Volume 31, Issue 1

Gestational diabetes mellitus (GDM) usually develops in the second half of pregnancy and, in order to address the impact of GDM on the conceptus, several issues must be raised: what are the immediate implications for the fetus and the neonate and why do they happen? What are the consequences for the offspring? What can be done? In a theoretical model the whole pathogenesis and spectrum of fetal and neonatal mortality and morbidity could primarily be attributed to the excessive transferal of glucose from mother to fetus, inducing fetal hyperglycemia, leading to fetal pancreatic islet hypertrophy and β-cell hyperplasia with a consequent rise in insulin secretion. However, besides, and in addition to glucose, it is quite possible that other metabolic fuels, from amino acids to lipids, may also cross the placenta further contributing to the adverse intrauterine environment. Depending upon the time of gestation during critical developmental stages, the same metabolic fuels would have different effects upon the fetus, the neonate and quite possibly, upon the long-term outcome from neurological and psychosocial impairment to the adult development of metabolic and cardiovascular disorders Based on clinical and experimental evidence that poor maternal homeostasis is at the core of the problem, it is of paramount importance to identify women at risk of GDM and to keep a tight metabolic control in order to avoid immediate and long-term consequences for their offspring.

Objective. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are expressed in many inflammatory conditions and contribute to connective tissue breakdown. Stromelysin 1 [matrix metalloproteinase 3 (MMP-3)], a novel member of this family, is produced in the context of infection and is able to activate the latent forms of other MMPs. The purpose of this study was to determine if parturition (either term or preterm), premature rupture of the membranes (PROM), and microbial invasion of the amniotic cavity are associated with changes in amniotic fluid concentrations of MMP-3. Study design. A cross-sectional study was conducted, which included women who underwent transabdominal amniocentesis (n = 365) in the following categories: (1) mid-trimester with a subsequent normal pregnancy outcome (n = 84) and a subsequent fetal loss (n = 10); (2) preterm labor with intact membranes without microbial invasion of the amniotic cavity who delivered at term (n = 36), or prematurely (n = 50), and preterm labor with microbial invasion of the amniotic cavity (n = 25); (3) preterm PROM with (n = 25) and without (n = 26) microbial invasion of the amniotic cavity; (4) term with intact membranes in the absence of microbial invasion of the amniotic cavity, in labor (n = 52) and not in labor (n = 31); and (5) term with PROM in the absence of microbial invasion of the amniotic cavity and not in labor (n = 26). MMP-3 concentrations in amniotic fluid were measured by a sensitive and specific immunoassay that was validated for amniotic fluid. MMP-3 concentrations were normalized using logarithmic transformation for statistical analysis. Parametric statistics were used and a p value <0.05 was considered statistically significant. Results. (1) MMP-3 was detected in 99.5% (363/365) of amniotic fluid samples, and its concentration did not change with advancing gestational age. (2) Spontaneous parturition at term and preterm was associated with a significant increase in amniotic fluid MMP-3 concentrations (p = 0.04 and p = 0.002, respectively). (3) Spontaneous rupture of membranes in term and preterm gestations was not associated with significant changes in amniotic fluid MMP-3 concentrations. (4) Intra-amniotic infection was associated with a significant increase in amniotic fluid MMP-3 concentrations in both women with preterm labor and intact membranes (p = 0.03), and women with preterm PROM (p = 0.02). (5) Subsequent fetal loss after genetic amniocentesis was not associated with significant changes in mid-trimester concentrations of amniotic fluid MMP-3. Conclusions. (1) MMP-3 is a physiologic constituent of amniotic fluid. (2) MMP-3 may play a role in the mechanisms of human parturition and in the regulation of the host response to intrauterine infection.

Objective: To study maternal lipoprotein(a) levels in normal pregnancy and in pregnancy with evidence of vascular disease in the maternal uteroplacental circulation defined by Doppler ultrasound study. Samples: Maternal venous blood was collected from 75 normal pregnant women and 68 pregnant women with evidence of potential uteroplacental vascular disease identified by Doppler ultrasound study. Methods: Plasma lipoprotein(a) levels in maternal blood were measured using an enzyme-liked immunosorbent assay method. Main outcome measures: Plasma lipoprotein(a) levels and pregnancy outcome were examined. Results: None of the normal group had lipoprotein(a) levels greater than 30 mg/dl, a cutoff level which has been associated with increased risk of atherosclerosis. 28 of the 68 women with uteroplacental insufficiency had lipoprotein(a) levels greater than this cutoff level. In this group there was a statistically significant higher prevalence of preeclampsia in comparison with women with a normal lipoprotein(a) level (p < 0.001). The lipoprotein(a) level was significantly higher in severe (n = 13, median 60.5 mg/dl, P < 0.001] than in mild preeclampsia (n = 5, median 34 mg/dl). Those with high levels (> 30 mg/dl) exhibited significantly more adverse indices of fetal outcome. Conclusion: This study has demonstrated that high levels of lipoprotein(a) interfere with uteroplacental circulation and play a role in the pathophysiology of preeclampsia. Lipoprotein(a) concentrations are associated with the severity of the disease. We suggest that high levels of lipoprotein(a) might affect the placenta and fetus.

Aims: Newborns following denied pregnancies are delivered after either late onset or total absence of antenatal care, with a presumed subsequently increased risk for neonatal outcome. For this specific group, several characteristic outcome parameter are investigated. Methods: During the period July 1, 1995 to June 30, 1996, a prospective case sampling was performed for denied pregnancies in Berlin. Besides determination of the parameters' frequency, comparison with two control groups is performed: a normal group (BBR, all Berlin deliveries in 1995) and a high risk group (VIR, all deliveries at a perinatal center in 1996). Results: Altogether 69 neonates occurred. For gestational age < 37 weeks, birth weight < 2500 g, small for gestational age, transferal rate of newborns to neonatal unit and surgical delivery, a statistically significant worse outcome is demonstrated for denied pregnancies versus BBR and VIR (p-level < 0.05). Neonatal mortality is 5.8% in all cases, the corrected rate is 1.5% (excluding three non-viable cases of 21 st and 23 rd week of gestation). Conclusions: The data underline the elevated fetal outcome risk for newborns after denial of pregnancy. In this group, total absence or late onset of antenatal care results in a manifestation of pregnancy dependent risks. Preterm births and small for gestational age newborns, together with deaths, may be classified as at least potentially avoidable.

Objective: To assess the consequences of a systematic screening for toxoplasma infection in pregnant women in a potentially high risk population. Methods: We have investigated all consecutive women with likely toxoplasma seroconversion in a referral center setting. Data were obtained from 68 women for whom an acute infection during pregnancy was considered likely or definite. They were all treated with antibiotics in the first instance and offered, if in the first or second trimester, amniocentesis for detection of vertical transmission (PCR and IFAT). Third trimester seroconversions and positive cases after amniocentesis were offered more aggressive antibiotic treatment. Results: Five fetuses/neonates (7%) were found to be infected. Four of them were diagnosed prenatally at amniocentesis, two women decided for termination of pregnancy, two were treated and gave birth to seronegative, normally developing children. One case was found postnatally, after a third trimester conversion; this developed into hydrocephalus with neurologic impairment. Discussion: Prenatal screening and antibiotic treatment of mothers infected with toxoplasmosis showed good feasibility in our infection-susceptible population. However, there were some weak points; for example, the high number of invasive procedures and the questionable prevention of mother to child transmission in the second to third trimester.

Aims: To assess ceftriaxones effect on uterine contraction frequency and determine risk factors for subsequent preterm birth in women with pyelonephritis. Methods: Seventy-one women with pyelonephritis at greater than 24 weeks' gestation with continuous external tocodynamometry after antibiotic administration were studied. Patients received 2 doses of ceftriaxone 1 gram intramuscularly at 24-hour intervals. Temperatures, timing of antibiotic administration, and gestational age at delivery were recorded. Results: Uterine contraction frequency was measured for the hour prior to antibiotic administration, as well as the six hours after. Uterine activity steadily and significantly decreased from a mean of 5.1±7.3 at presentation to 2.0±2.9 uterine contractions per hour (P = .04, student t-test) six hours after ceftriaxone administration. The maximal number of contractions per hour each woman experienced did not correlate with temperature (r = .02, linear regression analysis). Uterine contractility and recurrent urinary tract infection were both associated with subsequent preterm birth (P = .004 and .016 respectively using nominal logistic regression analysis). Conclusions: (1) A significant decrease in uterine activity from baseline occurs after ceftriaxone administration for acute pyelonephritis in pregnancy. (2) Temperature elevations are not associated with increased uterine activity. (3) Patients with significant uterine activity or recurrent urinary tract infection are at risk for preterm birth.

The present study investigates the population of β 2 -receptors on lymphocytes in pregnant women with premature labor between the 29 th and 34 th week of pregnancy. The population of receptors on lymphocytes correlates with that on the myometrium, which is not accessible for study during pregnancy. Fourteen patients received a pulsatile tocolysis, while ten women received a continuous tocolysis with Fenoterol. Assuming an equal population of receptors in both groups before commencement of therapy, the numbers of receptors in the patients with continuous tocolysis fell to about 35% of the initial value after 72 hours. Under pulsatile tocolysis, the numbers of receptors remained unchanged for a period of three days and was still only just below 70% of the initial value by the seventh day. Our data demonstrate that continuous administration of the short-acting β 2 -agonist Fenoterol resulted in a substantial loss of β 2 -adrenoceptors on lymphocytes. In contrast, intermittent administration of the same β 2 -adrenergic agonist prevented the onset of receptor down-regulation in pregnant women with preterm labor. Further studies are required to investigate the impact of the decreased loss of β 2 -adrenoceptor density on the good clinical experience with intermittent tocolysis.

The objective of this study was to examine maternal and fetal endothelin-1 (ET-1) in pregnancies complicated with intrauterine growth restriction (IUGR) and to correlate these data with umbilical artery Doppler flow velocity waveforms (FVW). Higher mean maternal (13.8±6,4 vs 9.2±3,4 pmol/L, p < 0.05 ) and fetal (18.5±9.6 vs 11.7±6.9 pmol/L, p < 0.05) ET-1 levels were found in pregnancies complicated with IUGR than in controls. Fetal ET-1 level was related to birth weight percentile for gestational week. Maternal and fetal ET-1 concentrations were not related to umbilical artery Doppler flow S/D ratio, PI and RI. Maternal or fetal ET- 1 concentrations were also not related to umbilical artery pH, PO 2 and PCO 2 . Pregnancy-induced hypertenXsion was significantly associated with an elevated fetal and maternal ET-1 concentration. In conclusion, increased production and secretion of ET-1 may play a role in the pathophysiology of idiopathic IUGR. Over-production of ET-1 in IUGR is not associated with increased placental resistance as reflected in abnormal umbilical artery Doppler FVW.

Background: Late-onset sepsis in the NICU is a major problem associated with high morbidity and mortality. Objective: To determine if clinical characteristics, hematological parameters and serial measurements of serum IL-6 and IL-8 can detect late-onset sepsis in premature neonates prior to positive blood cultures. Design: The study was done in 2 phases. The first phase (S1) was a retrospective evaluation of clinical signs and timing of blood culture positivity in all neonates with late-onset culture proven sepsis from 1991–1998. The second phase (S2) was a prospective study that enrolled infants ≥72 hours old, suspected of sepsis based on the presence of criteria identified in S1. At that time (day 0), blood was drawn for a CBC with differential, blood culture, IL-6 and IL-8 levels; cytokine levels were repeated on day 1. Infants with positive cultures were diagnosed as confirmed sepsis; those with negative cultures, as no sepsis. Results: S1: Of the 48 episodes of culture proven, late-onset sepsis, 54% of the blood cultures were positive by 24 hours and 90% by 48 hours. The most common presenting signs were desaturations (50%) and increased gastric residuals (33%); I/T ratio > 0.16 differentiated between gram-positive, negative and fungal infections (p = 0.007). S2: 27 infants were enrolled. Eight (mean [SEM] gestational age of 28.2 [0.94] weeks; birth weight of 1.15 [0.11] kg) had positive blood cultures; 19 (gestational age of 27.7 [0.9] weeks; birth weight of 1.06 [0.13] kg) had no sepsis. Infants with sepsis were more likely to have apnea/bradycardia (p = 0.002); no differences in hematological profile, as compared to those with no sepsis. Seven (88%) infants had positive blood cultures by 48 hours. Median values of IL-6 (pg/ml) were higher in infants with sepsis vs. those with no sepsis on days 0 [40 vs.13] (p = 0.03) and 1 [24 vs. 9] (p < 0.001). IL-8 levels were not significantly different. Conclusions. In both S1 and S2, a majority of the blood cultures were positive by 48 hours. IL-6 levels on days 0 and 1 were significantly higher in infants with confirmed sepsis, prior to the blood culture being positive. IL-6 levels may be useful in the initiation as well as early termination of antibiotic therapy in late-onset neonatal sepsis.

In order to evaluate parameters of cerebrospinal fluid (CSF) we studied 105 CSF samples of 50 neonates with seizures of unknown origin for cell count and chemistry (protein, albumin, glucose, IgG-index and albumin-ratio). Viral studies for 13 different microbes were performed from serum and CSF. CSF parameters of the babies with a suggested viral infection (n = 13) were compared with those without any viral findings (n = 37), and followed up to the age 45 weeks since conception. CSF mononuclear white blood cell count was≤20×10 6 /l at the age of ≤40 weeks since conception, and thereafter i.e. at term it was≤10×10 6 /l in all neonates without viral infection, whereas mononuclear cell count was above these limits in 8 of 13 neonates with viral infection. The rate of IgG-index remained high only in the neonates with a viral infection when studied at the age of over 43 weeks since conception. We conclude that studies of CSF are a valuable diagnostic aid in CNS viral infections of neonates when evaluated in reference to the age since conception, and the limits of mononuclear white blood cells in normal CSF of neonates are in lower limits than reported before.

The aim of this study was to determine the incidence of viral infections in the central nervous system (CNS) of neonates with seizures of unknown origin. Serum and cerebrospinal fluid (CSF) samples of 50 neonates were studied for antibodies to 13 different microbes by enzyme immunoassay, and CSF samples were investigated for four specific nucleic acids by polymerase chain reaction. For viral cultures throat, stool and CSF samples were obtained. CNS viral infection was suggested in 13 of the 50 neonates (26%). Antibodies to varicella, herpes simplex 1, influenza A or B, parainfluenza 1, adeno or enteroviruses were detected in the CSF of nine children; and herpes simplex 2 specific DNA was found in one child. Cytomegalovirus was cultured from the urine of two children. In one child unspecified, but evident pleocytosis in the CSF was observed. The incidence of CNS viral infections in association with neonatal seizures may be much higher than previously reported.

Objectives: To confirm the accuracy and precision of transcutaneous bilirubin (TcB) values measured by a new device with two optical paths (JM-103) and the value of total serum bilirubin (TSB) level in clinical units of measurement. Methods: For comparison of the levels of accuracy and precision of JM-103 and the old device (JM-102), serum samples were collected from 77 Japanese infants in three different hospitals including 24 preterm infants and 53 term infants. Measurement of TcB by JM-103 and JM- 102 were performed on the forehead of each infant within 30 min before or after blood sampling. Results: The range of TSB was limited to 19.6 mg/dL and to 17 mg/dL for preterm infants. The correlation coefficients for all subjects (r = 0.94) and for term and preterm subjects between TcB measured by JM-103 and TSB was higher than that between TcB measured by JM-102 and TSB. The regression line in term infants between TcB measured by JM-103 and TcB was similar to that in preterm infants. The error distribution of TcB measured by JM-102 and TSB for all subjects (0.00±2.21) and for term and preterm subjects was larger than that of TcB measured by JM-103 and TSB (all subjects, 0.30±1.55).