Most of the colorectal cancer (CRC) screening programmes are based on fecal occult blood tests (FOBT). However, there is little information on the utility of FOBT in familial-risk CRC screening. A recently published study has evaluated the diagnostic accuracy of fecal immunochemical tests (FIT) for CRC and advanced colonic neoplasia detection in this population.

by Dr Inés Castro and Dr Joaquín Cubiella

Relevance of colorectal cancer screening
Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer deaths in developed countries [1]. Several factors have been related to the risk of developing CRC. Age, gender and CRC familial history, especially if there are first-degree relatives (FDR) with CRC, are the strongest associated risk factors [2]. Furthermore, CRC risk is directly related to the number of FDRs and inversely related to the age of youngest FDR [3, 4].

Evidence from several studies has shown that CRC screening is effective for CRC prevention in the average-risk population (asymptomatic individuals between 50 and 69 years) [2]. Indeed, both flexible sigmoidoscopy and fecal occult blood tests (FOBT) have been shown to reduce CRC-specific mortality and incidence in randomized controlled trials [2, 5, 6]. This reduction is based on CRC early detection and prevention through adenoma detection and endoscopic resection [2]. Accordingly, these two strategies, along with colonoscopy, have been universally accepted and recommended for CRC screening [2]. In Europe, annual or biennial FOBT is the most widespread CRC screening strategy.

Approximately 95% of CRCs develop on advanced adenomatous polyps (larger than 10 mm, with high-grade dysplasia or villous architecture). These lesions, and early CRC, are characterized by intermittent microscopic blood loss in the stool that can be detected with FOBTs before they are clinically apparent.

Advantages and disadvantages of the different FOBTs
FOBTs detect through blood or blood products (such as globin) in feces with different methods. Mainly, there are two types of FOBTs: chemical (cFOBT) or immunological (FIT).

Chemical fecal occult blood tests
cFOBTs are simple, qualitative tests that use different indicators such as guaiac resin (Hemoccults, Hemoccult II^®, SmithKline Diagnostics, Sunnyvale, California, USA), orthotolidine (Hematest^®, MilesLaboratories, Elkhart, Indiana, USA) or benzidine (Hemofec^®, Med-Kjemi AS, Asker, Norway). By an oxidative reaction and in the presence of a developer solution, hemoglobin seudoperoxidase activity produces a colour change in the paper impregnated with guaiac resin, orthotolidine or benzidine.

However these tests have multiple drawbacks: first, they are not specific to human hemoglobin. Oxygenation reactions may occur with foods with peroxidase activity such as vegetables or uncooked red meat, so it is recommended to withdraw them from the diet for 3 days before sample collection to reduce false positive results. In addition, hemoglobin from the upper gastrointestinal digestive tract is also detected. So, gastrolesive drugs (NSAIDs or aspirin) should be interrupted 7 days before testing. Besides, two stool samples on three consecutive bowel movements are required, limiting adherence to screening programmes [7]. Furthermore, as it is a qualitative test, its result is subjected to interpretation. Finally, their sensitivity for CRC and advanced adenoma detection is low. This is associated with an interval CRC rate ranging between 30 and 50%.

Fecal immunochemical tests
FITs are based on the reaction of monoclonal or polyclonal antibodies specific for human hemoglobin, albumin or other fecal blood components. Thus, they require no dietary or pharmacological restriction, as long as they do not react with blood from upper digestive tract or with any food component. The greatest advantage is determined by its ability to detect and quantify fecal hemoglobin concentrations 7 to 15 times lower than those detected by chemical tests, significantly improving CRC and advanced adenoma detection sensitivity. Besides, FITs allows a reliable and accurate automated analysis, avoiding subjective interpretation. Up to 50 samples an hour can be processed, making this test ideal for population-based screening [7].

The most used and better evaluated methods nowadays for CRC screening are those based on latex agglutination (OC-Sensor^®, OC-Micro^®, Eiken Chemical Co., Ltd, Japan; FOB-Gold^® Sentinel Diagnostics^®, Milan) or magnetized gelatin particles (Magstream1000^®, Fujirebio Inc.,Tokyo, Japan).

Effectiveness of FOBT-based CRC screening in the the average-risk population
As previously commented, multiple studies have demonstrated that CRC screening with cFOBT in the average-risk population significantly reduces CRC mortality [8]. So far, there are no data available on the effect of FIT in CRC mortality or incidence. However, several diagnostic test studies have compared cFOBT and FIT for CRC and advanced adenomas detection. These studies have shown that FIT is more sensitive and specific for CRC and advanced adenomas detection and is a cost effective screening test [9]. On this basis, CRC screening programmes are based mainly on FIT.

Efficacy of FOBT CRC screening in the familial-risk population
Evidence on the best screening strategy in this population is limited and its quality is low [10, 11]. At present, it is unclear which is the best screening strategy in individuals with a FDR with CRC [12]. Clinical practice guidelines recommend more aggressive screening than in the average-risk population, based on studies that have shown that endoscopic screening reduces CRC incidence and mortality in individuals with a FDR with CRC [2, 6]. Screening is recommended from 40 years or 10 years before the youngest proband. However, this approach has an empirical basis and no prospective controlled study has compared different screening strategies in this population. Furthermore, colonoscopy is an invasive technique that requires sedation, is associated with rare but serious complications (perforation or hemorrhage), requires a substantial financial investment in equipment and expertise and has a limited adherence.

Data on the utility of FOBT for CRC screening in this population are scarce. Our group has recently evaluated FIT diagnostic accuracy for advanced colorectal neoplasia (CRC or advanced adenoma) in asymptomatic individuals with at least one first-degree relative with CRC submitted to a colonoscopy [13]. Patients with an advanced neoplasia had a fecal hemoglobin concentration statistically higher than those without an advanced neoplasia. Fecal hemoglobin concentration was significantly higher among individuals with CRC or advanced adenomas when compared with subjects with non-advanced adenomas or without neoplasia. In contrast, no significant differences were found between individuals with CRC and advanced adenomas as shown in Figure 1. Diagnostic accuracy for CRC detection was high, reaching 100% at a fecal hemoglobin threshold below 115 ng/ml. On the other hand, depending on the number of determinations and the positivity threshold cut-off used sensitivity for advanced neoplasia detection ranged between 34.38 and 50% and specificity between 92.66 and 98.72%. In fact, analysing two samples did not improve diagnostic accuracy and, instead, increased the number of colonoscopies needed to detect a CRC or an advanced neoplasia and the costs per lesion detected [Fig. 2]. These data suggest that FIT is an adequate CRC screening test in this population. However, FIT as a screening method must be evaluated in prospective controlled studies designed to determine CRC mortality reduction in the long term.

Conclusion
The reduction in mortality in FOBT-based CRC screening programmes and the improved sensitivity of immunochemical tests for CRC and advanced adenomas detection makes FIT CRC screening programmes a cost effective strategy. Preliminary data show that FIT is equally effective in the familial-risk population. Thus, FIT could be an adequate CRC screening technique in this population.

References
1. Ferlay J, Shin H-R, Bray F, Forman D, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127(12): 2893–2917.
2. Levin B, Lieberman DA, McFarland B, Andrews KS, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology 2008; 134: 1570–1595.
3. Baglietto L, Jenkins MA, Severi G, Giles GG, et al. Measures of familial aggregation depend on definition of family history: meta-analysis for colorectal cancer. J Clin Epidemiol. 2006; 59(2): 114–124.
4. Butterworth AS, Higgins JPT, Pharoah P. Relative and absolute risk of colorectal cancer for individuals with a family history: a meta-analysis. Eur J Cancer 2006; 42(2): 216–227.
5. Mandel JS, Church TR, Bond JH, Ederer F, et al. The effect of fecal occult-blood screening on the incidence of colorectal cancer. NEJM 2000; 343(22): 1603–1607.
6. Atkin WS, Edwards R, Kralj-Hans I, Wooldrage K, et al. Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet 2010; 375(9726): 1624–1633.
7. Quintero E. [Chemical or immunological tests for the detection of fecal occult blood in colorectal cancer screening?]. Gastroenterología y hepatología 2009; 32(8): 565–576.
8. Hewitson P, Glasziou P, Watson E, Towler B, Irwig L. Cochrane systematic review of colorectal cancer screening using the fecal occult blood test (hemoccult): an update. Am J Gastroenterol. 2008; 103(6): 1541–1549.
9. Guittet L, Bouvier V, Mariotte N, Vallee JP, et al. Comparison of a guaiac based and an immunochemical faecal occult blood test in screening for colorectal cancer in a general average risk population. Gut 2007; 56(2): 210–214.
10. Dove-Edwin I, Sasieni P, Adams J, Thomas HJW. Prevention of colorectal cancer by colonoscopic surveillance in individuals with a family history of colorectal cancer: 16 year, prospective, follow-up study. BMJ 2005; 331(7524): 1047.
11. Gimeno-García AZ, Quintero E, Nicolás-Pérez D, Hernández-Guerra M, et al. Screening for familial colorectal cancer with a sensitive immunochemical fecal occult blood test: a pilot study. Eur J Gastroenterol Hepatol. 2009; 21(9): 1062–1067.
12. Winawer S, Fletcher R, Rex D, Bond J, et al. Colorectal cancer screening and surveillance: clinical guidelines and rationale-Update based on new evidence. Gastroenterology 2003; 124(2): 544–560.
13. Castro I, Cubiella J, Rivera C, González-Mao C, et al. Fecal inmunochemical test accuracy for colorectal cancer and advanced neoplasia detection in familial risk colorectal cancer screening. Int J Cancer 2013; doi: 10.1002/ijc.28353 (Epub ahead of print).

The authors
Inés Castro MD and Joaquín Cubiella* PhD
Department of Gastroenterology, Complexo Hospitalario Universitario de Ourense, Ourense, Spain

*Corresponding author
E-mail: Joaquin.cubiella.fernandez@sergas.es

Preimplantation genetic screening is a diagnostic approach dedicated to patients undergoing IVF with the proper indications (advanced maternal age, recurrent implantation failure, recurrent pregnancy loss) in order to increase pregnancy rates per transfer via euploid embryo selection. This strategy, and all the associated techniques, are in constant evolution and will shed more light on unexplored aspects of embryology, such as female meiosis or chromosomal mosaicism, creating new criteria for embryo selection.

by Dr D. Cimadomo, Dr A. Capalbo, Dr L. Rienzi and Dr  F. M. Ubaldi

Background
Preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS) are two diagnostic approaches increasingly exploited in recent decades within assisted reproduction facilities in the presence of specific indications. PGD is used to identify unaffected embryos in couples at high reproductive risk of a hereditary disease. Usually, these couples conceive naturally and undergo prenatal genetic testing, i.e. villocentesis or amniocentesis; procedures that are invasive and carry a high risk of subsequent miscarriage. The ultimate aim of PGD is, therefore, to prevent the conception of a fetus affected specifically and uniquely by a pathology whose causative mutations have been identified and characterized in the parental genomes before conception. Consequently, PGD depends on a preliminary ad hoc work-up for each couple approaching to an IVF cycle. PGS, instead, is meant to identify only chromosomally normal embryos, thus looking for the presence of chromosomal abnormalities. Since the development of aneuploidies is a de novo event directly linked to maternal age, this diagnostic method is independent from any specific preliminary set-up, thus being identical for each PGS cycle. The indications for this analysis are mainly advanced reproductive maternal age (more than 35 years old; AMA), recurrent implantation failure (more than three failed IVF attempts; RIF) and recurrent pregnancy loss (more than three miscarriages; RPL). From an embryological perspective there is no difference between PGD and PGS. Indeed, strategy and planning of the cycle and biopsy techniques are similar, whereas the genetic technical aspects are significantly different.

Testing for aneuploidy
Interestingly, the data collected by the ESHRE PGD consortium IX showed a constant increase in the number of the PGD cycles approached uniquely for euploid embryo selection. In particular, more than 60% of PGD cycles were actually PGS for AMA, RIF or RPL patients, and this percentage is still currently increasing. There is, in fact, a striking impact of aneuploidies on human reproduction. In particular, their incidence in newborns is around 0.3%, mostly represented by trisomies of chromosomes 13, 18 and 21 and sex chromosome aneuploidies. However, tracking backwards through the developmental stages sees this incidence sharply increase, involving other chromosomes and reaching an incidence of up to 60% in preimplantation embryos and 70% in eggs or polar bodies [1]. On the contrary, this incidence in sperm is definitely less severe, as it is never greater than 3–4%. Moreover, a significant number of spontaneous abortions are linked to aneuploidies (more than 60% of products of conception follow chromosomal abnormalities), both increase exponentially with maternal age and fertility rate collapses (Fig. 1) [2].

From a biological perspective, the origin of high trisomy rates found in clinically recognized pregnancies (which sharply increases in patients older than 35 years) resides mainly in maternal meiosis I and II [3]. Recent data obtained through array comparative genomic hybridization (aCGH) on polar bodies (PBs) showed that chromatid errors in female meiosis, such as premature separation of sister chromatids, definitely outnumber impairments involving whole chromosomes as previously thought [4, 5]. Capalbo et al. [5] performed analyses on biopsies at sequential stages of development, in particular the two PBs, a single blastomere at day 3 of embryo development and also a trophectoderm (TE) sample at the blastocyst stage (Fig. 2). This study design allowed the determination of PB analysis accuracy and the impact of male and mitotic errors as well as the evaluation of the occurrence of correction mechanisms throughout preimplantation development. It came to light that 76 out of 78 (97.4%) abnormal meiotic segregations concerned errors involving chromatids rather than whole chromosomes at meiosis I. Furthermore, it unveiled not only a false positive rate in PB biopsy analysis of 20.5%, as just 79.5% (62/78) of meiotic segregation errors identified in PB biopsies were confirmed in blastomeres, but also a false negative rate of 47.6%, as 10 out of 21 embryos showed mitotic or male-derived aneuploidies confirmed at day 3 and at the blastocyst stage of development, which are, obviously, not observable in PBs. This evidence subverts our previous scenario of chromosomal aneuploidy genesis, as well as undermining the reliability of the PB analysis strategy.

Chromosomal mosaicism
From a diagnostic perspective in PGS, post-zygotic mitotic segregation errors are definitely more troubling than meiotic ones, as, whereas the latter involve the same aberrant chromosomal layout in the whole developing embryo, the former entail the phenomenon of chromosomal mosaicism. In the last decade several publications focused on the problem of mosaicism and its influence on PGD/PGS, claiming an incidence fluctuating between 25% [6, 7] and up to more than 70% [8]. Even when these data are analysed with a critical approach, it still emerges that mosaicism is a substantial source of misdiagnosis when the embryo is biopsied at day 3 post-fertilization. This evidence encouraged a shift of the biopsy strategy toward the blastocyst stage and, to this end, different studies were conducted in order to thoroughly describe its cytogenetic constitution and the impact of biopsy itself on embryonic developmental competence. In particular, Capalbo et al. [9] published data outlining the impact of chromosomal mosaicism on a diagnosis at day 5/6 of embryo development as well as the aneuploid cells setting between inner cell mass (ICM) and TE. To this end, a novel method of ICM biopsy was conceived [as described in 9], characterized via KRT18 staining [as described in 10] and its efficiency tested. It led to the absence of TE contamination in 85.7% of the ICM biopsy products, and a low TE contamination rate (only 2% of TE cells) in the rest of them. These data attest the reliability of this biopsy procedure to test the influence of mosaicism at the blastocyst stage. The study design entailed a preliminary aCGH analysis on a TE biopsy during blastocyst-stage PGS clinical cycles, followed by FISH re-analysis of three further fragments of TE and of the ICM from those blastocysts found to be carriers of copy-number chromosomal errors as well as euploid embryos. This revealed that at the blastocyst stage of development, 79.1% of the aneuploidies were constitutional, while 20.9% of them were mosaic. However, only 4% of the blastocysts were found to be mosaic diploid/aneuploid, being at risk of misdiagnosis due to mosaicism when testing at the blastocyst stage. These data strengthen the theory that the impact of mosaicism could be critical at day 3 of embryo development, but it has definitely less influence at the blastocyst stage, thus strongly presenting the latter as the most reliable candidate biopsy stage to perform PGS. Importantly, in the same paper, Capalbo et al. demonstrated that, after excluding low grade mosaicism (<20% of aneuploid cells) and mosaicism confined to one or two TE sections, in 97.1% of cases concordance for all chromosomes re-analysed by FISH between ICM and TE was observed. On a per embryo analysis, instead, complete concordance in TE-based prediction of ICM chromosomal complement was reported (Fig. 3) [9]. Northrop et al. [11] conducted a similar analysis exploiting a single nucleotide polymorphism (SNP) array, which is a comprehensive chromosomal screening technique. This method was found to detect aneuploidy in samples possessing more than 25% aneuploidy, thus when as few as 2 of the 5 cells within a TE biopsy contain the same chromosomal error. Their data showed no preferential aneuploid cell migration to the TE layer, as aneuploidy was observed in 31% of ICM samples (15 out of 48 ICM products) and 32% of TE ones (46 of 144 TE products). Furthermore, a mosaicism rate of 24% was attested, since 12 out of 50 blastocysts screened showed more than a single diagnosis in all of the multiple sections that were re-analysed.

Does the biopsy procedure affect embryo reproductive competence?
One  concern about PGS is that biopsy could affect embryo reproductive competence. To investigate this possibility, Scott et al. [12] designed a randomized and paired clinical trial. They selected two of the best quality embryos from the same patient to be transferred and randomized them, one to undergo biopsy, either at day 3 or at day 5 of embryo development, and the other as a control. The biopsy was submitted to SNP array analysis. If only one embryo implanted, buccal DNA obtained from the neonate after delivery was analysed by SNP array to determine whether the implanted embryo was the control one or not. The data collected clearly showed that conducting the biopsy at the cleavage stage affects the clinical outcome, as an absolute reduction in implantation rate of 19.6% with respect to the control was reported. On the contrary, blastocyst biopsy led to a non-significant overall reduction of implantation of 3%; thus an implantation rate equivalent to the control. It is still unclear whether this is due to a smaller proportion of the embryo’s total number of cells being removed, or to the fact that only extra-embryonic cells are involved, or to a higher stress-tolerance of the blastocyst; however, it is still additional important evidence supporting TE biopsy as the ‘gold standard’ for PGS. From a clinical perspective, the same authors also published a randomized controlled trial [13] comparing the clinical outcomes of single euploid blastocyst transfer versus double untested blastocyst transfer. Ongoing pregnancy rates per randomized patient were similar between the two groups (60.7% in the study group vs 65.1% in the control group), whereas a higher multiple pregnancy rate in the control group was recorded (54% vs 0% in the study group). Ultimately then, PGS on TE biopsy associated with a single euploid blastocyst transfer elicits the same clinical outcomes as conventional IVF, but reduces its risks.

Conclusion
In conclusion, PGS is an important diagnostic approach for patients with the proper indications (AMA, RIF or RPL), performed in order to boost implantation rate per transfer. Euploid embryo selection prevents useless and potentially detrimental embryo transfers. Consequently, further advantages of performing PGS are a lower time-to-pregnancy and a higher cost-effectiveness of each single treatment. Moreover, by adopting a biopsy strategy at day 5/6, it is possible to take advantage of a more robust genetic analysis, a high clinical predictive value, the absence of impact of the biopsy on embryo quality, a low influence of mosaicism, as well as a reduced number of embryos to analyse per cycle, as only developmentally competent ones would reach the blastocyst stage. These last aspects will help in reducing costs, thus extending the patients population that can benefit from this technology. Finally, novel comprehensive chromosomal screening techniques, i.e. aCGH, SNP array and quantitative real-time PCR (qPCR), provide us with reliable, sensible and accurate analysis methods, making of PGS also a technically solid approach.

References
1. Nagaoka SI, Hassold TJ, Hunt PA. Human aneuploidy: mechanisms and new insights into an age-old problem. Nat Rev Genet. 2012; 13(7): 493-504.
2. Heffner LJ. Advanced maternal age–how old is too old? N Engl J Med. 2004; 351(19): 1927-1929.
3. Hassold T, Hunt P. To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet. 2001; 2(4): 280-291.
4. Handyside AH, Montag M, Magli MC, Repping S, et al. Multiple meiotic errors caused by predivision of chromatids in women of advanced maternal age undergoing in vitro fertilisation. Eur J Hum Genet. 2012; 20(7): 742-747.
5. Capalbo A, Bono S, Spizzichino L, Biricik A, et al. Sequential comprehensive chromosome analysis on polar bodies, blastomeres and trophoblast: insights into female meiotic errors and chromosomal segregation in the preimplantation window of embryo development. Hum Reprod. 2013; 28(2): 509-518.
6. Voullaire L, Slater H, Williamson R, Wilton L. Chromosome analysis of blastomeres from human embryos by using comparative genomic hybridization. Hum Genet. 2000; 106(2): 210-217.
7. Wells D, Delhanty JD. Comprehensive chromosomal analysis of human preimplantation embryos using whole genome amplification and single cell comparative genomic hybridization. Mol Hum Reprod. 2000; 6(11): 1055-1062.
8. Mertzanidou A, Wilton L, Cheng J, Spits C, et al. Microarray analysis reveals abnormal chromosomal complements in over 70% of 14 normally developing human embryos. Hum Reprod. 2013; 28(1): 256-264.
9. Capalbo A, Wright G, Elliott T, Ubaldi FM, et al. FISH reanalysis of inner cell mass and trophectoderm samples of previously array-CGH screened blastocysts shows high accuracy of diagnosis and no major diagnostic impact of mosaicism at the blastocyst stage. Hum Reprod. 2013; 28(8): 2298-2307.
10. Cauffman G, De Rycke M, Sermon K, Liebaers I, Van de Velde H. Markers that define stemness in ESC are unable to identify the totipotent cells in human preimplantation embryos. Hum Reprod. 2009; 24(1): 63-70.
11. Northrop LE, Treff NR, Levy B, Scott RT Jr. SNP microarray-based 24 chromosome aneuploidy screening demonstrates that cleavage-stage FISH poorly predicts aneuploidy in embryos that develop to morphologically normal blastocysts. Mol Hum Reprod. 2010; 16(8): 590-600.
12. Scott RT Jr, Upham KM, Forman EJ, Zhao T, Treff NR. Cleavage-stage biopsy significantly impairs human embryonic implantation potential while blastocyst biopsy does not: a randomized and paired clinical trial. Fertil Steril. 2013; 100(3): 624-630.
13. Forman EJ, Hong KH, Ferry KM, Tao X, et al. In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial. Fertil Steril. 2013; 100(1): 100-107.

The authors
Danilo Cimadomo BSc, Antonio Capalbo* PhD, Laura Rienzi MS, Filippo Maria Ubaldi MS
G.EN.E.R.A. Centre for Reproductive
Medicine, Clinica Valle Giulia, Via G. De Notaris 2b, 00197 Rome, Italy
*Corresponding author
E-mail: capalbo@generaroma.it

Recently a senior Dutch health official claimed that sugar is ‘the most dangerous drug of the times’ and called for cigarette packet-type warnings stating that ‘sugar is addictive and bad for health’ to be mandatory on the labels of products such as soft drinks and sweets.
A plethora of studies has examined the effects of overconsumption of sugar. Many are based on consumers reporting the amount of sugar in their diet; under-reporting is very common in such surveys, though a recently discovered biomarker based on the ratio of Carbon 12 and 13 can now measure long-term sugar intake from a single blood or hair sample. Other studies don’t distinguish between free monosaccharides and disaccharides added to food products and those occurring naturally in food. While recognising the limitations of many studies, most of us would accept that overconsumption of sugar is linked to obesity, dental caries, macular degeneration and Alzheimer’s disease in older age, cardiovascular disease and diabetes. And hypoglycemia (defined as a blood glucose level of < 2.5mmol/L), a frequent problem in diabetes patients receiving treatment, can also occur in non-diabetic subjects as a result of a diet that is too high in refined sugars and too low in complex carbohydrates. And the treatment for hypoglycemia is the sugar dextrose (= glucose), given orally or by intravenous drip depending on how low the glucose level is and how alert the patient.
Hypoglycemia is unfortunately becoming more common in neonates. Around one in three suffer from the condition in the West, reflecting the increase in gestational and maternal diabetes as well as the rising number of pre-term births. Careful management of the newborn is necessary to avoid seizures and serious brain injury, and this normally involves extra feeding with formula (in addition to breast milk, which often interrupts normal breastfeeding) and repeated blood glucose tests involving heel pricks. If a seriously low glucose level persists, babies are admitted to intensive care and intravenous dextrose is administered. However the good news is that a New Zealand study has just been published in ‘The Lancet‘ involving 514 neonates considered at high risk of hypoglycaemia. The babies diagnosed with the condition were randomly assigned to one of two groups. One hundred and eighteen were treated with six applications of 40% dextrose gel over two days, applied to the inside of the cheek, and 119 were treated with placebo gel. The blood glucose levels of the former group stabilised quicker, fewer babies needed extra formula feeds and fewer were admitted to intensive care. Sugar may be a ‘dangerous drug’ but it can also be invaluable!