Localization of a major susceptibility locus influencing preterm birth.

Preterm birth (PTB) is a complex trait, but little is known regarding its major genetic determinants. The objective of this study is to localize genes that influence susceptibility to PTB in Mexican Americans (MAs), a minority population in the USA, using predominantly microfilmed birth certificate-based data obtained from the San Antonio Family Birth Weight Study. Only 1302 singleton births from 288 families with information on PTB and significant covariates were considered for genetic analysis. PTB is defined as a childbirth that occurs at <37 completed weeks of gestation, and the prevalence of PTB in this sample was 6.4%. An ∼10 cM genetic map was used to conduct a genome-wide linkage analysis using the program SOLAR. The heritability of PTB was high (h(2) ± SE: 0.75 ± 0.20) and significant (P = 4.5 × 10(-5)), after adjusting for the significant effects of birthweight and birth order. We found significant evidence for linkage of PTB (LOD = 3.6; nominal P = 2.3 × 10(-5); empirical P = 1.0 × 10(-5)) on chromosome 18q between markers D18S1364 and D18S541. Several other chromosomal regions (2q, 9p, 16q and 20q) were also potentially linked with PTB. A strong positional candidate gene in the 18q linked region is SERPINB2 or PAI-2, a member of the plasminogen activator system that is associated with various reproductive processes. In conclusion, to our knowledge, perhaps for the first time in MAs or US populations, we have localized a major susceptibility locus for PTB on chromosome 18q21.33-q23.

Longitudinal evaluation of polymorphonuclear leukocyte chemiluminescence in premature infants.

A chemiluminescence (CL) microassay was used to evaluate polymorphonuclear leukocyte (PMN) function in premature newborn infants longitudinally during a 2-month period and in healthy adult control subjects. At postnatal ages of 12, 26, 40 and 54 days the infants' mean peak CL activity was significantly lower than that of the adults. Infants with one or more low CL responses were more severely ill than those with normal CL activity. The infants with low CL responses had longer hospital stays and a higher frequency of serious infections, as well as more days of level 3 care, antimicrobial therapy, supplemental oxygen, assisted ventilation, and total parenteral nutrition. The PMN CL activity before, during, and after episodes of serious infection did not differ. In addition, a high frequency of depressed CL activity was observed at the time of infection. Our findings are consistent with previous studies suggesting that defective PMN oxidative metabolic responses are more common in neonates undergoing stress. Our results further suggest that defective PMN function may persist for the first 2 months of life and during the course of serious infection. Enhancement of PMN host defense may be an important strategy in the management of neonatal sepsis.

Transmission of genital mycoplasmas from mother to neonate in women with prolonged membrane rupture.

Colonization of the neonate with genital mycoplasmas occurs during passage through a colonized birth canal or in utero via contamination of the amniotic fluid. To define further the route of transmission we obtained cultures from the maternal vagina, the amniotic fluid and the neonatal pharynx in 131 mother-baby pairs. Sixty-six percent (33 of 50) of the corresponding amniotic fluids were colonized when the vagina was colonized with Mycoplasma hominis. When the amniotic fluid contained M. hominis, 26% (9 of 34) of the neonates were colonized. Sixty percent (66 of 110) of the corresponding amniotic fluids were colonized when the vagina was colonized with Ureaplasma urealyticum. When the amniotic fluid contained U. urealyticum, 32% (22 of 69) of the neonates were colonized. No neonates were colonized with M. hominis without prior colonization of both the vagina and the amniotic fluid. We conclude that colonization of the amniotic fluid is an important intermediate step in colonization of the neonate with genital mycoplasmas.

Neonatal serologic response at term to the genital mycoplasmas.

Genital mycoplasmas are frequently found in the amniotic fluid (AF) of women with ruptured membranes but are infrequent pathogens in the neonates born to these women. The serologic response to the genital mycoplasmas, Mycoplasma hominis and Ureaplasma urealyticum, was studied in 35 mother-baby pairs following term deliveries. Amniotic fluid and neonatal surface cultures were obtained in all cases, as were maternal and neonatal acute and convalescent sera. Despite significant maternal serologic response, there was essentially no neonatal response. Mothers with M. hominis in the AF were significantly more likely than those with negative cultures for M. hominis to exhibit IgG seroconversion and had significantly greater changes in IgG concentrations. Their infants, however, did not exhibit a significant seroresponse regardless of the AF and neonatal culture results. There was also a significant maternal seroresponse to U. urealyticum. However, this did not correlate with the presence of U. urealyticum in the AF. Significantly fewer neonates exhibited a seroresponse to U. urealyticum, again with no relation to culture results.

A randomized trial of intrapartum versus immediate postpartum treatment of women with intra-amniotic infection.

A randomized trial of intrapartum versus postpartum antibiotic treatment of women with intra-amniotic infection was conducted. Intra-amniotic infection was treated with ampicillin and gentamicin during labor (at the time of diagnosis) in 26 women and immediately after umbilical cord clamping in 19 women. Intrapartum treatment led to a lower incidence of neonatal sepsis (0 versus 21%; P = .03) and a shorter neonatal hospital stay (3.8 versus 5.7 days; P = .02) when compared with postpartum treatment. There were no significant differences in the microbiologic results, the gestational age, or the birth weight between the groups. Intrapartum-treated mothers had a shorter mean postpartum stay, a lower mean number of febrile days, and a lower mean peak postpartum temperature than did postpartum-treated mothers; these differences were all statistically significant (P = .05). The treatment of clinical intra-amniotic infection during labor results in improved outcome.

Luminol-dependent chemiluminescence microassay for phagocytic function.

A luminol-dependent chemiluminescence (CL) microassay was developed to measure phagocytic function of peripheral blood leukocytes. Buffy coats, obtained by centrifugation of only 100 microliter of whole blood, provided an enriched population of polymorphonuclear leukocytes (PMNs). The total reaction mixture, consisting of leukocytes-luminol-inducer (opsonized zymosan), was 450 microliter. Peak CL activity was seen 5 min after addition of inducer at 37 degrees C with cells tested within 60 min after collection. Tests to determine precision and reproducibility of the microassay gave a coefficient of variation of 8.5% and 11%, respectively. There was no significant difference between the mean peak CL values for 20 healthy adult donors compared to 14 premature neonates, however, the newborns' CL activity declined more rapidly; CL activity was severely depressed in cells obtained from a patient with chronic granulomatous disease. Results suggest that this microassay provides a simple, rapid, and reliable test of phagocytic function in cases where the amount of blood available for testing is limited.

A comparison of intrapartum versus immediate postpartum treatment of intra-amniotic infection.

There are no reported randomized trials to determine the ideal timing of antibiotic treatment for intra-amniotic infection. We evaluated the effect of intrapartum versus immediate postpartum treatment of intra-amniotic infection on maternal and neonatal morbidity and mortality. Two hundred fifty-seven women with clinically diagnosed intra-amniotic infection who had amniotic fluid cultures were evaluated. Patients received treatment with penicillin and gentamicin, but the timing of the treatment was determined at the physician's discretion. Most patients (82%) received intrapartum treatment; the remaining women (18%), mainly those with an anticipated short interval before delivery, received the same antibiotics immediately postpartum. As expected, the postpartum treatment group had a significantly shorter diagnosis-to-delivery interval (1.9 +/- 2.1 versus 4.7 +/- 4.3 hours; P less than .001) and a lower maximum temperature during labor (100.8 +/- 0.7 versus 101.0 +/- 0.8F; P = .038). The two treatment groups did not differ in distribution of low birth weight infants, frequency of maternal bacteremia, mode of delivery, or organisms isolated from the amniotic fluid. There were no differences in maternal outcome, but the incidence of neonatal sepsis was significantly lower in the intrapartum treatment group (2.8 versus 19.6%; P less than .001). Neonatal mortality from sepsis was also lower in the intrapartum treatment group (0.9 versus 4.3%), but this difference was not statistically significant. The reduced frequency of neonatal septicemia observed in the intrapartum-treated group might reflect early intrauterine therapy for the infected fetus.

Postnatal alteration in hematocrit and viscosity in normal and polycythemic infants.

This study was done to document postnatal alterations in hematocrit and viscosity in the first 18 hours of life in 99 full-term infants, to better understand the age-dependent variations in these measurements that may have a bearing on the diagnosis of neonatal polycythemia. The peripheral venous Hct was highest at 2 hours of age, and dropped to cord blood levels by 18 hours. The whole blood viscosity of peripheral venous samples did not change significantly with age. In infants with peripheral venous Hct greater than or equal to 64%, and therefore considered to have polycythemia, a similar postnatal variation in Hct level was seen. Only 38% of infants with Hct greater than or equal to 64% at 2 hours of age continued to have a high level beyond 12 hours of age. The viscosity level in these infants tended to follow that of the Hct. The mean +/- 2 SD viscosity values obtained from peripheral venous samples was much higher than the upper limits of viscosity used in previous studies in which cord blood viscosity was used as the norm. Cord blood Hct correlated better with peripheral venous Hct than with capillary hematocrit, and provided a noninvasive method for screening. These findings suggest that the postnatal variations in Hct should be taken into consideration in the diagnosis of neonatal polycythemia.

Operative closure of patent ductus arteriosus in premature infants in the neonatal intensive care unit.

Fifty-two premature infants underwent hemoclip closure of patent ductus arteriosus in the neonatal intensive care unit after a brief trial of fluid restriction and diuretics. Indomethacin was used in only four patients. The median time from diagnosis to operation was 3 days. There were no deaths directly attributable to operation. Nine operative complications developed in nine patients (17 percent). There were no surgical infections. Complications related to prematurity resulted in 20 deaths (38 percent). Patent ductus arteriosus closure in the neonatal intensive care unit prevented the complications of hypothermia, inadvertent extubation, and interruption of vascular access and monitoring. Early operative closure in the neonatal intensive care unit is the treatment of choice in most premature infants with patent ductus arteriosus.

Cohort study of Silastic obstetric vacuum cup deliveries: II. Unsuccessful vacuum extraction.

In a cohort analysis of Silastic vacuum extractor deliveries, 65% were completed with the vacuum extractor alone, 24% with outlet forceps, 3% with midforceps, and 7% with cesarean section (vacuum extractor-cesarean). Control groups were formed by using the next sequential forceps delivery, spontaneous vaginal delivery, and every second cesarean section after a trial of labor. The infants were examined using a neurobehavioral scale, an encephalopathy assessment, cranial ultrasound, and indirect ophthalmoscopy. In the combined vacuum extractor and forceps delivery subgroup (vacuum extractor-forceps), all but 3% were converted from a high mid-forceps delivery to outlet forceps by the initial vacuum extractor procedure, thus eliminating many difficult midforceps deliveries. The study yielded no significant difference in maternal morbidity between vacuum extractor-forceps and forceps delivery, no difference in vaginal trauma for vacuum extractor-cesarean versus vacuum extractor delivery, and no greater hospital stay, infection rate, or need for transfusion for either vacuum extractor-forceps versus forceps delivery or vacuum extractor-cesarean versus cesarean delivery. Neonatal morbidity did not differ between successful and unsuccessful trial of vacuum extractor, except for an increased frequency of retinal hemorrhage. The frequency of scalp trauma, including cephalohematoma, did not differ between vacuum extractor-forceps and forceps delivery, or between vacuum extractor-cesarean and vacuum extractor delivery. For vacuum extractor-forceps versus forceps delivery and vacuum extractor-cesarean versus cesarean section, there were no significant differences in neurobehavioral or encephalopathy scores, or in the frequency of neonatal jaundice, facial palsy, anemia, fractures, or mortality.(ABSTRACT TRUNCATED AT 250 WORDS)

Cohort study of silastic obstetric vacuum cup deliveries: I. Safety of the instrument.

A prospective study was undertaken to determine the safety of the Silastic vacuum extractor. Between November 1982 and July 1983, a cohort of 84 successful vacuum extractor deliveries was examined, using the next sequential forceps delivery and spontaneous vaginal delivery as controls. In addition to routine neonatal morbidity measures, Scanlon early neonatal neurobehavioral scale and a modified Sarnat encephalopathy staging examination were used to critically assess neurologic functioning; a cranial ultrasound scan was performed to look for intracerebral hemorrhage, and an indirect ophthalmologic examination was done to assess the incidence of retinal hemorrhage. The study yielded no significant increase in maternal vaginal trauma for vacuum extractor versus spontaneous vaginal delivery, but there was a significantly greater incidence for forceps delivery (60%) versus vacuum extractor (25%) and more associated blood loss for forceps delivery (P less than .01). There was no significant increase in neonatal morbidity for vacuum extractor compared with forceps delivery nor in serious morbidity compared with spontaneous vaginal delivery. Specifically, for vacuum extractor versus forceps delivery there was no difference in one- and five-minute Apgar scores, extent of resuscitation, cosmetic injury, jaundice, mean neonatal intensive care unit stay, or incidence of retinal hemorrhage. Notably, there was no mortality related to delivery method, but there were two unrelated deaths. There were no cases of intraventricular or subgaleal hemorrhage on clinical or ultrasound examination, but one stillborn infant, who succumbed to a generalized coagulation defect, had a subarachnoid hemorrhage. Finally, there was no significant difference in Sarnat encephalopathy staging or Scanlon neurobehavioral assessment between spontaneous vaginal, forceps, and vacuum extractor deliveries.(ABSTRACT TRUNCATED AT 250 WORDS)

Perinatal mortality in a large perinatal center: five-year review of 31,000 births.

The perinatal mortality rate for 30,928 babies born at Medical Center Hospital, San Antonio, Texas, between 1978 and 1982, was 20.3/1,000 births. Neonatal and fetal mortality rates were, respectively, 10.1/1,000 live births and 10.4/1,000 births. Exclusion of babies who weighed less than 500 gm yielded adjusted fetal, neonatal, and perinatal mortality rates of, respectively, 9.2, 9.8, and 17.9. Birth weight-specific mortality rates were calculated by groups of 250 gm birth weight for all neonates and by increments of 100 gm for babies who weighed 500 to 1,499 gm. Male infants, intrauterine growth-retarded babies, and babies whose mothers were less than 15 years old contributed more deaths than would be expected from the characteristics of the obstetric population. Presumptive cause of fetal death was unknown in 32%, fetal anoxia in 21%, maternal pathologic conditions in 20%, inappropriate fetal growth in 13%, congenital malformations in 8%, and systemic fetal infections in 6%. Leading presumptive causes of neonatal death were immaturity (29%), congenital malformations (18%), hemorrhages (16%), and systemic infections (10%). Hyaline membrane disease and necrotizing enterocolitis contributed, respectively, 7% and 6% of deaths. Past and future trends of perinatal mortality are discussed.

Congenital syphilis: a diagnostic and therapeutic dilemma.

Seventy-eight newborn infants born to mothers with serologic evidence of syphilis (positive serum rapid plasma reagin and fluorescent treponemal antibody-absorption tests) were prospectively evaluated to derive diagnostic and therapeutic criteria for congenital syphilis. Sixty-one infants were asymptomatic with normal serum IgM and normal roentgenograms (Group I). Eight infants had clinical and/or laboratory evidence of infection at birth (Group II). Nine infants presented with late onset infection (Group III). Elevated serum IgM and abnormal roentgenologic findings were consistently present in symptomatic infants in Groups II and III. Cerebrospinal fluid (CSF) examination was normal in all asymptomatic infants and in all infants with late onset disease. One of the eight infants in Group II examined at birth had positive CSF Venereal Disease Research Laboratory determinations, but all other CSF findings were within normal limits, and a second infant with a slight increase in CSF protein had no clinical evidence of central nervous system (CNS) involvement. Of those asymptomatic infants who returned for follow-up 75% and 100% were seronegative by 3 and 6 months, respectively. The symptomatic infants remained seropositive up to 18 months of age. Infants who had no clinical evidence of CNS involvement at birth remained normal at follow-up and had normal CSF findings. The two infants with CNS symptoms at birth continued to have developmental delay despite normal CSF findings. The incidence of CNS involvement in congenital syphilis appears to be extremely low. The value of routine spinal fluid examination is discussed.

Penicillin in infants weighing two kilograms or less with early-onset Group B streptococcal disease.

We studied the effect of penicillin on early-onset Group B streptococcal disease over a 52-month period in neonates who were at high risk of infection. Shortly after birth, 1187 neonates weighing 2000 g or less had blood samples taken for cultures and were randomized into an early-treatment group (given intramuscular penicillin G within 60 minutes of birth) or a control group. The incidence of early-onset disease was 20 per 1000 live births (24 of 1187); the number of infants in the early-treatment group who had disease (10 of 589) was similar to that in the control group (14 of 598). The fatality rates were similar in both groups (6 of 10 vs. 8 of 14). Cultures from blood obtained with one hour of birth were positive in 21 of the 24 infants with disease; 22 of the 24 were symptomatic within four hours of birth. Thus, infection was well established before the first hour of postnatal life. At autopsy, gram-positive cocci were seen in lung sections of four infants in whom cultures of blood obtained after treatment had been sterile; this indicates that giving routine antibiotic therapy before culture samples are obtained can obscure bacteriologic diagnosis. We conclude that penicillin given at birth to neonates weighing 2000 g or less does not prevent early-onset streptococcal disease or reduce excess mortality associated with disease.

Body water estimates in neonatal polycythemia.

To determine whether neonatal polycythemia and its treatment by partial exchange transfusion affect body water estimates, 10 normocythemic and eight polycythemic neonates were studied within 12 hours of birth. Total body water, extracellular water, and plasma volume were estimated immediately prior to and following exchange. Intracellular and interstitial water contents were calculated. There were no significant differences between normocythemic and preexchange polycythemic neonates in mean total body water, extracellular water, interstitial water, and intracellular water contents. In the polycythemic group, exchange did not affect mean total body water, but was associated with decreases in mean extracellular water and mean interstitial water and an increase in mean intracellular water. Mean transcapillary escape rate of T-1824 was not affected by exchange but was quite rapid both before (35 +/- SE 3%/hr) and after the procedure (30 +/- 4.9%/hr). These data suggest that moderate polycythemia in normal term neonates does not affect total and extravascular body water estimates, but that a fluid shift from the extracellular to the intracellular space may accompany the exchange procedure.

Neonatal polycythemia: I. Criteria for diagnosis and treatment.

In order to better define criteria for diagnosis and treatment of neonatal polycythemia, 74 neonates with peripheral venous hematocrit levels greater than or equal to 65% were studied. The hematocrit levels of capillary (Cap Hct), peripheral venous (PV Hct), and umbilical venous (UV Hct) blood was measured. Viscosity of umbilical venous blood (UV eta) was determined. Mean +/- SE Cap Hct (75 +/- 0.5%) was significantly higher than PV Hct (71 +/- 1.0%, P less than .001) and PV Hct was higher than mean UV Hct (63 +/- 0.6%, P less than .001). Cap Hct correlated with neither PV Hct nor UV Hct, but PV Hct and UV Hct correlated moderately (r = .54, P less than .001). Of the neonates with UV Hct greater than or equal to 63%, 80% and UV eta in excess of 3 SD above the normal mean (in excess of 14.6 cps at shear rate 11.5 sec(-1)), whereas 94% of the neonates with UV Hct less than 63% had UV eta within normal range. Neonates with hyperviscosity were seen with two or more clinical symptoms more often than their peers with normal viscosity (P less than .04). Partial exchange transfusion in 21 neonates reduced mean UV Hct from 61 +/- 1.1% to 50 +/- 1.0% (P less than .001) and mean UV eta from 13.0 +/- 0.64 cps to 8.6 +/- 0.54 cps (P less than .001). These data suggest that Cap Hct and PV Hct may be used to screen neonates for polycythemia, but that the final diagnosis and therapeutic decisions should be based on UV Hct or even preferably on UV eta. They further suggest that UV Hct greater than or equal to 63% is strongly indicative of hyperviscosity and should be treated by partial exchange transfusion.

Neonatal polycythemia: II. Plasma, blood and red cell volume estimates in relation to hematocrit levels and quality of intrauterine growth.

Volumes of plasma (PV), blood (BV), and red cells (RCV) were estimated within 32 hours of birth in 39 neonates with normal growth, 14 neonates with intrauterine growth retardation, and 20 neonates with macrosomia. Total PV, BV, and RCV increased linearly with birth weight and were unaffected by deviation in the quality of fetal growth. In proportion to body weight, PV/kg, BV/kg, and RCV/kg correlated neither with birth weight nor with the quality of intrauterine growth. Neonates with umbilical vein hematocrit (UV Hct) levels 51% to 60%, 61% to 65%, and 66% to 77% had progressively lower, but not statistically different, mean PV/kg (38.1 +/- 4.49, 37.6 +/- 5.41, and 34.8 +/- 5.16 ml/kg, respectively). On the other hand, they had progressively higher mean BV/kg (90 +/- 10.1 vs 101 +/- 13.7 ml/kg, P less than .002, and vs 110 +/- 19.0 ml/kg, P less than .001). They also had progressively higher mean RCV/kg (52 +/- 7.4, 64 +/- 8.7, and 75 +/- 16.4 ml/kg, P less than .001). Although PV/kg did not correlate with UV Hct, both BV/kg and RCV/kg increased linearly with increasing UV Hct (r = .58 and r = .79, respectively). Volume estimates were repeated after partial exchange transfusion in 29 neonates. Mean UV Hct decreased from 63 +/- 5.9% preexchange to 51 +/- 5.2% postexchange (P less than .001), mean PV increased from 37.7 +/- 5.56 to 47.6 +/- 7.99 ml/kg (P less than .001) and mean RCV decreased from 67 +/- 16.5 to 51 +/- 12.3 ml/kg (P less than .001). Despite precautions to keep the partial exchange isovolemic, mean BV decreased from 105 +/- 18.7 to 98 +/- 18.0 ml/kg (P = .001) and the mean PV increase (10 ml/kg) was less than the mean RCV decrease (16 ml/kg). These data suggest that neonates with polycythemic have normal PV but their RCV and BV are elevated in direct proportion to UV Hct. "Isovolemic" partial exchange transfusion decreases UV Hct, RCV, and BV and increases PV.

Candida albicans meningitis in a premature neonate successfully treated with 5-fluorocytosine and amphotericin B: a case report and review of the literature.

Candida albicans meningitis was diagnosed in a 45-day-old premature infant whose birth weight was 1,616 gm. Symptoms consisted of poor weight gain and poor suckling. The combined use of amphotericin B and 5-fluorocytosine (5-FC) resulted in negative CSF cultures after 12 days of therapy. Amphotericin B was given for 45 days (total 83 mg) and 5-FC for 60 days (total 19 mg). Only one other premature infant has been reported in the literature who had similar treatment. A review of Candida meningitis diagnosed before death in 11 other infants less than 1 year of age is presented.