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NeoReviews™ Vol.15 No.3 March 2014

Articlese83 Diabetic Pregnancy and Fetal Consequences

Kari Teramo

e91 Neonatal Hypoglycemia: Are Evidence-based Clinical

Guidelines Achievable?Jane M. Hawdon

Index of Suspicion in the Nursery Case 1: Persistent Severe Metabolic Acidosis in a Newborne99 Case 2: Late Preterm Infant With a Diffi cult Intubation

Case 1: Deepak Sharma, Srinivas Murki, Oleti Tejopratap, Vasikarla MadhaviCase 2: Zachary A. Vesoulis, Akshaya J. Vachharajani

e103 Correction

e104 Legal Briefs: Late-Onset Group B Streptococcus Meningitis:

Should It Happen in a Newborn Intensive Care Unit?Maureen E. Sims

e108 Strip of the Month: March 2014Maurice L. Druzin, Nancy Peterson

e115 Visual Diagnosis: Abdominal Swelling in a Newborn With

Trisomy 21Michael Nweze, Mely Mathew

Answer key appears on page e103.

DOI: 10.1542/neo.15-3-e832014;15;e83Neoreviews

Kari TeramoDiabetic Pregnancy and Fetal Consequences

http://neoreviews.aappublications.org/content/15/3/e83located on the World Wide Web at:

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Diabetic Pregnancy and Fetal ConsequencesKari Teramo, MD, PhD*

Author Disclosure

Dr Teramo has

disclosed that he

answers patient

questions on the

NovoNordisk website.

This commentary does

not contain

a discussion of an

unapproved/

investigative use of

a commercial product/

device.

Practice Gaps

1. There is a need for new strategies to help decrease risk of fetal and neonatal

complications in diabetic pregnancy.

2. While important, it can be challenging to estimate fetal weight in diabetic pregnancy.

AbstractPerinatal morbidity andmortality, congenital malformations, abnormal fetal growth, bothspontaneous and iatrogenic preterm birth, hypoxic complications, and trauma during de-livery are increased in diabetic pregnancies. Perinatal mortality in diabetic pregnancies isstill three to five times higher than the perinatal mortality in the general population. Still-births during the last weeks of pregnancy are often considered unexplained, although re-cent studies indicate that most of these stillbirths are caused by fetal chronic hypoxia.Importantly, perinatal mortality has not changed during the past 3 decades in diabeticpregnancies, which emphasizes the need to find new methods and strategies to improveperinatal outcome. Congenital malformations have decreased in pregestational diabeticpregnancies because of general improvement of glycemic control among diabetic women.However, the rate of fetal malformations is still two to four times higher in type 1 and type2 diabetic pregnancies than in the general population. Prepregnancy counseling decreasesthe risk of fetal malformations. Efforts should be made to improve the attendance of di-abetic women in prepregnancy clinics. Fetal overgrowth during the last trimester of preg-nancy is the most common fetal complication in diabetic pregnancies. Accurate estimationof fetal weight by ultrasound is especially difficult in macrosomic fetuses. Magnetic reso-nance imaging can be used to assess fetal total volume, shoulder width, and fat amount inaddition to obtaining accurate pelvic measurements. More studies on the clinical use ofmagnetic resonance imaging in obstetrics are urgently needed. Increased fetal erythropoi-etin (EPO) level is an indicator of fetal chronic hypoxia, which can be detected antenatallyby measuring amniotic fluid EPO concentration. Sufficiently large controlled studies areneeded before amniotic fluid EPO measurement can be recommended for clinical use.

Objectives After completing this article, readers should be able to:

1. Describe the main fetal and neonatal complications in type 1 and type 2 diabetic

pregnancies.

2. Explain the role of poor glycemic control in the pathogenesis of maternal and fetal

complications in diabetic pregnancies.

3. Address the importance and problems in the estimation

of fetal weight in diabetic pregnancies.

4. Discuss possible new strategies that could improve

offspring outcomes in diabetic pregnancies.

IntroductionPregnancies complicated by maternal diabetes have majoreffects on the developing fetus throughout pregnancy. Con-genital malformations, abnormal fetal growth, hypoxic

Abbreviations

CI: confidence intervalEPO: erythropoietinFHR: fetal heart rateGDM: gestational diabetes mellitusMRI: magnetic resonance imagingOR: odds ratio

*Department of Obstetrics and Gynecology, University Central Hospital, Helsinki, Finland.

Article endocrinology

NeoReviews Vol.15 No.3 March 2014 e83

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complications, and trauma during delivery are increasedin pregnancies of diabetic women. Although the exactpathogenetic mechanisms of fetal complications in dia-betic pregnancies are not well understood in all instances,maternal hyperglycemia, and hence fetal hyperglycemia,is associated with several fetal complications (Table). Inthis review, early and late fetal complications, detection,management, and prevention in pregnancies complicatedby maternal diabetes is discussed.

Perinatal MortalityPerinatal mortality has remained unchanged at 2% to 4%in type 1 diabetic pregnancies during the past 30 years inmost centers specializing in the care of diabetic pregnan-cies. (1)(2)(3) Congenital malformations (30%–40% ofperinatal deaths), preterm birth (20%–30%), and intra-uterine hypoxia (20%–30%) are the main causes of

perinatal deaths in type 1 diabetic pregnancies. Detectionof lethal fetal malformations by sonography decreases theperinatal mortality by w0.5 percentage units when thesepregnancies are interrupted before 20 weeks’ pregnancy(unpublished observation).

The stillbirth rate in type 1 diabetic pregnancies in-creased linearly during the last weeks of pregnancy beforefetal electronic monitoring was available, reaching 20% atterm. (4) The pathogenesis of this increasing trend ofstillbirths toward the end of pregnancy is unknown. Al-though the stillbirth rate has been considerably lowerduring recent decades than in the 1950s, unexplainedstillbirths still occur during the last weeks of pregnancyin pregestational diabetes pregnancies. (3) Maternal dia-betes remains an independent risk factor of fetal death.(5) Most of the stillbirth fetuses before 32 weeks’ gesta-tion are growth restricted. (3) However, in a recent birthregistry study from Norway, the stillbirth rate before 37weeks’ gestation in type 1 diabetic pregnancies did notdiffer from the stillbirth rate of the background popula-tion. (6) In contrast, the stillbirth rate in term pregnan-cies was five times higher in type 1 diabetic pregnanciesthan in the general population. Also infant deaths duringthe first year after birth was higher in type 1 diabetespregnancies than in the general population. (6) More-over, both the stillbirth rate and perinatal mortality intype 1 diabetic pregnancies did not decrease significantlybetween 1985 and 2004 in Norway.

Fetal MalformationsThere is now general agreement that poor maternal gly-cemic control (hyperglycemia) at conception and duringthe first trimester of pregnancy is the main cause of fetalmajor malformations in diabetic pregnancies. (7)(8)(9)(10)Poor glycemic control increases also the miscarriage riskin these pregnancies. (7) Hyperglycemia in the develop-ing fetus alters lipid metabolism, generates an excess ofreactive oxygen species, and activates apoptosis, whichall can result in fetal malformations. (11) Although therisk of fetal malformations has decreased during the past3 decades due to improved glycemic control in womenwith diabetes, (8) the rate of malformations is still twoto four times higher in type 1 and type 2 diabetic preg-nancies than in the general population. (8)(9)(10)(12)

The most common malformations in diabetic preg-nancies occur in the heart, central nervous system, andurinary system. (13) Multiple malformations are alsocommon in fetuses of pregestational diabetic women.Caudal regression syndrome, although rare, is seen in di-abetic pregnancies only. There is not an increased risk of

Table. Fetal and NeonatalConsequences of FetalHyperglycemia andHyperinsulinemia in DiabeticPregnancies

Increased fetal substrate uptakeIncreased risk of fetal macrosomiaIncreased risk of fetal shoulder dystocia at deliveryIncreased risk of fetal trauma at delivery (Erb palsy,fractures)

Increased risk of stillbirth at deliveryIncreased risk of neonatal asphyxia at deliveryIncreased risk of maternal traumaIncreased rate of cesarean deliveriesDecreased rate of intrauterine growth restriction

Fetal Chronic HypoxiaIncreased oxygen consumption and decreased arterialoxygen content

Increased fetal erythropoietin synthesisFetal polycythemiaIncreased nucleated red cell count in cord bloodDecreased or depleted fetal iron storesIncreased fetal and neonatal distress and asphyxiaIncreased risk of stillbirth

Delayed lung maturationIncreased risk of neonatal respiratory distresssyndrome

Increased risk of neonatal transient tachypneaNeonatal hypoglycemiaIncreased risk of hypoglycemia during the first daysafter birth

endocrinology diabetic pregnancy

e84 NeoReviews Vol.15 No.3 March 2014




malformations in the offspring of women with gestationaldiabetes (GDM), although there are reports that the riskof congenital malformations is slightly increased inwomen diagnosed with GDM. However, malformationsin these pregnancies are likely to occur in hyperglycemicwomen with undiagnosed type 2 diabetes.

Preconception care is important in type 1 and type 2 di-abetic pregnancies because fetal malformations are formedearly during fetal development, (14) usually before first an-tenatal visit. A threefold reduction in the risk of major mal-formations has been reported in offspring of women whoreceived prepregnancy care compared with offspring ofwomen without such care. (15) Unfortunately, approxi-mately half of pregnancies are not planned, and thereforeonly 30% to 40% of the diabetic patients attend a clinicfor prepregnancy care. Folic acid and vitamin supplemen-tation is recommended to all women in reproductiveage. (16) This is especially important in type 1 and type2 diabetes patients. At the prepregnancy visit, diabetescomplications should be evaluated, and the risk of preg-nancy and fetal complications should be discussed in addi-tion to controlling the glycemic status. (17) Most centersrecommend that the HbA1c should be less than 7% beforeconception, but this cannot be achieved in all type 1 diabe-tes patients. The rate of major malformations in offspring oftype 2 diabetic pregnancies does not differ from the rates inoffspring of type 1 diabetic pregnancies. (18)

A thorough sonographic examination of the fetal struc-tures should be offered to all diabetic patients at 18 to 20weeks’ gestation. If the glycemic control is not optimal in earlypregnancy (HbA1c >8%), a fetal echocardiography is recom-mended atw20 weeks’ gestation. Even in patients with poorglycemic control in early pregnancy (HbA1c >10%), 85% to90% of the fetuses do not have major malformations. (8)(9)Therefore, a high HbA1c value alone in early pregnancyshould not be an indication to interrupt the pregnancy.

Preterm BirthPoor glycemic control (hyperglycemia) has been reportedto increase the risk of spontaneous preterm birth rate intype 1 diabetic pregnancies. (19) Pre-eclampsia and dia-betic nephropathy can cause fetal growth restriction in di-abetic pregnancies, which increases iatrogenic pretermbirth because severe early pre-eclampsia necessitates de-livery on maternal or fetal indications before 30 weeks’gestation. Glucocorticoids also should be used in threat-ened preterm labor in diabetic pregnancies. However,glucocorticoid administration to womenwith pregestationalor insulin-treated gestational diabetes can result inlong-lasting hyperglycemia and increased risk of ketoacidosis.

Increasing the insulin dose by 30% to 50% for a few days isoften necessary when glucocorticoids are used in diabeticpregnancies. (17)

Fetal GrowthFetal overgrowth during the last trimester of pregnancy isthe most common fetal complication in pregnancies ofwomen with diabetes. The birthweight should be ex-pressed as relative to the gestational age. Large for gesta-tional age is best defined as more than 2 SD (>97.7th

percentile) above the mean birthweight of a standardpopulation, but birthweight more than 90th percentileis also frequently used. Small for gestational age is definedas more than 2 SD (<2.3th percentile) below the refer-ence mean. (20) Ethnicity, genetic, and environmentalfactors (eg, maternal BMI, parity, smoking, and nutri-tion) influence the size of the fetus.

Fetal macrosomia is often defined as birthweight morethan 4,000 g, but the foregoing definition of large for ges-tational age is preferred as the definition for macrosomia. Atpresent, 18% of newborn infants weigh more than 4,000 gat birth in Finland. The corresponding figure in the UnitedStates is 9%. In type 1 diabetic pregnancies, the rate ofmacrosomia defined as more than 2 SD above the meanof the reference population is more than 30% in Finlandand Sweden. (2)(21) The birthweight distribution in type1 diabetic pregnancies is normal Gaussian but shifted tothe right (22)(23), that is, the number of small for ges-tational age fetuses in diabetic pregnancies is lower thanin the general population. In Sweden, 3% of birthweightswere below the 10th percentile in type 1 diabetic preg-nancies compared with 9.1% in the general population.(23)

Fetal hyperinsulinemia is the main cause of fetal over-growth in diabetic pregnancies. (24)(25) Chronic hyper-insulinemia in euglycemic rhesus monkeys results in fetalmacrosomia and organomegaly. (24) Interestingly, macro-somic fetuses of nondiabetic mothers with a birthweightmore than 2 SD above the mean of the background pop-ulation are not hyperinsulinemic. (25) Fetal body compo-sition of diabetic mothers differs often from fetal bodycomposition of healthy mothers. (26) Macrosomic fe-tuses of diabetic mothers have increased adipose tissue andorganomegaly, but their head size is not increased. Severeshoulder dystocia can result in brachial plexus injury duringvaginal delivery, which occurs 10 times more often inoffspring of type 1 diabetic pregnancies than in the gen-eral population. (2)(27) The majority of brachial plexusinjuries and fractures occurs in fetuses weighing morethan 4,000 g at birth. (28)






The most accurate method for pregnancy dating is bymeasuring the fetal crown to rump length at w10 to 12weeks’ gestation. Accurate dating is important when es-timating the fetal weight in diabetic pregnancy during thelast trimester of pregnancy. However, estimating the fetalweight by sonography has been disappointing. (29) Themean error in the estimation of fetal weight by sonogra-phy is 10% to 15% for normal weight fetuses, but it in-creases to 15% to 20% when predicting birthweightsmore than 4,000 g. (30) For example, a fetus with an es-timated weight of 4,000 g by ultrasound can actuallyweigh 5,000 g, which can have serious consequencesfor both the mother and the child. Sonographic modelsusing three or four fetal biometric measurements aremore accurate than methods using abdominal circumfer-ence alone or two biometric measurements. (30)

Fetal weight, shoulder width, and pelvic capacity canbe measured using magnetic resonance imaging (MRI),(31)(32)(33) but large clinical studies about the usefulnessof MRI in obstetrics are still lacking. It is now also possibleto measure fetal fat volume and body composition usingMRI. (34) Studies for evaluating the clinical value of MRIin detecting fetal macrosomia and abnormal body composi-tion are urgently needed, particularly in diabetic pregnancies.

Fetal growth restriction in diabetic pregnancies occursmainly in women with nephropathy, in whom pre-eclampsia often further complicates the outcome of theiroffspring. Because diabetes also increases the birthweightof growth-restricted fetuses, it is possible that growth re-striction of fetuses of type 1 diabetic women should bedefined differently from pregnancies of nondiabetic preg-nancies. Amniotic fluid erythropoietin (EPO) is a specificindicator of fetal chronic hypoxia. (35) We have shownthat relative birthweight correlates in a U-shaped fashionwith amniotic fluid EPO concentration in type 1 diabeticpregnancies. (36) Amniotic fluid EPO concentration cor-related negatively with birthweight when the birthweightz score was below –0.6 SD units (r ¼ –0.63, P < .001)but positively when the birthweight z score was aboveþ1.0 SD units (r ¼ 0.32, P ¼ .001). (36) This could ex-plain why unexpected stillbirths occur also in fetuses with“normal” birthweight (birthweight z score above –2 SDbut below þ2.0 SD). More studies are clearly needed toevaluate the optimal birthweight in diabetic pregnancies.

Fetal Chronic HypoxiaClinical signs of fetal hypoxia (abnormal fetal heart rate[FHR] changes, umbilical artery acidosis, and low Apgarscores at birth) are more common in diabetic than non-diabetic pregnancies. (37) Neonatal polycythemia and

increased nucleated red cells in cord blood occur also fre-quently in pregestational diabetic pregnancies. (37) Thefetus adapts to chronic hypoxia by redistributing its car-diac output and maintaining its blood flow to the brainand heart and by increasing its EPO synthesis to increasethe oxygen-carrying capacity in the blood. Both elevatedfetal plasma and amniotic fluid EPO levels are markers ofintrauterine chronic hypoxia. (35) Fetal EPO levels arefrequently elevated in type 1 diabetic pregnancies, (36)which provides evidence that fetal chronic hypoxia oftencomplicates these pregnancies.

Increased erythropoiesis requires increased amountsof iron. Iron is therefore preferentially absorbed from fe-tal iron stores during increased production of red cells.(38) The iron stores of stillbirth fetuses of diabetic moth-ers are extremely low or totally depleted, (39) suggestingthat chronic hypoxia is the main cause of late fetal deaths.In line with this are the observations that the iron distri-bution is abnormal and the ferritin levels are low in new-born infants of diabetic mothers. (39) Fetal chronichypoxia and associated fetal iron deficiency may be re-sponsible for abnormal neurodevelopment in offspringof diabetic mothers. (40)

In the fetal sheep, both hyperinsulinemia and hypergly-cemia result in an increase in fetal oxygen consumption anda fall in arterial oxygen content. (41)(42) Fetal insulin levelscorrelate directly with fetal EPO levels in diabetic pregnan-cies, (43) suggesting that hyperinsulinemia also results infetal chronic hypoxia in human pregnancies. MaternalHbA1c levels obtained during the last month before deliv-ery in type 1 diabetic pregnancies correlates directly withfetal EPO levels, (35)(43) emphasizing the importance ofmaintaining good glycemic control throughout pregnancy.Forced stepwise multiple regression analysis has shown thatboth maternal hyperglycemia (ie, fetal hyperglycemia) andfetal hyperinsulinemia independently can cause fetal chronichypoxia as indicated by elevated fetal EPO levels. (43)

The fact that perinatal mortality has not decreased indiabetic pregnancies in most centers during the past fewdecades indicates that the current methods and strategiesfor fetal surveillance are not satisfactory. Twice weeklynonstressed testing of FHR has been suggested for pre-vention of stillbirths during the last weeks of pregnancy.(44) However, several studies have shown that non-stressed FHR and biophysical testing have limited valuein diabetic pregnancies, (45)(46) which is probably ex-plained by different pathogenetic mechanism of fetal hyp-oxia in diabetic pregnancies compared with fetal hypoxiaresulting from placental insufficiency. For the same rea-son, studies on uterine or umbilical artery Doppler flowassessment have concluded that this method is not






reliable in fetal surveillance in diabetic pregnancies withthe possible exception of pregnancies complicated bypre-eclampsia or growth restriction. (47)

Exponentially increasing EPO levels in the amniotic fluidis associated with fetal hypoxia (for review, see Teramo andWidness). (35) In our own study, abnormal high amnioticfluid EPO levels were detected antenatally in 21 of 156(13.5%) consecutive type 1 diabetic pregnancies. (36) Highamniotic fluid EPO levels predicted fetal macrosomia (oddsratio [OR] 5.4, 95% confidence interval [CI] 1.9–15.3),obstructive cardiomyopathy (OR 12.5, 95% CI 2.6–59.3),neonatal hypoglycemia (OR 11.3, 95% CI 3.8–33.7)and NICU admission (OR 3.4%, 95% CI 1.1–10.8).(36) Fetal EPO synthesis increases regardless of the eti-ology of hypoxia. It is therefore possible to detect fetalchronic hypoxia antenatally by amniotic fluid EPO mea-surement in type 1 diabetic pregnancies. (35) However,sufficiently large controlled studies should be performedbefore possible clinical benefits of amniotic fluid EPOmeasurements in diabetic pregnancies can be recommended.

Timing and Mode of DeliveryThe American College of Obstetricians and Gynecolo-gists recommends elective cesarean delivery when the es-timated fetal weight is more than 5,000 g in pregnanciesof nondiabetic women and when the estimated weight ismore than 4,500 g in diabetic women. (48) Arrest of de-scent of the fetal head or prolonged second stage of laborare also indications for cesarean delivery when the esti-mated fetal weight is more than 4,500 g. Vacuum extrac-tion and forceps delivery increase the risk of shoulderdystocia of macrosomic fetuses in diabetic pregnancies.

The proportionally high stillbirth rate in term type 1diabetic pregnancies has influenced clinical guidelinesfor timing of delivery. The National Institute for HealthCare and Excellence guidelines in the United Kingdomrecommends that women with pregestational diabetesshould be offered induction of labor or elective cesareandelivery at completed 38 weeks’ pregnancy. (49) TheAmerican Diabetes Association recommends that dia-betic women with good glycemic control and withoutother complications can wait for spontaneous labor until39 to 40 weeks’ pregnancy. (50) National guidelines inNorway recommend induction of labor at approximately40 weeks in women with pregestational diabetes when in-dications for earlier induction are not present. (6) Be-cause unexpected stillbirths still occur and perinatalmortality has not decreased during the past 30 years, newstrategies for identifying diabetic pregnancies with a highrisk of fetal hypoxic complications needs to be developed.

References1. Gabbe SG, Graves CR. Management of diabetes mellituscomplicating pregnancy. Obstet Gynecol. 2003;102(4):857–8682. Persson M, Norman M, Hanson U. Obstetric and perinataloutcomes in type 1 diabetic pregnancies: a large, population-basedstudy. Diabetes Care. 2009;32(11):2005–20093. Teramo KA. Obstetric problems in diabetic pregnancy—the roleof fetal hypoxia. Best Pract Res Clin Endocrinol Metab. 2010;24(4):663–6714. Hagbard L. Pregnancy and diabetes mellitus; a clinical study.Acta Obstet Gynecol Scand Suppl. 1956;35(suppl 1):1–1805. Engel PJ, Smith R, Brinsmead MW, et al. Male sex and pre-existing diabetes are independent risk factors for stillbirth. Aust N Z JObstet Gynaecol. 2008;48(4):375–3836. Eidem I, Vangen S, Hanssen KF, et al. Perinatal and infantmortality in term and preterm births among women with type 1diabetes. Diabetologia. 2011;54(11):2771–27787. Hanson U, Persson B, Thunell S. Relationship between haemo-globin A1C in early type 1 (insulin-dependent) diabetic pregnancyand the occurrence of spontaneous abortion and fetal malformationin Sweden. Diabetologia. 1990;33(2):100–1048. Suhonen L, Hiilesmaa V, Teramo K. Glycaemic control duringearly pregnancy and fetal malformations in women with type Idiabetes mellitus. Diabetologia. 2000;43(1):79–829. Jensen DM, Korsholm L, Ovesen P, et al. Peri-conceptionalA1C and risk of serious adverse pregnancy outcome in 933 womenwith type 1 diabetes. Diabetes Care. 2009;32(6):1046–104810. Murphy HR, Steel SA, Roland JM, et al. Obstetric andperinatal outcomes in pregnancies complicated by type 1 and type2 diabetes: influence of glycaemic control, obesity and socialdisadvantage. Diabet Med. 2011;28(9):1060–106711. Reece EA. Diabetes-induced birth defects: what do we know?What can we do? Curr Diab Rep. 2012;12(1):24–3212. Towner D, Kjos SL, Leung B, et al. Congenital malformationsin pregnancies complicated by NIDDM. Diabetes Care. 1995;18(11):1446–145113. Martínez-Frías ML. Epidemiological analysis of outcomes ofpregnancy in diabetic mothers: identification of the most charac-teristic and most frequent congenital anomalies. Am J Med Genet.1994;51(2):108–11314. Mills JL, Baker L, Goldman AS. Malformations in infants ofdiabetic mothers occur before the seventh gestational week.Implications for treatment. Diabetes. 1979;28(4):292–29315. Ray JG, O’Brien TE, Chan WS. Preconception care and therisk of congenital anomalies in the offspring of women with diabetesmellitus: a meta-analysis. QJM. 2001;94(8):435–44416. Wilson RD, Johnson JA, Wyatt P, et al; Genetics Committee ofthe Society of Obstetricians and Gynaecologists of Canada and The

American Board of Pediatrics Neonatal-PerinatalContent Specifications

• Know the effects on the fetus and/ornewborn infant of maternal diabetes 2mellitus (including gestational diabetes)and their management

• Know the hormonal factors that affectintrauterine fetal growth






Motherrisk Program. Pre-conceptional vitamin/folic acid supple-mentation 2007: the use of folic acid in combination witha multivitamin supplement for the prevention of neural tube defectsand other congenital anomalies [published correction appears inJ Obstet Gynaecol Can. 2008;30(3):193]. J Obstet Gynaecol Can.2007;29(12):1003–102617. McCance DR. Pregnancy and diabetes. Best Pract Res ClinEndocrinol Metab. 2011;25(6):945–95818. Balsells M, García-Patterson A, Gich I, Corcoy R. Maternal andfetal outcome in women with type 2 versus type 1 diabetes mellitus:a systematic review and metaanalysis. J Clin Endocrinol Metab.2009;94(11):4284–429119. Lauszus FF, Fuglsang J, Flyvbjerg A, Klebe JG. Pretermdelivery in normoalbuminuric, diabetic women without preeclamp-sia: the role of metabolic control. Eur J Obstet Gynecol Reprod Biol.2006;124(2):144–14920. Clayton PE, Cianfarani S, Czernichow P, et al. Management ofthe child born small for gestational age through to adulthood:a consensus statement of the International Societies of PediatricEndocrinology and the Growth Hormone Research Society. J ClinEndocrinol Metab. 2007;92(3):804–81021. Klemetti M, Nuutila M, Tikkanen M, et al. Trends in maternalBMI, glycaemic control and perinatal outcome among type 1diabetic pregnant women in 1989–2008.Diabetologia. 2012;55(9):2327–233422. Bradley RJ, Nicolaides KH, Brudenell JM. Are all infants ofdiabetic mothers “macrosomic”? BMJ. 1988;297(6663):1583–158423. Persson M, Pasupathy D, Hanson U, Norman M. Birth sizedistribution in 3,705 infants born to mothers with type 1 diabetes:a population based study. Diabetes Care. 2011;34:1145–114924. Susa JB, McCormick KL, Widness JA, et al. Chronic hyper-insulinemia in the fetal rhesus monkey: effects on fetal growth andcomposition. Diabetes. 1979;28(12):1058–106325. Schwartz R, Teramo KA. Effects of diabetic pregnancy on thefetus and newborn. Semin Perinatol. 2000;24(2):120–13526. Catalano PM, Thomas A, Huston-Presley L, Amini SB.Increased fetal adiposity: a very sensitive marker of abnormal inutero development. Am J Obstet Gynecol. 2003;189(6):1698–170427. Confidential Enquiry into Maternal and Child Health (CEMACH).Pregnancy in Women With Type 1 and Type 2 Diabetes in 2002–2003,England, Wales and Northern Ireland. London, UK: CHEMACH;200528. Bjørstad AR, Irgens-Hansen K, Daltveit AK, Irgens LM.Macrosomia: mode of delivery and pregnancy outcome. ActaObstet Gynecol Scand. 2010;89(5):664–66929. Chauhan SP, Charania SF, McLaren RA, et al. Ultrasono-graphic estimate of birth weight at 24 to 34 weeks: a multicenterstudy. Am J Obstet Gynecol. 1998;179(4):909–91630. Melamed N, Yogev Y, Meizner I, Mashiach R, Pardo J, Ben-Haroush A. Prediction of fetal macrosomia: effect of sonographicfetal weight-estimation model and threshold used. UltrasoundObstet Gynecol. 2011;38(1):74–8131. Baker PN, Johnson IR, Gowland PA, et al. Fetal weightestimation by echo-planar magnetic resonance imaging. Lancet.1994;343(8898):644–64532. Tukeva TA, Salmi H, Poutanen VP, et al. Fetal shouldermeasurements by fast and ultrafast MRI techniques. J Magn ResonImaging. 2001;13(6):938–942

33. Spörri S, Thoeny HC, Raio L, Lachat R, Vock P, Schneider H.MR imaging pelvimetry: a useful adjunct in the treatment of womenat risk for dystocia? AJR Am J Roentgenol. 2002;179(1):137–14434. Anblagan D, Deshpande R, Jones NW, et al. Measurement offetal fat in utero in normal and diabetic pregnancies using magneticresonance imaging. Ultrasound Obstet Gynecol. 2013;42(3):335–34035. Teramo KA, Widness JA. Increased fetal plasma and amnioticfluid erythropoietin concentrations: markers of intrauterine hyp-oxia. Neonatology. 2009;95(2):105–11636. Teramo K, Kari MA, Eronen M, Markkanen H, Hiilesmaa V.High amniotic fluid erythropoietin levels are associated with anincreased frequency of fetal and neonatal morbidity in type 1diabetic pregnancies. Diabetologia. 2004;47(10):1695–170337. Mimouni F, Miodovnik M, Siddiqi TA, Khoury J, Tsang RC.Perinatal asphyxia in infants of insulin-dependent diabetic mothers.J Pediatr. 1988;113(2):345–35338. Georgieff MK, Landon MB, Mills MM, et al. Abnormal irondistribution in infants of diabetic mothers: spectrum and maternalantecedents. J Pediatr. 1990;117(3):455–46139. Petry CD, Eaton MA, Wobken JD, Mills MM, Johnson DE,Georgieff MK. Iron deficiency of liver, heart, and brain in newborninfants of diabetic mothers. J Pediatr. 1992;121(1):109–11440. Lozoff B, Georgieff MK. Iron deficiency and brain develop-ment. Semin Pediatr Neurol. 2006;13(3):158–16541. Hay WW Jr, Meznarich HK. The effect of hyperinsulinaemiaon glucose utilization and oxidation and on oxygen consumption inthe fetal lamb. Q J Exp Physiol. 1986;71(4):689–69842. Philipps AF, Porte PJ, Stabinsky S, Rosenkrantz TS, Raye JR.Effects of chronic fetal hyperglycemia upon oxygen consumption inthe ovine uterus and conceptus. J Clin Invest. 1984;74(1):279–28643. Widness JA, Teramo KA, Clemons GK, et al. Direct relation-ship of antepartum glucose control and fetal erythropoietin inhuman type 1 (insulin-dependent) diabetic pregnancy. Diabetologia.1990;33(6):378–38344. Kjos SL, Leung A, Henry OA, Victor MR, Paul RH, MedearisAL. Antepartum surveillance in diabetic pregnancies: predictors offetal distress in labor. Am J Obstet Gynecol. 1995;173(5):1532–153945. Devoe LD, Youssef AA, Castillo RA, Croom CS. Fetalbiophysical activities in third-trimester pregnancies complicated bydiabetes mellitus. Am J Obstet Gynecol. 1994;171(2):298–303,discussion 303–30546. Tincello D, White S, Walkinshaw S. Computerised analysis offetal heart rate recordings in maternal type 1 diabetes mellitus. Br JObstet Gynaecol. 2001;108:853–85747. Wong SF, Chan FY, Cincotta RB, McIntyre DH, Stone M.Use of umbilical artery Doppler velocimetry in the monitoring ofpregnancy in women with pre-existing diabetes. Aust N Z J ObstetGynaecol. 2003;43(4):302–30648. American College of Obstetricians and Gynecologists. FetalMacrosomia. ACOG Practice Bulletin Number 22. Washington,DC: American College of Obstetricians and Gynecologists; 200049. Guideline Development Group. Management of diabetes frompreconception to the postnatal period: summary of NICE guidance.BMJ. 2008;336(7646):714–71750. Kitzmiller JL, Block JM, Brown FM, et al. Managing preexist-ing diabetes for pregnancy: summary of evidence and consensusrecommendations for care. Diabetes Care. 2008;31(5):1060–1079






NeoReviews Quiz RequirementsTo successfully complete 2014 NeoReviews articles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance level of60% or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity. If you score less than60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved. NOTE:Learners can take NeoReviews quizzes and claim credit online only at: http://neoreviews.org.

1. A mother who has history of diabetes controlled by insulin is pregnant and asks about the risk of fetalmalformations. Which of the following statements regarding risk of fetal malformation in diabetic pregnancyis correct?

A. The highest risk of a major malformation occurs when there is poor maternal glycemic control during thesecond and third trimesters.

B. The rate of malformation is two to four times higher in type 1 and type 2 pregnancies than in the generalpopulation.

C. The most common malformations in diabetic pregnancies involve the upper and lower extremities.D. The risk of malformations in gestational diabetes is equal to the risk found in type 1 and type 2 diabetes.E. Unlike typical pregnancies, folic acid should be avoided in pregnant women with type 1 diabetes, as the risk

of folic acid excess is higher than that of neural tube defects.

2. A 28-year-old woman is pregnant with her second child. Her first pregnancy resulted in a spontaneous pretermdelivery at 28 weeks’ gestational age. Her second pregnancy is complicated by diabetes. Which of the followingis true regarding her risk of preterm birth?

A. One risk of preeclampsia and diabetic nephropathy is fetal growth restriction, which may increase the riskof iatrogenic preterm birth, if there are fetal indications.

B. As her first child was born preterm, it is highly unlikely that she will have a second preterm child, as onemother having two preterm births in a row is a rare occurrence.

C. Spontaneous preterm birth is most likely to be an increased occurrence in gestational diabetes, as comparedto type 1 diabetic pregnancies.

D. If preterm birth is likely to occur, it is important to remember that glucocorticoids are contraindicated indiabetic mothers.

E. While preterm birth is an increased risk in diabetic pregnancies, late preterm birth is generally moreacceptable than non-diabetic pregnancies, as these infants tend to be larger and more mature for theirgestational age.

3. A pregnant woman with diabetes is evaluated at 35 weeks’ gestational age. Fetal growth parameters areestimated using physical examination and ultrasound. Which of the following statements regarding growth indiabetic pregnancies is correct?

A. Ultrasound estimate of fetal weight is more accurate in diabetic pregnancies than in non-diabetics due,particularly in larger fetuses more than 4,000 grams, as there is a higher ratio of solid mass to fluid.

B. Fetal hyperinsulinemia is the main cause of fetal overgrowth in diabetic pregnancies.C. The most accurate method for pregnancy dating is fetal crown-rump length at 18 to 20 weeks’ gestational

age.D. Although macrosomia is more common in type 1 diabetic pregnancies at 18% to 30%, the incidence of

small for gestational age is also increased to 10% to 25%.E. In macrosomic infants of diabetic mothers, the head size is disproportionately increased up to 30% of

normal size, compounding risk of delivery problems.

4. A 39-week-gestational-age male infant is born by spontaneous vaginal delivery to a mother who hadgestational diabetes which was diet controlled. He develops respiratory distress and an evaluation includeshematocrit which is noted to be 72% two hours after birth. Which of the following statements regarding thisclinical circumstance is correct?

A. A hematocrit at age 2 hours is more reflective of the mother’s hematocrit and should not be considered aspart of the diagnostic work-up of an infant.




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B. While polycythemia can occur in type 1 diabetic pregnancies, it is not associated with gestational diabetesand is likely to arise from a different etiology in this scenario.

C. This infant may have had some degree of chronic hypoxia and increased erythropoietin synthesis in order toincrease oxygen carrying capacity.

D. This infant’s ferritin levels are likely to be abnormally elevated.E. Erythropoietin would have been rapidly consumed by this fetus and if an amniotic fluid sample was

obtained before delivery, it is likely that erythropoietin levels in the fluid would be low or non-existent.

5. A mother presents with intermittent contractions to the clinic at 40 weeks’ gestational age. She hasgestational diabetes which has been poorly controlled, and is suspected to have risk of a macrosomic fetusbased on recent visits. Which of the following regarding her delivery course and management is correct?

A. Although her infant may be macrosomic, the risks of non-spontaneous labor induction on respiratoryoutcomes balance out risks of macrosomia, and therefore, delivery should be deferred until spontaneouslabor or induction at 41 weeks.

B. Fetal weight estimates should not have a role in decisions about mode of delivery due to their inaccuracy.C. While cesarean delivery is more common in diabetic pregnancies, they can be avoided in situations when

the infant is mildly macrosomic (>4,500–5,000 grams) with vacuum extraction or forceps assistance, withdecreased risk of shoulder dystocia.

D. Cesarean delivery is probably indicated when the estimated fetal weight is more than 4,500 grams andthere is arrest of descent of the head or a prolonged second stage of labor.

E. A key principle in the management of diabetic mothers is to disregard estimated fetal weight in thedecision to perform cesarean section due to its inaccuracy and lack of ability to predict clinicalcomplications.

Parent Resources from the AAP at HealthyChildren.org

• English: http://www.healthychildren.org/English/ages-stages/prenatal/Pages/Tests-During-Pregnancy.aspx• Spanish: http://www.healthychildren.org/spanish/ages-stages/prenatal/paginas/tests-during-pregnancy.aspx




http://www.healthychildren.org/English/ages-stages/prenatal/Pages/Tests-During-Pregnancy.aspx

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Kari TeramoDiabetic Pregnancy and Fetal Consequences

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Jane M. HawdonNeonatal Hypoglycemia: Are Evidence-based Clinical Guidelines Achievable?











Neonatal Hypoglycemia: Are Evidence-based ClinicalGuidelines Achievable?Jane M. Hawdon, MA,

MBBS, MRCP, FRCPCH,

PhD*

Author Disclosure

Dr Hawdon has

disclosed that she

speaks at and chairs

sponsored meetings

and receives honoraria

from Chiesi

Pharmaceuticals Inc.

This commentary does

not contain a discussion

of an unapproved/

investigative use of a

commercial product/

device.

Educational Gaps:

1. There is a lack of evidence to inform definitive clinical guidelines for neonatal

hypoglycemia.

2. In infants who do not have risk factors for impaired or delayed neonatal metabolic

adaptation, blood glucose levels uniformly and steadily fall and then increase for the first

3 to 4 hours after birth, allowing for establishment of feedings to lead to glucose balance.

AbstractDiffering risk factors, biological variability, and lack of high-quality research studies leadto the impossibility of “genuine evidence-based clinical guidelines” for neonatal hypo-glycemia. However, texts to date have described a pragmatic approach that, in the ab-sence of high-quality evidence, should be adopted. Understanding of normal physiologyshould also inform practice. Blood glucose levels fall in the hours after birth in all infants.For most, the normal process of neonatal metabolic adaptation initiates glucose releaseand production, as well as the mobilization of alternative fuels (eg, ketone bodies) fromstores so that the physiologic fall in blood glucose is tolerated. However, some infants areat risk of impaired neonatal metabolic adaptation in that blood glucose levels may notrise and the protective metabolic responses do not occur. For these infants, it is impor-tant to prevent hypoglycemia, to recognize clinically significant hypoglycemia, and tomanage this situation without causing unnecessary separation of mother and infantor disruption of breastfeeding. Investigations for the underlying cause of hypoglycemiashould be performed if hypoglycemia is persistent, resistant, or unexpected.

Objectives After completing this article, readers should be able to:

1. Understand the processes of metabolic adaptation at birth.

2. Appreciate that infants vary in their ability to tolerate low blood glucose levels.

3. Identify those infants at risk of impaired metabolic adaptation.

4. Understand that a single “cutoff” value for hypoglycemia cannot be defined.

5. Apply operational thresholds to the prevention and management of neonatal

hypoglycemia.

IntroductionMuch debate surrounds neonatal hypoglycemia in terms of the definition of the condition,its clinical significance, and its optimal management. This debate exists in part because thereis a continuum between the normal postnatal metabolic changes, with a physiologic fall inblood glucose after birth accompanied by protective metabolic responses, and the moreworrying situation in which there is delay or failure of the normal metabolic adaptationafter birth. Therefore, hypoglycemia cannot strictly be applied as a pathologic diagnosticterm, and it is preferable to consider a diagnosis of impaired metabolic adaptation. Invari-ably, “neonatal hypoglycemia” is used as a shorthand term for this condition.

For many decades, clinicians and scientists have been struggling to evaluate or even pro-vide an evidence base for the diagnosis and management of neonatal hypoglycemia. I joinedthese ranks in 1989 when I commenced a research project to investigate the processes of

*Consultant Neonatologist, Clinical Academic Group Director, Women’s and Children’s Health, Barts Health NHS Trust, London,

United Kingdom.

Article endocrinology





metabolic adaptation after birth. One aspect of the proj-ect was to investigate the endocrine and metabolic re-sponses to neonatal hypoglycemia, which are describedin the following sections.

Looking back, the case selection for the project was be-low the standard that would be required for high-qualityresearch. The study sample size was larger than it shouldhave been as the diagnostic cutoff of 2.6 mmol/L (47mg/dL) had found its way into use (discussed later in de-tail). Many infants on my arrival seemed surprisingly welland were physically resisting all efforts to insert nasogastrictubes and intravenous cannulae, and their condition was inpart explained by laboratory measurements that did notconfirm the diagnosis of hypoglycemia according to initialreagent strip findings. Other study infants were admittedto the neonatal unit for another reason and had a bloodglucose measurement very shortly after birth or at the timeof the universal nadir. Based on this single measurement,infants were labeled as hypoglycemic, while if left to theirown devices or with routine NICU care, their blood glu-cose levels would have subsequently risen.

As the study elapsed and after discussion with experts(including Marvin Cornblath [now deceased]), it becameevident thatmany of these infants did not have a pathologiccondition. Rather, they were simply doing what infants doin the process of adaptation after birth: mounting a meta-bolic response to a physiologic fall in blood glucose level.

Marvin and I discussed the flood of litigation that thediagnosis of hypoglycemia had unleashed, and this occur-rence has been well recognized in the United States andUnited Kingdom. Marvin summed this up in a lecture atHot Topics in Neonatology (Washington, DC, 2000), stat-ing that we had become human litogens (a litogen havingpreviously been described as “a drug that does not causemalformations but does cause lawsuits”). We enjoyed manycontinued years of discussion and when he knew he was dy-ing, he said to Dr Tony Williams and me: “you seem tohave common sense, I pass the baton to you.”

Neonatal Metabolic AdaptationIt is important to keep in mind what is known about nor-mal physiology and neonatal metabolic adaptation (Table 1).During pregnancy, the human fetus receives from itsmother, via the placental circulation, a supply of sub-strates necessary for growth, for the deposition of fuelstores that are essential after birth, and for energy to meetthe basal metabolic rate and requirements for growth.When the continuous flow of nutrients from the placentais abruptly discontinued at birth, immediate postnatalmetabolic changes preserve fuel supplies for vital organfunction. The newborn infant must adapt to the fast-feed

cycle and to the change in major energy source, from glu-cose transfer across the placenta to fat released from ad-ipose tissue stores and ingested with milk feedings. Afterbirth, plasma insulin levels fall, and there are rapid surgesof catecholamine and pancreatic glucagon release. Theseendocrine changes switch on the essential enzymes forglycogenolysis (the release of glucose stored as glycogenin liver, cardiac muscle, and brain), gluconeogenesis (glu-cose production from three-carbon precursor moleculesby the liver), lipolysis (release of fatty acids from adiposetissue stores), and ketogenesis (the b-oxidation of fattyacids by the liver to produce ketone bodies). Some tissues(eg, the kidney) are obligate glucose users, but others burnfatty fuels to provide energy. Of the organs that use fuelsalternative to glucose, it is most significant that the neona-tal brain takes up and oxidizes ketone bodies at higherrates than seen in adults and uses ketone bodies more ef-ficiently than glucose. Lactate has also been identified as analternative fuel. In each group of infants studied, after cor-recting for blood glucose level, ketone body levels werelower for bottle-fed infants than for breastfed infants.

To translate these findings into clinical practice:

• Low blood glucose concentrations are commonly foundduring the first postnatal days in healthy, normally grown,term neonates, particularly those who are breastfed.

• These infants have high ketone body levels when bloodglucose concentrations are low, and it is likely that thesealternative fuels protect them from neurologic injury.

• Formula feeding is associated with lower ketone bodylevels compared with levels in breastfed infants.

Impaired or Delayed Metabolic AdaptationCertain groups of infants are at risk of a more profound orprolonged fall in blood glucose, or more importantly,a failure to mount the normal metabolic responses to thisfall. At-risk groups include infants who have hyperinsulin-ism (eg, after poor control of maternal diabetes in preg-nancy), those who have intrauterine growth restriction,

Table 1. Endocrine and MetabolicChanges of Neonatal MetabolicAdaptation

Hormonal Metabolic

YInsulin Glycogenolysis[Glucagon Gluconeogenesis[Catecholamines Lipolysis/free fatty acids[Cortisol Ketogenesis

endocrinology neonatal hypoglycemia





preterm infants, and those who have other pathologicconditions such as infection or inborn errors of metabo-lism. Untreated, the low blood glucose levels in the ab-sence of fuels alternative to glucose will cause clinicalsigns and, in the extreme case, brain injury.

Clinical Significance of Impaired or DelayedMetabolic AdaptationNo study has yet satisfactorily addressed the duration ofabsent or reduced availability of metabolic fuels that isharmful to the human neonate. Animal studies indicatethat hours (rather than minutes) of hypoglycemia are re-quired to cause injury and that injury is unlikely to occurif abnormal clinical signs are absent. For infants in whomprolonged neonatal hypoglycemia has been associatedwith abnormal clinical signs (most usually hypotonia, re-duced level of consciousness, or seizures), adverse long-term outcomes have been reported. There is evidencefrom case reports that profound and prolonged hypogly-cemia is associated with both transient and permanentstructural changes in the brain, especially if seizures oc-cur. Grey matter damage is most commonly reported,with the parieto-occipital regions being most affected.

Clinical experience and data from studies and case reportsindicate that when neonatal hypoglycemia results in clinicalsigns or brain injury, the temporal evolution is as follows:

• Low blood glucose levels are found, but the infantdoes not have clinical signs because he or she is stillable to draw on alternative fuel stores (eg, glycogenand fat). This condition could be termed biochemicalhypoglycemia with adequate metabolic adaptation.

• If untreated, the infant exhausts alternative fuel storesand develops subtle clinical signs that are not specificto hypoglycemia (eg, irritability, lethargy, poor feed-ing), but hypoglycemia is not damaging at this stage.This state is the onset of impaired metabolic adaptation.

• If untreated, the infant develops obvious and severeclinical signs (eg, seizures, coma) but may escape dam-age if treated promptly. Metabolic adaptation has failed.

• If not treated sufficiently soon after the onset of thesesevere clinical signs, hypoglycemia becomes damagingand in severe cases results in cardiorespiratory arrest.

The time period for this process will be highly variable.For example, with severe hyperinsulinism, metabolic ad-aptation is completely suppressed, and the infant is ex-tremely vulnerable to a sustained postnatal fall in bloodglucose. For the moderately preterm infant who doesnot attain sufficient milk intake, the process (if left unman-aged) will be more gradual as the infant’s reduced fat

stores become exhausted. Therefore, the duration oflow blood glucose cannot be woven into the definition.

“Evidence-based” Clinical DiagnosisThe challenge is to arrive at a diagnostic definition of sig-nificant hypoglycemia, taking into account that the levelsof fuels alternative to glucose cannot easily be measuredin clinical practice. The process of diagnosis must firstidentify those infants at risk of failure or delay in meta-bolic adaptation and then monitor blood glucose levelsand clinical signs. Alternatively, for an infant not previ-ously thought to be at risk but who presents with anyconcerning clinical signs, there must be prompt and ac-curate blood glucose measurements.

There have been swings in opinion and controversy overthe years regarding the numerical definition of neonatal hy-poglycemia. This debate arises from the clinical scientificworld setting itself an unrealistic task in an area that containsso many variables. Attempts to arrive at a single definition,usually to 1 decimal place in the context of devices that can-not measure accurately to –0.5 mmol/L (–9 mg/dL) andfailing to take into account biological variability, have no ra-tional basis.Of concernwas thewidespread adoptionof a sin-gle numerical value based on two published papers (whoseresults are now generally considered not to justify their con-clusions) that a level of less than 2.6mmol/L (<47mg/dL)should be used to define neonatal hypoglycemia.

As described earlier, this numerical definition gener-ally leads to overdiagnosis and treatment but, more wor-risome, measurement with inaccurate devices could givefalse reassurance regarding infants for whom a recordedlevel of 2.6 mmol/L is too low should metabolic adapta-tion fail. Despite widespread knowledge of the concernregarding inaccuracy of near-patient testing devices inboth the United Kingdom and the United States, theuse of these devices remains prevalent.

Any attempt to arrive at an evidence-based definitionof hypoglycemia should include consideration of:

• The blood glucose concentration considered to be theminimum safe level.

• The duration beyond which the low blood glucoselevel is considered to be harmful.

• The presence of clinical signs.• The group of infants studied.• The consideration of alternative fuel availability.• The conditions of sampling and the assay methods.

These factors have not been adequately addressed inscientific studies, and it is unlikely that they will be inthe future. Therefore, a pragmatic approach based on






thresholds for intervention was proposed in 2000 bya group of interested clinicians from the United Kingdomand the United States:

• If there are neurologic signs in association with bloodglucose levels less than 2.5 mmol/L (<45.0 mg/dL),there should be an urgent investigation to identify anunderlying cause and institution of treatment.

• For infants who have no clinical signs but are at risk ofimpaired metabolic adaptation (ie, hyperinsulinism, in-trauterine growth restriction, prematurity, infection,inborn error of metabolism), intervention to raisethe infant’s blood glucose level should be institutedif two consecutive blood glucose levels are less than2 mmol/L (<36 mg/dL), measured by using an accu-rate device, or a single blood glucose level is less than 1mmol/L (<18 mg/dL).

The paper by the group from the United Kingdomand the United States sets higher therapeutic goals thanthe blood glucose levels for intervention, especially for in-fants thought to have significant hyperinsulinism.

Groups of experts since 2000 have reviewed the evidencebase in light of more recent publications and have presentedno arguments to move from this pragmatic consensus.

Prevention and Management of NeonatalHypoglycemiaIt is important to prevent potentially damaging hypogly-cemia in vulnerable infants, but this goal must be bal-anced against the risks of overly invasive management:separation of mother and infant, placing at risk the estab-lishment of breastfeeding, and unnecessary administra-tion of formula or intravenous glucose, which in turnimpairs metabolic adaptation to postnatal life.

There is a sufficient evidence base that healthy, normallygrown, term neonates often have low blood glucose concen-trations in the first postnatal days but are protected by thepresence of ketone bodies and lactate as alternative fuels.These infants do not need routine blood glucosemonitoringor formula supplementation of breastfeedings. However,staff should be alert to systemic conditions (eg, neonatal in-fection) that may affect feeding and the risk of neonatal hy-poglycemia, as well as the very rare risk that an infant who isapparently healthy at birth may have an underlying meta-bolic disorder. Appropriate investigations, including a bloodglucose measurement, should be performed for any infantwho presents with abnormal clinical signs.

Similarly, there is sufficient evidence base from clinicalexperience and published studies to advise managementof infants at risk of impaired metabolic adaptation.

• At-risk infants should have regular clinical monitoringto include feeding behavior and prefeeding blood glu-cose monitoring (approximately every 4 hours).

• Blood glucose monitoring should commence beforethe second feeding (ie, not so soon after birth thatthe physiologic fall in blood glucose level causes con-fusion and overtreatment), and prefeeding monitoringshould be continued until the infant has had at leasttwo satisfactory measurements.

• Monitoring should be recommenced if the infant’sclinical condition worsens or energy intake decreases.If monitoring is performed by using reagent strips,low levels must be confirmed promptly by accuratemeasurement.

The importance of early milk feeding has been appre-ciated for many years and more recently the recognitionof provision of important gluconeogenic precursors andfatty acids for b-oxidation. Therefore, all infants whoare expected to tolerate enteral feedings should be fedwith milk as soon as possible after birth and then at fre-quent intervals thereafter. Infants who are capable ofsucking should be offered the breast at each feeding (ifthis is the mother’s wish). If it is likely that infants willneed supplementary formula feedings, maternal humanmilk expression should be encouraged. The requirementfor formula feedings must be titrated against the clinicalcondition of the infant, blood glucose monitoring, andthe supply of maternal human milk. In the breastfed in-fant, formula intake should be kept to the minimum nec-essary, with the goal of enhancing breastfeeding andavoiding suppression of normal metabolic adaptation.

A recent high-quality, randomized, double-blind,placebo-controlled intervention study by Harris et aldemonstrated that at-risk infants who develop hypoglyce-mia benefit from buccal dextrose gel in terms of avoidingadditional treatments and supporting breastfeeding.

In the at-risk infant who is establishing oral feedings, thereis a potential nadir at which body stores are steadily reducingbut milk feedings have not yet started to replenish thesestores. For this reason, vulnerable infants should not be trans-ferred to the community at less than age 48 hours and onlywhen experienced staff are satisfied that feeding is effective.

If an infant requires intravenous glucose, usually 10%dextrose at 3 mL/kg/h (5 mg glucose/kg/min) is suf-ficient to prevent or reverse hypoglycemia. If fluid restric-tion is required, a central line should be inserted for infusionof more concentrated dextrose solutions. Boluses of con-centrated glucose solution should be avoided because ofthe risk of rebound hypoglycemia and cerebral edema. Ifboluses are required (eg, if there are neurologic signs of






hypoglycemia), they should be of 10% dextrose (3–5 mL/kg), given slowly, and always followed by an infusion. Allreductions in infusion rate should be gradual, and any in-terruption of infusion should be promptly remedied.

There are a number of additional specific treatmentsfor specific causes of neonatal hypoglycemia (eg, neonatalhyperinsulinism). These are covered in standard texts.

ConclusionsIf “neonatal hypoglycemia” is to continue in use asa shorthand diagnostic term, it should be accurately de-fined as “a persistently low blood glucose level, measuredwith an accurate device, in an infant at risk of impairedmetabolic adaptation but with no abnormal clinical signs;or a single low blood glucose level in an infant presentingwith abnormal clinical signs.” There has been no recentevidence to argue against the pragmatic operationalthreshold values described in 2000.

The impact of hypoglycemia and its treatment on themother and infant must be considered. The early neona-tal period is an emotionally sensitive time, and the diag-nosis of hypoglycemia may create or increase anxiety forthe parents. Treatment of the infant with intravenousglucose involves separation of the infant and mother,with a negative impact on breastfeeding, and may be per-ceived as invasive or painful. Because formula supplemen-tation also disrupts breastfeeding and has a negative effecton normal neonatal metabolic adaptation, it should beavoided unless there is a clear clinical indication. Empha-sis should be on the early prevention of hypoglycemia andstrategies of management that do not involve the separa-tion of mother and infant.

We are trained as clinicians to make assessments anddecisions to avoid harm arising from the underlying con-dition but also to avoid iatrogenic harm, such as the ef-fects of separation of mother and infant. Attempting toapply “evidence-based” numerical definitions of hypogly-cemia and algorithms for management cannot replacethese clinical skills (Table 2).

Suggested ReadingAuer RN, Siesjö BK. Hypoglycaemia: brain neurochemistry and

neuropathology. Baillieres Clin Endocrinol Metab. 1993;7(3):611–625

Boluyt N, van Kempen A, Offringa M. Neurodevelopment afterneonatal hypoglycaemia: a systematic review and design ofoptimal future study. Pediatrics. 2006;117(6):2231–2243

Cornblath M, Hawdon JM, Williams AF, et al. Controversiesregarding definition of neonatal hypoglycemia: suggested oper-ational thresholds. Pediatrics. 2000;105(5):1141–1145

de Rooy LJ, Hawdon JM. Nutritional factors that affect thepostnatal metabolic adaptation of full-term small- and large-for-gestational-age infants. Pediatrics. 2002;109(3):E42

Eidelman AI. Hypoglycemia and the breastfed neonate. PediatrClin North Am. 2001;48(2):377–387

Harris DL, Weston PJ, Signal M, Chase JG, Harding JE. Dextrose gelfor neonatal hypoglycaemia (the Sugar Babies Study): a rando-mised, double-blind, placebo-controlled trial [published onlineahead of print September 24, 2013]. Lancet. doi:10.1016/S0140-6736(13)61645-1

Hawdon JM. Disorders of metabolic homeostasis in the neonate. In:Rennie JM, ed. Textbook of Neonatology. 5th edition. EdinburghUK: Churchill Livingstone;2012:850–867

Hawdon JM. Neonatal complications after diabetes in pregnancy.In: Rennie JM, ed. Textbook of Neonatology. 5th edition.Edinburgh UK: Churchill Livingstone;2012:387–394

Hawdon JM, Aynsley-Green A, Bartlett K, Ward Platt MP. Therole of pancreatic insulin secretion in neonatal glucoregulation.II. Infants with disordered blood glucose homoeostasis. ArchDis Child. 1993;68(3 spec no):280–285

Hawdon JM, Ward Platt MP, Aynsley-Green A. Patterns ofmetabolic adaptation for preterm and term infants in thefirst neonatal week. Arch Dis Child. 1992;67(4 spec no):357–365

Hay WW Jr, Raju TN, Higgins RD, Kalhan SC, Devaskar SU.Knowledge gaps and research needs for understanding andtreating neonatal hypoglycemia: workshop report from EuniceKennedy Shriver National Institute of Child Helath and HumanDevelopment. J Pediatr. 2009;155(5):612–617

Medical Devices Agency. Extra-laboratory use of blood glucose metersand test strips: contraindications, training and advice to the users.Safety Notice MDA SN 9616, 1996. Available at: www.mhra.gov.uk/home/groups/dts-bi/documents/publication/con007332.pdf.Accessed December 30, 2013

Table 2. Factors to Identify andDocument

• Risk factors• Coexisting conditions• Clinical signs/normality• Accurate blood glucose measurements• Response to treatment

American Board of Pediatrics Neonatal–PerinatalContent Specifications

• Know the fuels used for brain metabolism.• Know the causes (including

hyperinsulinemic hypoglycemia) ofneonatal hypoglycemia syndromes.

• Recognize the clinical and laboratoryfeatures of neonatal hypoglycemia.

• Recognize the approach to therapy and prevention ofneonatal hypoglycemia.

• Know the potential sequelae of neonatal hypoglycemia.




http://www.mhra.gov.uk/home/groups/dts-bi/documents/publication/con007332.pdf

http://www.mhra.gov.uk/home/groups/dts-bi/documents/publication/con007332.pdf



Rozance PJ, Hay WW. Hypoglycemia in newborn infants: featuresassociated with adverse outcomes. Biol Neonate. 2006;90(2):74–86

SrinivasanG, Pildes RS, Cattamanchi G, Voora S, Lilien LD. Plasma glucosevalues in normal neonates: a new look. J Pediatr. 1986;109(1):114–117

Vannucci RC, Vannucci SJ. Hypoglycemic brain injury. SeminNeonatol. 2001;6(2):147–155

Williams AF. Neonatal hypoglycaemia: clinical and legal aspects.Semin Fetal Neonatal Med. 2005;10(4):363–368


• English only: http://www.healthychildren.org/English/health-issues/conditions/chronic/Pages/Causes-of-High-

Blood-Glucose-and-Low-Blood-Glucose.aspx




http://www.healthychildren.org/English/health-issues/conditions/chronic/Pages/Causes-of-High-Blood-Glucose-and-Low-Blood-Glucose.aspx

http://www.healthychildren.org/English/health-issues/conditions/chronic/Pages/Causes-of-High-Blood-Glucose-and-Low-Blood-Glucose.aspx



NeoReviews Quiz RequirementsTo successfully complete 2014 NeoReviews articles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance level of60% or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity. If you score less than60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved. NOTE:Learners can take NeoReviews quizzes and claim credit online only at: http://neoreviews.org.

1. You are called to evaluate a newborn female infant who was born at 39-weeks’ gestational age and is now 30minutes old. Although the reason for the test is unclear, a bedside reagent strip test has been completed andresults indicate a blood glucose level of 50 mg/dL. The infant is crying vigorously and otherwise appears well.Which of the following statements regarding glucose testing and metabolic changes occurring in this infant iscorrect?

A. In infants who do not have diabetes or hyperinsulinemic states, blood glucose levels increase uniformly andsteadily for the first 2 to 4 hours after birth, allowing for establishment of feedings and eventual glucosebalance.

B. Although the infant appears well, the glucose level noted is low for this age, and this finding aloneindicates a high likelihood of potential brain injury.

C. This low level is due largely to the normal rapid and large neonatal insulin release that occurs shortly afterbirth until w6 hours of age, along with a simultaneous decrease in catecholamine release.

D. During the time after birth, enzymes for glycogenolysis and ketogenesis will be “switching on” to facilitateglucose release and production of ketone bodies, respectively.

E. This patient’s liver function should be watched closely, as the liver is an obligate glucose user, whereasorgans such as the kidneys and brain burn fatty fuels for energy.

2. You are told that a newborn infant has been followed up with several glucose tests for hypoglycemia due tosymptoms of jitteriness. You are reviewing the medical record for possible risk factors. Which of the followingstatements regarding metabolic risk factors is correct?

A. The most common cause of persistent hypoglycemia in the newborn period is remnants of maternallyinjected insulin for diabetes that have crossed the placenta.

B. Although preterm birth is associated with poor growth, hypoglycemia is very rare in the first several hoursafter birth because there are sufficient mechanisms for maternal transfer and neonatal adaptation.

C. Infants with intrauterine growth restriction are at risk for a longer and deeper fall in glucose, as well asdecreased ability to achieve an adequate metabolic response to hypoglycemia.

D. One of the main challenges a newborn infant faces is that the neonatal brain is unable to use alternativefuels such as ketones and lactate and, therefore, even a short period of low glucose levels can lead to long-term brain injury.

E. Serum glucose levels can be misleading after birth because there is a rapid increase in gluconeogenesis inthe first 6 hours, leading to decreased glucose levels in the serum but sufficient energy substrates in vitalorgans.

3. You are reviewing a case of an infant who is now 5 years old who has developmental delays that wereappreciated starting at age 6 months. He has a history of brain injury that may have been caused by neonatalhypoglycemia. Which of the following statements most accurately describes a step in the pathway that mayhave led to this injury?

A. During the neonatal period, it is unlikely that there were any clinical symptoms; severe hypoglycemic injurythat leads to long-term adverse outcomes generally does not manifest until school-age.

B. The initial noticeable symptoms of hypoglycemia that may indicate exhaustion of alternative fuel storesare often nonspecific, such as irritability, lethargy, or poor feeding.

C. The time course of hypoglycemia leading to permanent brain injury is fairly consistent across gestationalage and predisposing factors such as maternal diabetes, hyperinsulinism, growth restriction, or infection.

D. The infant who is formula feeding is more likely to have increased ketone bodies compared withbreastfeeding infants and is therefore more likely to have brain injury compounded by ketotic coma.

E. When a low blood glucose level is found in the first 1 to 2 hours, but the infant does not have any clinicalsigns or symptoms, the bulk of the brain injury is likely to have already occurred.




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4. A healthy term infant in was noted to have poor feeding and lethargy at age 24 hours, and a glucose level waschecked and found to be 35 mg/dL. Results of a repeat test after 30 minutes show a level of 34 mg/dL. Whichof the following is true regarding this clinical scenario?

A. Because the patient has been well until this fairly late time after delivery, these levels are highly unlikely,and a repeat level should be obtained after 3 hours with a new instrument, while testing for otheretiologies of symptoms is considered.

B. Although the evidence is still accumulating regarding an absolute number to define hypoglycemia, it isfairly clear that 2.5 mmol/L (45 mg/dL) is a safe level in all circumstances to provide reassurance even inthe context of any clinical symptom.

C. At this stage of the clinical course, the patient probably still has sufficient and adequate stores of glycogenand fat to use for energy.

D. Because there are no evidence-based studies to show any benefit of interventions for hypoglycemia, themain utility of these tests is not to guide any intervention but to provide reassurance that there is no othercause of the symptoms, which in this case would be the difficulty feeding.

E. In this scenario, it would be reasonable to investigate the etiology of the hypoglycemia and to institutetreatment to increase glucose levels.

5. You are on a committee that is developing procedural policies for your maternal–infant care unit. Which of thefollowing steps to prevent and treat neonatal hypoglycemia is most appropriate to consider including in yourpolicy?

A. Any infant who presents with abnormal clinical signs, such as lethargy, should undergo blood glucosemeasurement, with other relevant testing based on symptoms.

B. Due to the inherent risk of transitioning from placental to intermittent, sporadic feedings, all newbornsshould have at least 1 glucose check within the first 24 hours after delivery.

C. For infants who require intravenous glucose, the minimum dose of initiating therapy should be 6 mL/kg/h(10 mg glucose/kg/min), with increases as needed based on response.

D. The standard feeding regimen for term infants of diabetic mothers should include formulasupplementation starting with the second feeding and continuing until 48 hours, after which formula canbe weaned off if breastfeeding has been well established.

E. For infants who are small for gestational age, blood glucose levels should be checked at 30 minutes, 1 hour,and 90 minutes, and if greater than 50 mg/dL at those time points, the infant can be transferred to regularnewborn care.







Jane M. HawdonNeonatal Hypoglycemia: Are Evidence-based Clinical Guidelines Achievable?














The reader is encouraged to writepossible diagnoses for each casebefore turning to the discussion.We invite readers to contributecase presentations and discussions.Please inquire first by contactingDr. Philip at [email protected].

Author Disclosure

Drs Sharma, Murki, Tejopratap,

Madhavi, Vesoulis, and Vachharajani

have disclosed no financial

relationships relevant to this article.

This commentary does contain

discussion of unapproved/

investigative use of a commercial

product/device.

Case 1: Persistent Severe Metabolic Acidosis ina Newborn

Case 2: Late Preterm Infant With a Difficult Intubation

Case 1 PresentationA female preterm infant was born at28-weeks’ gestation to a G3P2A1mother (third degree consanguineousmarriage) by emergency cesareandelivery due to severe fetal growthrestriction, oligohydramnios, and in-creasing liver transaminase levels inthe mother. First conception was mis-carriage at 12-weeks’ gestation. Thesecond conception was intrauterinefetal demise at 30-weeks’ gestation;the pregnancy was complicated withacute fatty liver of pregnancy (AFLP)and acute kidney injury. Placentashowed massive perivillous fibrin de-position. Present pregnancy was spon-taneously conceived. Pre-pregnancy,mother was diagnosed as hypothyroidand was started on thyroxine. She hadalso been started on aspirin since thelast pregnancy and had receiveda complete course of antenatal ste-roids at 27-weeks’ gestation. Bloodpressure of the mother at the timeof admission was 140/90 mmHg.This pregnancy was also complicatedwith AFLP, with serum glutamic-pyruvic transaminase levels of 586U/L and lactate dehydrogenase levelsof 863 U/L. The infant at birthweighed 960 g, required resuscitationwith bag and mask for 30 seconds,and had Apgar scores of 5 and 7 at1 minute and 5 minutes, respectively.Immediately after resuscitation, theinfant was noted to have respiratorydistress (Silverman-Andersen score of8 of 10). In view of this distress, theinfant was shifted to the NICU ona T-piece resuscitator and was startedon continuous positive airway pres-sure at 15 minutes of age with a posi-tive end-expiratory pressure of 5 cmand fraction of inspired oxygen of

0.50. Chest radiograph revealed surfac-tant deficiency. Surfactant (INSURE[intubation, surfactant administration,and extubation]) was given at 2 and6 hours after birth in view of persis-tent respiratory distress and increasedfraction of inspired oxygen require-ment, respectively. She also had poorcirculation, was off-color, and had in-creased capillary perfusion startingfrom 2 hours after birth. This shockwas initially managed with a fluid bo-lus, then with increasing inotropic sup-port of dopamine and dobutamine.Blood gas analysis revealed persistentmetabolic acidosis (Table 1), whichdid not respond to fluids, inotropes,packed cell transfusion, ventilation, so-dium bicarbonate infusion, or (lastly)exchange transfusion. The infant wasstarted on mechanical ventilation at 6hours after birth and then on high-frequency oscillation for persistent re-spiratory distress, shock, and metabolic/respiratory acidosis.

Over the first 4 days after birth, theinfant had progressive illness com-plicated with shock, patent ductusarteriosus, renal failure, seizures, andpersistent metabolic acidosis. The in-fant experienced multiorgan dysfunc-tion and died 87 hours after birth.Investigations revealed the following:total WBC counts (2 hours), 25,300/mm3; platelets (2 hours), 2.6 lakh/mm3; C-reactive protein (22 hours),0.6 mg/dL; blood sugar levels (2hours), 54 to 146 mg/dL; hematocrit(2 hours), 41.3% to 28.4% (10 hours);blood urea (31 hours), 121 mg/dL;creatinine (31 hours), 1.8 to 2.3 (58hours) mg/dL; potassium (6 hours),5.9 to 8.5 (74 hours) mEq/L; am-monia (21 hours), 120.1 mm/dL; se-rum lactate (67 hours), 15.8 mmol/L;

index of suspicion in the nursery


mailto:[email protected].

and CSF lactate (70 hours), 16.1mEq/L. Ultrasound of the kidneysand urine ketone levels were normal.Cranial ultrasonography at 76 hoursafter birth revealed bilateral grade IIintraventricular hemorrhage. Resultsof blood cultures were sterile. Reportsof one investigation performed duringthe illness confirmed the diagnosis.

Case 2 PresentationA late preterm infant presents with se-vere stridor and respiratory distress atbirth. He was born to a 25-year-oldG1P1 mother via cesarean delivery dueto recurrent fetal decelerations and se-vere preeclampsia. Maternal historywas significant for severe preeclampsia(requiring treatment with magnesiumsulfate, labetalol, and hydralazine), aswell as insulin-dependent diabetes melli-tus, polyhydramnios, and depression.

The infant is noted to have gaspingbreaths at the time of delivery. By thetime he is brought to the warming ta-ble, he has developed severe retrac-tions and stridor. Positive pressureventilation is initiated although theheart rate remains greater than 100beats per minute. Multiple attemptsat intubation by the neonatology fel-low and attending as well as the anes-thesiology attending are unsuccessful.Although the vocal cords are easily vi-sualized by direct laryngoscopy, it is

not possible to pass an endotrachealtube through the opening.

Ultimately, the endotracheal tubeis held at the level of the cords, posi-tive pressure ventilation is continued,and the infant is rushed to the NICUfor further care.

Case 1 DiscussionPersistent metabolic acidosis in a pre-term extremely low birth weight infantcould occur due to shock, hypoxia,anemia, increased work of breathing,sepsis, and inborn errors of metabo-lism. In the index child, when all mea-sures to improve acidosis failed, astrong possibility of inborn error ofmetabolism was considered. Becausethe anion gap was increased and lac-tate levels were high, primary lactic ac-idosis was the first possibility. NormalCSF lactate levels negated this diagno-sis. Newborn screening was also nega-tive for organic acids. Persistentmetabolicacidosis, increased anion gap, andnegative urine ketones lead us to theclinical possibility of fatty acid oxida-tion defect. History of AFLP in themother, hyperammonemia, normalCSF lactate, absent urine organicacids, and acylcarnitine profile con-firmed the diagnosis of long-chain3-hydroxyacyl-coenzyme A dehy-drogenase (LCHAD) deficiency.The acylcarnitine profile revealed

a marked elevation of hydroxyhex-adecanoylcarnitine (C16OH), 2.94(0.02–0.11mmol/L); elevated hydroxy-tetradecenoylcarnitine (C14OH), 0.30(0.02–0.11mmol/L); elevated hydroxy-hexadecenoylcarnitine (C16:1OH), 0.51(0.04–0.16mmol/L);elevatedhydroxy-octadecenoylcarnitine (C18:1OH),0.30 (0.02–0.10 mmol/L); and markedelevation of the related LCHAD ra-tio, 13.5 (0.23–0.79), consistent withdiagnosis of fatty acid oxidation defect(LCHAD deficiency). There are threedifferent forms of presentation: (1) thesevere neonatal type, which is univer-sally fatal with cardiac involvement;(2) the infancy onset hepatic form;and (3) a milder, late onset with a neu-romyopathic phenotype. The age ofonset varies from neonate to severalyears of age, with amean age at presen-tation of 5.8 months. Fifteen percentof cases may present in the neonatal pe-riod. (1) In the indexed case, the infanthad the severe neonatal form, whichled to her having a turbulent coursein the nursery with refractory shockthat did not respond to high doses ofinotropes, steroids, and she died ofmultiorgan dysfunction, including re-nal failure and pulmonary hemorrhage.

The ConditionVery long-chain acyl-coenzyme A de-hydrogenase deficiency (VLCAD de-ficiency) is a condition that prevents

Table 1. Blood Gas Analysis With Anion Gap With Respect to HoursAfter Birth

Hours 6 10 17 22 30 36 51 62 70 74

pH 7.006 7.061 7.107 7.17 6.962 7.014 7.00 7.23 7.121 7.106PCO2, mm Hg 66.3 47.1 32.4 41.5 59.8 28.3 84.5 21.3 39 40.1PO2, mm Hg 43 50 58 48 50 60 67 73 71 49Base excess(BE) –15 –17 –19 –13 –18 –24 –10 –18 –16 –17HCO3, mEq/L 16.6 13.3 10.2 15.2 13.5 7.2 20.9 9.1 12.9 12.6NaD, mEq/L 137 136 140 139 138 143 140 154KD, mEq/L 5.9 6.1 5.7 6.5 6.3 5.9 6.8 8.5Cl–, mEq/L 105 102 110Anion gap 20.5 28.9 31.4



the body from converting certain fatsto energy, particularly during periodswithout food (fasting). VLCAD defi-ciency is estimated to affect 1 in 40,000to 120,000 people. This conditionis inherited in an autosomal recessivepattern (2p23.3), which means bothcopies of the gene in each cell havemutations. The parents of an individ-ual who has an autosomal recessivecondition each carry one copy ofthe mutated gene, but they typicallydo not show signs and symptomsof the condition. VLCAD deficiencywas first discovered in 1992, andclinical experience with VLCAD defi-ciency has been accumulating rapidly.(2)(3) LCHAD is one of three en-zymatic activities that comprise thetrifunctional protein of the inner mi-tochondrial membrane. Patients whohave LCHADdeficiency activity usuallypresent at a median age of 6 months. Aminority of patients (up to 15%) maypresent during the neonatal period.LCHAD deficiency in a fetus predis-poses the mother to the gestationalcomplications HELLP syndrome (he-molysis, elevated liver enzymes, lowplatelet count) and AFLP. Patientsusually present with hypoketotic hy-poglycemia, cardiomyopathy, hypo-tonia, and hepatomegaly. Thesemetabolic crises occur more fre-quently in infancy and early child-hood. Some patients present withperipheral sensorimotor polyneurop-athy, myoglobinuria, and progressivevisual loss. Rarely, affected infantscan present with acute cholestasisjaundice or massive total hepatic ne-crosis in infancy. (1) A molecular de-fect that affects the mitochondrialtrifunctional protein causes LCHADdeficiency activity. In LCHAD defi-ciency, most of the patients are ho-mozygous for a guanine to cytosinetransversion at position 1528, involv-ing the alpha subunit of the mitochon-drial trifunctional protein in the activesite domain of the LCHAD activity

encoding region.Diagnosis of LCHADdeficiency is suggested by demonstrat-ing increased secretion of 3-hydroxydi-carboxylic acids in urine by using gaschromatography–mass spectrometryor by demonstrating accumulation of3-hydroxyacyl-carnitines as measuredby using tandem-mass spectrometryin plasma. (4) Confirmation of thediagnosis is possible by measuringLCHAD activity in lymphocytes, fibro-blasts, muscle or liver biopsies, (5) andaccording to mutational analysis. In themajority of LCHAD-deficient patients,at least one allele carries this point mu-tation (1528 G>C ). (6) The manage-ment of affected patients is directed atthe avoidance of fasting. Most patientsare provided with uncooked cornstarchand medium-chain triglyceride oil sup-plementation to further decrease expo-sure to fasting. Oral supplementationwith docosahexaenoic acid ethyl estermay be considered to improve visualfunction. Carnitine supplementation isgiven if there is hypocarnitinemia, andit is avoided during acute episodes be-cause there is a risk of arrhythmias. (7)

Lessons for the Clinician

1. Inborn errors of metabolism mustbe considered in all newborns pre-senting with persistent metabolicacidosis.

2. Persistent metabolic acidosis withincreased anion gap, negative urineketones along with maternal acutefatty liver of pregnancy or maternalHELLP syndrome (hemolysis, ele-vated liver enzymes, low plateletcount) suggest the possibility offatty acid oxidation defects.

(Deepak Sharma,MD, DNBNeonatol-ogy (Student), Srinivas Murki, MD,DM Neonatology, Oleti Tejopratap, MD,DM Neonatology, Vasikarla Madhavi,MD, Fellowship in Fetal Genetics,Fernandez Hospital, Hyderabad, AndhraPradesh, India)

References1. den Boer ME, Wanders RJ, Morris AA,IJlst L, Heymans HS, Wijburg FA. Long-chain 3-hydroxyacyl-CoA dehydrogenasedeficiency: clinical presentation and follow-up of 50 patients. Pediatrics. 2002;109(1):99–1042. Aoyama T, Souri M, Ushikubo S, et al.Purification of human very-long-chain acyl-coenzyme A dehydrogenase and character-ization of its deficiency in seven patients.J Clin Invest. 1995;95(6):2465–24733. Mathur A, Sims HF, Gopalakrishnan D,Gibson B, Rinaldo P, Vockley J, et al.Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiencycausing pediatric cardiomyopathy and suddendeath. Circulation. 1999;99(10):1337–13434. Millington DS, Terada N, Chace DH,et al. The role of tandem mass spectrometryin the diagnosis of fatty acid oxidation disor-ders. Prog Clin Biol Res. 1992;375:339–3545. Wanders RJ, IJlst L, Poggi F, et al.Human trifunctional protein deficiency:a new disorder of mitochondrial fatty acidbeta-oxidation. Biochem Biophys Res Com-mun. 1992;188(3):1139–11456. IJlst L, Ruiter JP, Hoovers JM, JakobsME, Wanders RJ. Common missensemutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase defi-ciency. Characterization and expressionof the mutant protein, mutation analysison genomic DNA and chromosomal lo-calization of the mitochondrial trifunc-tional protein alpha subunit gene. J ClinInvest. 1996;98(4):1028–10337. Gillingham M, Van Calcar S, Ney D,Wolff J, Harding C. Dietary management oflong-chain 3-hydroxyacyl-CoA dehydroge-nase deficiency (LCHADD). A case report

American Board of PediatricsNeonatal–Perinatal ContentSpecifications

• Recognize clinicalfeaturesassociated withautosomalrecessivedisorders.

• Know the clinical manifestations,laboratory features, and treatment ofdisorders in the metabolism of fattyacids.



and survey. J Inherit Metab Dis. 1999;22(2):123–131

Case 2 DiscussionThe differential diagnosis for congenitalstridor can be divided into two catego-ries: intrinsic obstruction or extrinsiccompression. Intrinsic causes include la-ryngeal web, tracheal stenosis, bilateralvocal cord paralysis, thyroglossal ductcyst, tracheal mass such as hemangiomaor papilloma, and laryngomalacia ortracheomalacia. Extrinsic causes includevascular rings, teratoma, lymphatic mal-formations, and thyromegaly.

Physical examination of the infantreveals mild micrognathia, a depressednasal bridge, and camptodactyly ofmultiple digits on both hands. He isimmediately brought to the operatingroom, where rigid bronchoscopy re-veals an anterior laryngeal web withextension into the subglottis as wellas a 70% stenosis of the subglottic tra-chea. Due to the severity of the steno-sis and the predicted difficulty insecuring an airway (should the endo-tracheal tube become dislodged),a tracheostomy is performed.

The ConditionThe most common cause of stridor inthe newborn period is laryngomalacia,which typically starts in the firstmonth after birth and is occasionallynoted at birth. Although the exactcause of laryngomalacia is not known,it is hypothesized that general neuro-muscular immaturity is a significantcomponent, with gastroesophagealreflux as a contributing factor. Thestridor associated with laryngomalaciais typically coarse in nature and is ex-acerbated by agitation and neck flex-ion. It generally resolves over thecourse of the child’s first year withoutintervention, although surgery (epi-glottoplasty) or even tracheostomy isoccasionally required in severe cases.

Between week 8 and 10 of gesta-tion, a rapidly proliferating epitheliallayer covers the larynx. This mem-brane is then resorbed, recanalizingthe laryngeal opening. Failure of re-sorption results in a laryngeal web.This obstruction is variable in presen-tation, with some infants initiallyasymptomatic at birth with progres-sive stridor over the first 2 months af-ter birth; others will have severerespiratory distress shortly after deliv-ery. Webs are typically located at thelevel of the glottis and extend anteri-orly toward the arytenoids. The stri-dor associated with laryngeal webs isdescribed as “biphasic” (both inspira-tory and expiratory). Symptomatic,thin webs can be treated with laser ab-lation, whereas thick, fibrous webs mayrequire tracheostomy placement. (1)

Congenital subglottic stenosis is anuncommon cause of airway narrowing.It usually occurs in association with ab-normally formed cricoid cartilage withsubsequent thickening of the subglottictissue. Similar to other congenital airwayanomalies, congenital subglottic stenosishas a heterogeneous presentation, oftengoing undetected well into childhoodor causing severe respiratory distress inthe delivery room. This outcome standsin contrast with the far more commonpresentation of subglottic stenosis,which is acquired after prolonged intu-bation and is caused by granuloma for-mation in response to irritation bya foreign body. Severe congenital sub-glottic stenosis may require surgicalmanagement either via “splitting” thecricoid ring to increase the airway diam-eter or placement of a tracheostomy un-til the infant has grown large enough forreconstructive surgery. (1)

Congenital high airway obstruc-tion syndrome was first described byHedricket al (2) in1994as aconstellationof findings, including the following: (1)upper airway obstruction; (2) large lungvolumes with dilated airways and flat-tened diaphragms; (3) polyhydramnios;

and (4) nonimmune hydrops fetalis.The underlying pathophysiology con-sists of airway obstruction, which leadsto accumulation of fetal lung fluid caus-ing the overdistension of the lungs,compression of the esophagus (with im-paired fetal swallowing leading to poly-hydramnios), and impaired cardiacoutput leading to hydrops fetalis.Whenthe syndrome is discovered on prenatalimaging, referral can bemade to a high-risk obstetric center so that ex utero in-trapartum treatment can be offered.

Lessons for the Clinician

1. Stridor in the newborn period isuncommon and can present asmonophasic stridor (inspiratoryonly) or biphasic (both inspiratoryand expiratory phases).

2. Laryngomalacia is the most com-mon cause of stridor in the newbornand, in most cases, will resolve overthe course of the child’s first year.

3. More serious airway anomalies mayrequire surgical intervention, anda prompt referral to an otolaryngol-ogist should be made. The out-comes of infants who have severeor complete airway obstructioncan be improved with prenatal di-agnosis and a carefully developeddelivery plan at a high-risk center.

(Zachary A. Vesoulis, MD, Akshaya J.Vachharajani, MD, Division of New-born Medicine, Department of Pediat-rics, Washington University School ofMedicine, St Louis, MO)


• Know the variouscauses of stridorin the newbornand how to assessseverity.



References1. Martin RJ, Fanaroff AA, Walsh MC.Fanaroff and Martin’s Neonatal-PerinatalMedicine: Diseases of the Fetus and Infant.

9th ed. Philadelphia, PA: Saunders/Elsevier;20112. Hedrick MH, Ferro MM, Filly RA,Flake AW, Harrison MR, Adzick NS.

Congenital high airway obstruction syn-drome (CHAOS): a potential for perinatalintervention. J Pediatr Surg. 1994;29(2):271–274

Correction

In the December 2013 NeoReviews article “The Pre- and Early Postnatal Microbiome: Relevance to Subsequent Health

and Disease” (Neu J. NeoReviews. 2013;14(12):e592-e599. doi: 10.1542/neo.14-12-e592), the following references were

omitted from the article’s reference list:

52. Renz-Polster H, David MR, Buist AS, et al. Caesarean section delivery and the risk of allergic disorders in childhood.

Clin Exp Allergy. 2005;35(11):1466-147253. Decker E, Engelmann G, Findeisen A, et al. Cesarean delivery is associated with celiac disease but not inflammatory

bowel disease in children. Pediatrics. 2010;125(6):e1433-e144054. Cardwell CR, Stene LC, Joner G, et al. Caesarean section is associated with an increased risk of childhood-onset type 1

diabetes mellitus: a meta-analysis of observational studies. Diabetologia. 2008;51(5):726-73555. Flemming K, Woolcott CG, Allen AC, Veugelers PJ, Kuhle S. The association between caesarean section and childhood

obesity revisited: a cohort study. Arch Dis Child. 2013;98(7): 526-532The journal regrets this error.

Answer Key for March 2014 Issue:Diabetic Pregnancy: 1. B; 2. A; 3. B; 4. C; 5. D.

Neonatal Hypoglycemia: 1. D; 2. C; 3. B; 4. E; 5. A.




Correction











References1. Martin RJ, Fanaroff AA, Walsh MC.Fanaroff and Martin’s Neonatal-PerinatalMedicine: Diseases of the Fetus and Infant.

9th ed. Philadelphia, PA: Saunders/Elsevier;20112. Hedrick MH, Ferro MM, Filly RA,Flake AW, Harrison MR, Adzick NS.

Congenital high airway obstruction syn-drome (CHAOS): a potential for perinatalintervention. J Pediatr Surg. 1994;29(2):271–274

Correction

In the December 2013 NeoReviews article “The Pre- and Early Postnatal Microbiome: Relevance to Subsequent Health

and Disease” (Neu J. NeoReviews. 2013;14(12):e592-e599. doi: 10.1542/neo.14-12-e592), the following references were

omitted from the article’s reference list:

52. Renz-Polster H, David MR, Buist AS, et al. Caesarean section delivery and the risk of allergic disorders in childhood.

Clin Exp Allergy. 2005;35(11):1466-147253. Decker E, Engelmann G, Findeisen A, et al. Cesarean delivery is associated with celiac disease but not inflammatory

bowel disease in children. Pediatrics. 2010;125(6):e1433-e144054. Cardwell CR, Stene LC, Joner G, et al. Caesarean section is associated with an increased risk of childhood-onset type 1

diabetes mellitus: a meta-analysis of observational studies. Diabetologia. 2008;51(5):726-73555. Flemming K, Woolcott CG, Allen AC, Veugelers PJ, Kuhle S. The association between caesarean section and childhood

obesity revisited: a cohort study. Arch Dis Child. 2013;98(7): 526-532The journal regrets this error.

Answer Key for March 2014 Issue:Diabetic Pregnancy: 1. B; 2. A; 3. B; 4. C; 5. D.

Neonatal Hypoglycemia: 1. D; 2. C; 3. B; 4. E; 5. A.







Correction













Maureen E. Simsa Newborn Intensive Care Unit?

Meningitis: Should It Happen inStreptococcusLegal Briefs: Late-Onset Group B











Author Disclosure

Dr Sims has disclosed that she has

been compensated for reviewing

records and providing testimony in

some of the cases highlighted in Legal

Briefs. This commentary does not

contain a discussion of an

unapproved/investigative use of

a commercial product/device.

Late-Onset Group B StreptococcusMeningitis: Should It Happen ina Newborn Intensive Care Unit?Maureen E. Sims, MD*

A 28-6 =7-weeks’-gestational-age boywhose birthweight was 1,340 g wasborn to a 32-year-old G3P0 womanwhose pregnancy was complicated bya short cervix and preterm labor.Two cervical cultures and 1 urine cul-ture were positive for group B Strepto-coccus (GBS), the latest positivecervical culture taken 2 days before de-livery. Antibiotics were not given de-spite preterm labor with a positiveGBS culture and bacteriuria. The in-fectious disease (ID) consult retainedby the plaintiff was critical of thisomission. The mother was given mag-nesium sulfate for tocolysis and antena-tal steroids. An emergency cesareandelivery was performed because ofheart rate (HR) decelerations downto the 70s for 6 to 7 minutes. At thetime of delivery, membranes were rup-tured and clear fluid was found. Apgarscores were 91 and 105. The GBS sta-tus was documented “unknown” inthe delivery and neonatal records andremained unknown throughout theinfant’s hospital stay. The plaintiffID expert was critical of the physi-cians caring for the infant becausehe felt they should have become awareof the maternal GBS status. The treat-ing neonatologists pointed out thatnothing would have been done differ-ently for the infant with that knowl-edge because the infant’s blood culturewas sent and he was given empiricantibiotic.

Continuous positive airway pres-sure was started immediately afterbirth, but because respiratory distress

syndrome developed, he was intubatedand given poractant alfa (Curosurf;Cornerstone Therapeutics, Inc, Cary,NC). The infant was extubated a fewhours later and remained on room airfor 1 month, initially with nasal con-tinuous positive airway pressure,then nasal cannula. The blood cul-ture was negative, and completeblood cell (CBC) count was normal.Ampicillin and gentamicin were dis-continued after 2 days. His baselineHRs averaged 146 beats per minuteuntil caffeine was started. Then itwas higher, averaging mostly 150 to160 beats per minute. He had a fewmild early apneic episodes attributedto the magnesium that the mother re-ceived. However, after the first coupleof days, he had an unremarkablecourse. He received increasing feedsof breast milk and was a stable growinginfant. After caffeine had begun, thebaseline HR was slightly higher, aver-aging 150 to 160 seconds. A cranialultrasound was normal on day 4. Al-though over 90% of the HR were lessthan 160 during the first month andalthough apneic, desaturation and bra-dycardic episodes were minimal andeach time could be explained by an ex-ternal event, on day 30 a significantand spontaneous bradycardic and de-saturation event occurred. Althoughonly a rare minimal gastric residual oc-curred during the previous 30 days,now a 10% residual occurred shortlyafter the bradycardic and desaturationevent. The plaintiff neonatologist sug-gested that although a premature in-fant is entitled to have both apneic,desaturation and bradycardic epi-sodes, as well as residuals on feedings,

Abbreviations

BP: blood pressureCBC: complete blood cellCNS: central nervous systemEOGBS: early-onset group B

StreptococcusGBS: group B StreptococcusHR: heart rateIAP: intrapartum antibiotic

prophylaxisID: infectious diseaseLOGBS: late-onset group B

Streptococcus *Professor of Pediatrics, University of California, Los

Angeles, Los Angeles, CA.

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this was atypical for this infant who hadnot behaved in this way previously. Fur-thermore, on this day, day 30, themajor-ity of the HRs were well over 160 beatsper minute. The plaintiff neonatologistpointed out that increased vigilancewas required at this point. The nurse re-tained by the defense said total vigilancewas practiced because she was on amon-itor. The defense attorney questioned theplaintiff neonatologist on how onewould know there was not a heightenedvigilance. The plaintiff neonatologistcontended that there was absolutely nodocumentation in the nursing notesor mention in the physicians’ chartingto acknowledge any awareness of thevarious “red flags.” These were signalsthat were different for this infant. Theneonatologist asserted that a proactiveapproach is needed when an infantacts differently. That would havedemonstrated a heightened sense ofvigilance. The approach could includemore frequent vital signs, blood pres-sure (BP) measurements, notificationto the neonatologist of the events,a CBC count, C-reactive protein, oreven potentially a blood culture. Stan-dard of care did not necessarily re-quire each and every one, but thesewere areas where a proactive approachcould be done. But an awareness ofthese events being out of the ordinarywas absent. The defense neonatologistdisagreed by saying that prematureinfants behave this way; if somethingwere unusual, the abnormality wouldhave persisted and been continuous,not intermittent. All of the HRswould have been very high, and intol-erance to feeds would have been 100%present. Furthermore, any abnormal-ities would have been very much worseand been simultaneously expressed bythe infant. He also contended thattachycardia in a newborn is a persis-tent HR greater than 180 beats perminute.

Later that day (day 30) the BPdropped to 53/16 with a mean of

31 mmHg. The plaintiff neonatolo-gist contended that not only was thediastolic pressure very, very low butthat the mean was significantly lowerthan what this infant had ever had.He pointed out that very long stretchesoccurred where the BP was not takenat all. The most recent BP was over 24hours previous and the next was 24hours later. Moreover, the physicianwas not notified of this low BP. The de-fense nurse said that this low BP couldbe explained by a number of possibil-ities; the infant might have been eat-ing or maybe it was taken from theleg. The HR was found to be 203beats per minute during the time thatthe BP was low. The plaintiff neona-tologist said that it was at this pointthat a septic evaluation, lumbarpuncture (if tolerated), and CRPshould have been performed and anti-biotics started. Not to do an evalua-tion and start antibiotics was belowthe standard of care. The defense neo-natologist disagreed. On day 31, theHRs continued to be high with an av-erage of 170 beats per minute. Feedswere increased on morning rounds.Later that day, the infant suddenly de-veloped 20 severe bradycardic epi-sodes for which he received positivepressure ventilation. He was thenplaced on a nasal cannula. He hada CBC count and blood culture sent.Initially the thought was aspiration,but chest radiograph results were neg-ative. Subsequently, a diagnosis of nec-rotizing enterocolitis was entertained,but abdominal radiograph results werenegative. The white blood count was5.0 � 103 u/L, the hematocrit levelwas 34% (.34), and the platelet countwas 804 � 103 u/L. One hour afterthe severe bradycardias, amikacin andvancomycin were ordered. The plain-tiff ID expert maintained that be-cause the mother was colonized withGBS, infection with GBS should havebeen suspected and antibiotics thatwould better attack GBS should have

been chosen. Furthermore, antibioticsthat could penetrate the central ner-vous system (CNS) should have beenchosen. An LP was not done, andthe ever-present possibility of menin-gitis should have been entertained.He pointed out that amikacin is noteffective against GBS, and vancomy-cin does not penetrate the CNS well.Three hours later, the infant was endo-tracheally intubated. Three and a halfhours after the event, amikacin wasgiven, and a half an hour later vanco-mycin was administered. Both theplaintiff ID and neonatologist werecritical of this excessive time lag be-tween symptoms consistent with infec-tion and the institution of antibiotics.Six hours later, piperacillin-tazobactam(Zosyn; Wyeth Pharmaceuticals, Inc,Philadelphia, PA) was started. Boththe plaintiff neonatologist and IDcontended that if the early signs, suchas the tachycardias, gastric resid-uals, and low BP, had been appreci-ated (36 to 48 hours before theevent), more frequent vital signs,BPs, and a CBC count would haverevealed that the infant was becomingsick. Timely intervention would haveprevented this dramatic deteriora-tion. The defense neonatologist dis-agreed. He declared that severebradycardias ushered in the sicknessand that the earlier signs that the plain-tiff neonatologist referred to as “redflags” were unrelated. The plaintiffneonatologist and ID stressed thatthe infant was bacteremic 24 to 36hours before the event. Furthermore,both maintained that a 3-½-hourdelay between the event and adminis-tration of the antibiotics was clearlysubstandard. The defense neonatolo-gist disagreed and pointed out thatmany things needed to be done includ-ing nasal cannula, radiographs, andblood tests. The plaintiff neonatologistcontended only a blood culture was re-quired before starting the antibioticsand that all the interventions could

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have and should have been performedsimultaneously.

Twelve hours after the blood cul-ture was done, GBS grew. The plain-tiff neonatologist and ID bothcontended that GBS infection waspresent for at least 1 day and a halfbefore deterioration. The defense neo-natologist said that GBS is fulminantand does not have a time period wherewarning signs are given, maybe a 30-minute period of bacteremia at mostbefore deterioration. The plaintiffneonatologist and ID disagreed andpointed out that late-onset sepsis fromGBS is typically insidious and presentsexactly as it did in this infant. Afterthe blood culture was found to be pos-itive, breast milk was sent for culture.It grew GBS and 2 other organisms.The plaintiff ID expert thought thatthe GBS was transmitted to the childvia the breast milk. He could not dif-ferentiate if it was from the skin andhandling of the milk or from the ductsof the mother’s breast, but thought theformer was more likely because themother did not have mastitis or bac-teremia. The plaintiff neonatologistwas asked if the infant acquired theGBS from the breast milk, and he re-sponded that he did not know becauseserotyping was not performed andthe mother did not have mastitis,but it was possible. Asked if themother should have been allowed tobreastfeed, he answered yes. Theplaintiff ID pointed out that heagreed that the infant should havebeen allowed to have breast milk,but that the mother should have beeninformed of her GBS status andshould have been told that there werecase reports linking mothers withGBS positive status with GBS posi-tive breast milk and potentiallylate-onset sepsis. Plaintiff ID agreedthat even with strict hand hygiene, itis not possible to eliminate all organ-isms on the skin. The environmentalsources could also be contaminated.

The plaintiff neonatologist said itwas not possible to tell from wherethe GBS originated. On day 32 (1day postbradycardic event), amikacinand vancomycin were discontinued,and ampicillin was started. On day32, a repeat cranial ultrasound wasnormal. On day 34, a lumbar punc-ture was done. The cerebral spinalfluid had 2,200 white blood cells,140,000 red blood cells, a proteinof 431 mg/dL, and a glucose of lessthan 5 mg/dL; cerebro- spinal fluidculture was negative. Repeat bloodcultures were positive for the GBSuntil the ampicillin was instituted.

Over the next few days, the infanthad a very stormy course includ-ing disseminated intravascular co-agulopathy. He developed septicemboli to both feet. The mother in-sisted in her deposition that the doc-tor did a heel stick from that footdespite the nurse admonishing himand signs on the incubator sayingnot to do so. The mother said in herdeposition that several of the nurseswore jewelry, and that she repeatedlycomplained that they did not useproper hygiene. Although the plain-tiff neonatologist agreed that properhand washing is vital, there was noevidence of departure in the medicalrecords. He pointed out that it wouldbe a jury call to determine the cred-ibility of the mother’s testimonyabout proper hygiene.

The defense neonatologist main-tained that 11% to 15% of 28-week in-fants die before discharge from aNICU. Plaintiff neonatologist stronglydisagreed stating thatmost survive. Thedefense neonatologist said that of thosewho survive, all are abnormal on follow-up. He further maintained that theyall need some level of assistance forthe rest of their lives. The plaintiff neo-natologist said that they tend to do wellunless they are born with anomalies orhave some sentinel event around thetime of labor and delivery or more

rarely a major problem in the NICU.Subsequent imaging was performeddemonstrating grade 3 and 4 intraven-tricular hemorrhages. The infant de-veloped progressive posthemorrhagicventriculomegaly requiring a ventri-culoperitoneal shunt. He was madeDNR (do not resuscitate) at 2 monthsof age and admitted to hospice care.He was subsequently discharged fromhospice to his home. He had a severaladmissions for seizure control. At 5years, he had spastic quadriparesiswith superimposed right hemiparesisand hypotonic trunk, neck, and facialmusculature. He had cortical visualimpairment. He was nonverbal andnonambulatory. He had some com-munication skills, and his seizureswere under control. After jury selection,a settlement agreement was reached.

DiscussionThree clinical patterns of GBS diseaseoccur among young infants with GBSinfection that are epidemiologically dis-tinct and related to age at onset. Early-onset GBS (EOGBS) disease rangesfrom 0 to 6 days and usually occurswithin the first 24 hours. Late-onsetGBS (LOGBS) disease has a range of7 to 89 days and typically occurs at 3to 4 weeks. Late, late-onset disease oc-curs beyond age 89 days and usually oc-curs in very preterm infants requiringprolonged hospitalizations. Intrapar-tum antibiotic prophylaxis (IAP) hasdramatically reduced EOGBS but hasnot changed the incidence of LOGBS.Although IAP does not preventLOGBS, studies have revealed that in-trapartum antibiotics are associatedwith delayed presentation of symptomsand milder LOGBS. The incidence ofLOGBS in the United States is approx-imately 0.3 to 0.4 cases per 1,000 livebirths, nearly equal to that of EOGBS.A European study demonstrateda lower incidence overall and revealedthat premature infants have a 6-time

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higher incidence of LOGBS comparedwith term infants (1.4 vs .24 per 1,000live births). The case-fatality ratio interm infants ranges from 1% to 3%but is higher in preterm neonates(20% for EOGBS and 5% for LOGBS).Approximately 50% of EOGBS still af-flicts term neonates and because the in-fection frequently manifests within 24hours, the infants are frequently inthe hospital. At least 50% of infants withLOGBS are born before 37 weeks’ ges-tation, but many are already at homewhen they develop LOGBS.

Anecdotal case reports have sug-gested that breast milk is a possiblesource of LOGBS, especially if GBSmastitis is present, because particularlymassive GBS inoculums may lead toheavy neonatal colonization, a knownrisk factor for invasive GBS disease.Many times the source ofGBS is unclearin LOGBS. In the discussed case, themother should have received IAP, butthe infant did not develop EOGBS.The Centers for Disease Control andPrevention guidelines were not fol-lowed. Whether the infant would havebenefited from IAP, one cannot be cer-tain. There is no explanation of why thenurses and the obstetrician did notknow or follow through with findingout the GBS status and bacteriuria.

In this case, the infant should havebeen at an advantage because he wasin a NICU on a continuous monitor.Unfortunately the signals that the in-fant sent out when he became 33weeks’ gestation at 31 days old (inter-mittent tachycardia, hypotension, gas-tric residuals, apnea, and desaturation)were not appreciated. The bacteremiapreceded the meningitis, as it generallydoes (except in cases of ventricular taps

where organisms might be inad-vertently introduced). The infantshowed signs of bacteremia. Fur-thermore, the 3.5-hour delay inthe antibiotic administration oncethe infant showed obvious signs ofdeterioration and the choice of anti-biotics were inappropriate consider-ing the GBS status of the mother.At some point during the bacteremicphase, the CNS became seeded. Dur-ing the 3.5-hour interval between the“crash” and administration of anti-biotics, the GBS was allowed to rap-idly replicate unchecked. As clinicalsymptomatology is often subtleand nonspecific in the early phaseof the disease (when interventionis the most effective), it is vitally im-portant to notice the signals thatthese little ones are providing, andnot delay in evaluation and treat-ment. Delays have important conse-quences in GBS infection. Once aninfant is clearly symptomatic, therisk of injury and death increasesconsiderably.

One approach that has been sug-gested to help with early diagnosisof GBS infection is to evaluate beat-to-beat HR monitoring. Althoughthis is appealing and hopefully willadd another dimension to help careproviders be more proactive, simplyappreciating the vital sign abnormal-ities such as increase in HR, changesin ambient temperatures, new onsetof apnea, desaturation and bradycar-dia, or new residuals provide a hugeamount of input to care physiciansand nurses. Ultimately GBS vaccina-tion in conjunction with IAP mayhelp to accomplish the ultimate goalof GBS disease elimination.

Suggested ReadingBaradi A, Rossi C, Lugli L, et al. Group B

streptococcus late-onset disease: 2003–2010. Pediatrics. 2013;131:e361–e368

Committee on Infectious Disease (AAP).Group B Streptococcal Infections. RedBook, 29th ed. Elk Grove Village, IL:American Academy of Pediatrics; 2012:680–685

Edwards MS. Group B streptococcal conju-gate vaccine: a timely concept for whichthe time has come.Hum Vaccin. 2008;4(6):444–448

Moorman JR, Carlo WA, Kattwinkel J.Mortality reduction by heart rate char-acteristic monitoring in very low birthweight neonates: a randomized trial.J Pediatr. 2011;159(6):900–906

Tumbaga PF, Philip AGS. Perinatal group Bstreptococcal infections: an update. Neo-Reviews. 2006;4:e524–e530

Tumbaga PF, Philip AGS. Perinatal group Bstreptococcal infections: current statusand future directions. NeoReviews. 2013;14:e306–e316

Verani JR, McGee L, Schrag SJ; Divisionof Bacterial Diseases, National Centerfor Immunization and Respiratory Dis-eases, Centers for Disease Control andPrevention (CDC). Prevention of peri-natal group B streptococcal disease—revised guidelines from CDC, 2010.MMWR Recomm Rep. 2010;59(RR-10):1–36


• Know theepidemiology,prevention, andpathogenesis ofperinatal/neonatal group Bstreptococcal infections.

• Know the clinical manifestations anddiagnostic criteria of group Bstreptococcal infections.


• English: http://www.healthychildren.org/English/health-issues/conditions/infections/Pages/Group-B-Streptococcal-

Infections.aspx• Spanish: http://www.healthychildren.org/spanish/health-issues/conditions/infections/paginas/group-b-streptococcal-

infections.aspx

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http://www.healthychildren.org/English/health-issues/conditions/infections/Pages/Group-B-Streptococcal-Infections.aspx

http://www.healthychildren.org/English/health-issues/conditions/infections/Pages/Group-B-Streptococcal-Infections.aspx

http://www.healthychildren.org/spanish/health-issues/conditions/infections/paginas/group-b-streptococcal-infections.aspx

http://www.healthychildren.org/spanish/health-issues/conditions/infections/paginas/group-b-streptococcal-infections.aspx




Maureen E. Simsa Newborn Intensive Care Unit?

Meningitis: Should It Happen inStreptococcusLegal Briefs: Late-Onset Group B















Maurice L. Druzin and Nancy PetersonStrip of the Month: March 2014











Strip of the Month: March 2014Maurice L. Druzin, MD,*

Nancy Peterson, RNC,

PNNP, MSN, IBLC†

Author Disclosure

Dr Druzin and Ms

Peterson have

disclosed no financial

relationships relevant

to this article. This

commentary does not

contain a discussion of

an unapproved/

investigative use of

a commercial product/

device.

Electronic Fetal Monitoring Case Review SeriesElectronic fetal monitoring (EFM) is a popular technology used to establish fetal well-being. Despite its widespread use, terminology used to describe patterns seen on themonitor has not been consistent until recently. In 1997, the National Institute of ChildHealth and Human Development (NICHD) Research Planning Workshop publishedguidelines for interpretation of fetal tracings. This publication was the culmination of2 years of work by a panel of experts in the field of fetal monitoring and was endorsedin 2005 by both the American College of Obstetricians and Gynecologists and the As-sociation of Women’s Health, Obstetric and Neonatal Nurses. In 2008, the AmericanCollege of Obstetricians and Gynecologists, NICHD, and the Society for Maternal-FetalMedicine reviewed and updated the definitions for fetal heart rate (FHR) patterns, inter-pretation, and research recommendations. The following is a summary of the terminologydefinitions and assumptions found in the 2008 NICHD workshop report. Normal valuesfor arterial umbilical cord gas values and indications of acidosis are defined in Table 1.

Assumptions From the NICHD Workshop

• Definitions are developed for visual interpretation, assuming that both the fetal heart rate(FHR) and uterine activity recordings are of adequate quality

• Definitions apply to tracings generated by internal or external monitoring devices• Periodic patterns are differentiated based on waveform, abrupt or gradual (eg, late de-

celerations have a gradual onset and variable decelerations have an abrupt onset)• Long- and short-term variability are evaluated visually as a unit• Gestational age of the fetus is considered when evaluating patterns• Components of FHR do not occur alone and generally evolve over time

DefinitionsBaseline Fetal Heart Rate

• Approximate mean fetal heart rate (FHR) rounded to increments of 5 beats per minutein a 10-minute segment of tracing, excluding accelerations and decelerations, periods ofmarked variability, and segments of baseline that differ by >25 beats per minute

• In the 10-minute segment, the minimum baseline duration must be at least 2 minutes(not necessarily contiguous) or the baseline for that segment is indeterminate

• Bradycardia is a baseline of <110 beats per minute; tachycardia is a baseline of >160beats per minute

• Sinusoidal baseline has a smooth sine wavelike undulating pattern, with waves havingregular frequency and amplitude

Baseline Variability

• Fluctuations in the baseline FHR of ‡2 cycles per minute, fluctuations are irregular inamplitude and frequency, fluctuations are visually quantitated as the amplitude of thepeak to trough in beats per minute

• Classification of variability:

Absent: Amplitude range is undetectableMinimal: Amplitude range is greater than undetectable to 5 beats per minuteModerate: Amplitude range is 6 to 25 beats per minuteMarked: Amplitude range is >25 beats per minute

*Professor and Vice-Chair, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Palo Alto, CA.†Director of Perinatal Outreach, Stanford University, Palo Alto, CA.

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Accelerations

• Abrupt increase in FHR above the most recently deter-mined baseline

• Onset to peak of acceleration is <30 seconds, acme is‡15 beats per minute above the most recently deter-mined baseline and lasts ‡15 seconds but <2 minutes

• Before 32 weeks’ gestation, accelerations are definedby an acme ‡10 beats per minute above the most re-cently determined baseline for ‡10 seconds

• Prolonged acceleration lasts ‡2 minutes but <10minutes

Late Decelerations

• Gradual decrease in FHR (onset to nadir ‡30 seconds)below the most recently determined baseline, with na-dir occurring after the peak of uterine contractions

• Considered a periodic pattern because it occurs withuterine contractions

Early Decelerations

• Gradual decrease in FHR (onset to nadir ‡30 seconds)below the most recently determined baseline, with na-dir occurring coincident with uterine contraction

• Also considered a periodic pattern

Variable Decelerations

• Abrupt decrease in FHR (onset to nadir <30 seconds)• Decrease is ‡15 beats per minute below the most re-

cently determined baseline lasting ‡15 seconds but<2minutes

• May be episodic (occurs without a contraction) orperiodic

Prolonged Decelerations

• Decrease in the FHR ‡15 beats per minute belowthe most recently determined baseline lasting ‡2minutes but <10 minutes from onset to return tobaseline

Decelerations are tentatively called recurrent if they oc-cur with ‡50% of uterine contractions in a 20-minuteperiod.

Decelerations occurring with <50% of uterine con-tractions in a 20-minute segment are intermittent.

Sinusoidal Fetal Heart Rate Pattern

• Visually apparent, smooth sine wavelike undulatingpattern in the baseline with a cycle frequency ofthree to five per minute that persists for ‡20minutes.

Uterine Contractions

• Quantified as the number of contractions in a 10-minutewindow, averaged over 30 minutes.

Normal: £5 contractions in 10 minutesTachysystole: >5 contractions in 10 minutes

InterpretationA three-tier FHR interpretation system has been recom-mended as follows:

• Category I FHR tracings: Normal, strongly predictiveof normal fetal acid-base status and require routinecare. These tracings include all of the following:

– Baseline rate: 110 to 160 beats per minute– Baseline FHR variability: Moderate– Late or variable decelerations: Absent– Early decelerations: Present or absent– Accelerations: Present or absent

• Category II FHR tracings: Indeterminate, requireevaluation and continued surveillance and reevalua-tion. Examples of these tracings include any of thefollowing:

– Bradycardia not accompanied by absent variability– Tachycardia– Minimal or marked baseline variability– Absent variability without recurrent decelerations

Table 1. Arterial Umbilical Cord Gas Values

pH Pco2 (mm Hg) Po2 (mm Hg) Base Excess

Normala ‡7.20 (7.15 to 7.38) <60 (35 to 70) ‡20 £L10 (L2.0 to L9.0)Respiratory acidosis <7.20 >60 Variable £L10Metabolic acidosis <7.20 <60 Variable ‡L10Mixed acidosis <7.20 >60 Variable ‡L10

aNormal ranges from Obstet Gynecol Clin North Am. 1999;26:695.

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– Absence of induced accelerations after fetal stimulation– Recurrent variable decelerations with minimal or

moderate variability– Prolonged decelerations– Recurrent late decelerations with moderate variability– Variable decelerations with other characteristics, such

as slow return to baseline• Category III FHR tracings: Abnormal, predictive of

abnormal fetal acid-base status and require prompt in-tervention. These tracings include:

– Absent variability with any of the following:n Recurrent late decelerationsn Recurrent variable decelerationsn Bradycardia

– Sinusoidal pattern

Data from Macones GA, Hankins GDV, Spong CY,Hauth J, Moore T. The 2008 National Institute of ChildHealth and Human Development workshop report on elec-tronic fetal monitoring. Obstet Gynecol. 2008;112:661–666and American College of Obstetricians and Gynecologists.Intrapartum fetal heart rate monitoring: nomenclature, inter-pretation, and general management principles. ACOG

Practice Bulletin No. 106. Washington, DC: American Col-lege of Obstetricians and Gynecologists; 2009.

We encourage readers to examine each strip in the casepresentation and make a personal interpretation of thefindings before advancing to the expert interpretationprovided.

Case PresentationHistory

This case involves a 27-year-old, G1P0 who presents at39 5/7 weeks’ gestation with premature rupture of mem-branes for the past 3 hours and contractions that started1 hour later. Her current pregnancy history was compli-cated by a low-lying placenta on early scan that has sinceresolved, and a history of marijuana use in early pregnancy,with repeat toxicology screens negative. Her social historyis significant for sexual abuse at age 13, as well as domesticviolence in a previous relationship. Her prenatal labs are allnormal and she is negative for Group B Streptococcus.Her vital signs are as follows: temperature 36.7°C, heartrate 78, and blood pressure 120/65. A vaginal examina-tion revealed a cervix that was 1 cm, long and posterior.An external fetal monitor is placed and is shown in Fig 1.

Figure 1. EFM Strip #1.

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Findings from EFM Strip #1 are as follows:

• Variability: Moderate• Baseline rate: 130 beats per minute• Episodic patterns: Accelerations• Periodic patterns: None• Uterine contractions: Irregular, palpate for intensity

and tone• Interpretation: Category I• Differential diagnoses: Normal FHR and early labor• Action: No intervention is required for the fetus at this

point. Moderate variability indicates an intact centralnervous system that is highly predictive of the absenceof metabolic acidemia. The effects of marijuana use inpregnancy and on fetal development are unclear. Thereis some evidence to suggest that marijuana use is as-sociated with childhood cognitive, psychosocial, anddevelopmental disorders, but, clearly, more research

needs to be done. (1) In addition, a history of child-hood sexual abuse (CSA) and domestic violence canbe considered an obstetrical risk factor for pregnancycomplications. It is estimated that 12% to 40% of chil-dren in the United States experience CSA. (2) Thesepatients should be screened universally and identifiedearly in the prenatal period and offered sensitivity withobstetric visits and examinations, acknowledgementthat CSA is fairly common and she is not alone, andcounseling referrals if appropriate. (2)

At this point, the plan is to admit her to labor and de-livery, and augment her labor with Pitocin if there is nocervical change in 1 hour. An hour later, Pitocin is startedand the contractions over the next couple of hours in-crease in frequency and intensity. A repeat vaginal exam-ination showed cervical progress to 4 cm, 90% effacedand a �1 station. The fetal tracing is shown in Fig 2.



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• Variability: Moderate• Baseline rate: 155 beats per minute• Episodic patterns: None• Periodic patterns: Recurrent variable decelerations• Uterine contractions: Unable to determine, requires

palpation• Interpretation: Category II• Differential diagnosis: Cord compression• Action: The presence of moderate variability is reassur-

ing and essentially rules out metabolic acidosis. Variabledecelerations are caused by transient compression of theumbilical blood vessels, which results in disruption ofoxygen transfer to the fetus. However, when these de-celerations are recurrent, they can lead to progressivehypoxemia. The most important intervention is to

improve blood flow to the fetus by relieving the cordcompression. This can be accomplished by maternalposition change, intravenous (IV) fluid bolus, and pos-sibly an amnioinfusion. An amnioinfusion involvesplacement of an intrauterine catheter into the amnioticcavity and infusing normal saline through it to relievethe cord compression. In this case, the amnioinfusionprocedure was successful and the variable decelerationpattern improved. Over the next several hours, theFHR continued with moderate variability and an occa-sional variable. The contraction pattern increased infrequency and intensity with continuous Pitocin infu-sion. A cervical examination showed progress to 6 to7 cm, 90% effaced, and 0 station.

One hour later, the following tracing is shown in Fig 3.Findings from EFM Strip #3 are as follows:



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• Variability: Moderate to marked in later part of tracing• Baseline rate: Unable to determine due to continuous

contraction pattern• Episodic patterns: Accelerations• Periodic patterns: Variable deceleration• Uterine contractions: Tachysystole pattern with more

than six contractions in 9 minutes with very little relax-ation in between. Palpation is required to determineadequate uterine relaxation between contractions.

• Interpretation: Category II• Differential diagnosis: Acute hypoxia most likely caused

by excessive uterine activity• Action: The etiology of marked variability is unknown,

but it is thought to be a compensatory mechanism trig-gered by a fetal sympathetic response and is an early signof acute hypoxia in a previously normoxic fetus. Themarked variability is most likely associated with exces-sive uterine activity causing a decrease in available oxy-gen to the fetus. Therefore, appropriate management

options should focus on improving placental bloodflow and optimizing fetal oxygenation. Tachysystoleis defined as five or more contractions in 10 minutes.Maternal lateral position change, discontinuing thePitocin infusion, and an IV fluid bolus can all help ac-complish these goals. If these interventions do not de-crease uterine activity, a tocolytic agent, such as terbutaline,can be considered to relax the uterus. In this case,the Pitocin was discontinued and 30 minutes later,the contraction pattern spaced out to 2 to 4 minutesapart. However, the marked variability and recurrentvariable deceleration pattern continued for anotherhour until FHR baseline of 150 was reestablishedand variable decelerations improved.

Two hours later, the patient began complaining ofrectal pressure and a vaginal examination found the cervixto be complete and the vertex at a þ2 station. The finaltracing is shown in Fig 4.



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• Variability: Moderate to marked• Baseline rate: Initially 150 beats per minute, then de-

creases to 70 to 80 toward the end• Episodic patterns: Variable• Periodic patterns: Prolonged deceleration• Uterine contractions: Readjust the monitor and pal-

pate contractions• Interpretation: Category II to III• Differential diagnosis: Sudden decrease in oxygenation• Action: A prolonged deceleration can be caused by pro-

lapsed cord, rapid fetal descent, placental abruption,and/or maternal hypotension or apnea. The patientwas repositioned on her side and then placed on all foursin an effort to increase the FHR. An IV fluid bolus wasgiven, and oxygen per rebreather mask was placed onthe patient. A vaginal examination ruled out a prolapsedcord. Terbutaline was given as well to relax the uterus inan attempt to improve blood flow and oxygenation. Af-ter 4 minutes of a persistent prolonged deceleration,a decision was made to take the patient to the operatingroomwhere a repeat vaginal examination was performedand the fetal vertex was now at þ3 station. The FHR

was noted to be 80 beats per minute and a discussionof a forceps-assisted delivery versus an emergency cesar-ean delivery took place with the patient and her partner.They consented to proceed with a forceps delivery.

OutcomeA viable female infant weighing 6 lb 2 oz was deliveredover a midline episiotomy after placement of forceps with-out difficulty. The Apgar scores were 8 at 1minute and 9 at5 minutes. The infant showed no residual effect of the for-ceps application and was taken to the well-infant nursery ingood condition. Cord gases revealed a mild respiratory ac-idosis, which is consistent with the prompt delivery of a fe-tus within the time frame of 12 minutes from onset ofa prolonged deceleration to delivery. Bothmom and infantwere discharged on day 3 in stable condition (Table 2).

References1. Brown HL, Graves CR. Smoking and marijuana use in preg-nancy. Clin Obstet Gynecol. 2013;56(1):107–1132. American College of Obstetricians and Gynecologists. Commit-tee on Health Care for Underserved Women. Committee opinionno. 498: Adult manifestations of childhood sexual abuse.ObstetGynecol. 2011;118(2 pt 1):392–395


Table 2. Arterial Umbilical Cord Gas Results

pH PCO2 (mm Hg) Po2 Base Excess

Normal ‡7.20 <60 ‡ 20 £L10Respiratory acidosis <7.20 >60 Variable £L10Metabolic acidosis <7.20 <60 Variable ‡L10Mixed acidosis <7.20 >60 Variable ‡L10Patient 7.15 60 19 8

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Maurice L. Druzin and Nancy PetersonStrip of the Month: March 2014














NR March2014

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