babies. Whether this group of mothers and babies are truly ‘safe to go home’ will depend on the feeding pattern and capacity of the mother to monitor her baby. This approach needs to be used with vigilance in particular high-risk groups (maternal physical and mental health co-morbidities).