Obstetric clinical pharmacology: coming of age.

Little is known about changes in drug disposition and effect during pregnancy. In this issue, which is devoted to maternal and child health, Andrew and colleagues from the University of Washington present research describing significant changes in the disposition of amoxicillin during pregnancy. The clinical significance is the potential for inadequate dosing during pregnancy of compounds that are renally cleared. Further research is needed to guide the appropriate, safe, and effective medical treatment of pregnant women. In 2003, the National Institute of Child Health and Human Development (NICHD) formed the Obstetric Pharmacology Research Units Network. This network serves in part as a proof-of-concept platform, to demonstrate that clinical investigations can be performed in pregnant women.

Human Ontogeny of Drug Transporters: Review and Recommendations of the Pediatric Transporter Working Group.

The critical importance of membrane-bound transporters in pharmacotherapy is widely recognized, but little is known about drug transporter activity in children. In this white paper, the Pediatric Transporter Working Group presents a systematic review of the ontogeny of clinically relevant membrane transporters (e.g., SLC, ABC superfamilies) in intestine, liver, and kidney. Different developmental patterns for individual transporters emerge, but much remains unknown. Recommendations to increase our understanding of membrane transporters in pediatric pharmacotherapy are presented.

Vitamin B-6 adequacy in neonatal nutrition: associations with preterm delivery, type of feeding, and vitamin B-6 supplementation.

Concerns about vitamin B-6 adequacy in neonatal nutrition relate to critical functions of the vitamin in development. Vitamin B-6 status was assessed in six groups of neonates: two groups each of breast-fed term and preterm infants whose mothers were supplemented with 2 or 27 mg pyridoxine-hydrochloride (PN-HCl); a subgroup of term infants (2-mg maternal group) supplemented with 0.4 mg PN-HCl/d; and a formula-fed preterm group. During the 28-d experimental period, weekly assessments showed lower concentrations of total vitamin B-6 and percentages of pyridoxal in milk from mothers of preterm infants than in milk from mothers of term infants, even when maternal PN-HCl supplementation was 27 mg/d. The vitamin B-6 concentration of milk and estimated intakes of the vitamin by breast-fed infants paralleled maternal supplements (ie, 2 and 27 mg). Plasma and erythrocyte measurements of infants correlated with their vitamin B-6 intakes; values were highest for infants given vitamin B-6 supplements and those that wee formula-fed. Vitamin B-6 adequacy was questionable for unsupplemented breast-fed infants of mothers in the 2-mg supplemented groups.

Q-oTc interval and blood calcium levels in newborn infants.

The interval from the beginning of the Q wave to the origin of the T wave (Q-oTc interval) and total and ionized serum calcium levels were measured in 27 full-term and 77 premature infants. The correlation between Q-oTc and total and ionized calcium levels was significant in both full-term and normal premature infants. No correlation was found in a group of critically ill premature infants, most of whom had evidence of CNS involvement. Constant infusion of calcium gluconate in a number of infants belonging to the latter group produced a significant shortening of the Q-oTc interval. It is speculated that the lack of correlation of Q-oTc interval and total or ionized calcium levels in sick premature infants could be explained on the basis of a dysfunction in cardiac sympathetics or alternatively by marked variations in serum catecholamines.

Expanded spectrum of findings in Marden-Walker syndrome.

Recently, we examined a small-for-gestational age infant with blepharophimosis, congenital contractures of elbows, hips, and knees, fixed facial expression, and hypotonia. These congenital anomalies are consistent with a diagnosis of the Marden-Walker syndrome. The infant also had an omphalomesenteric duct, left hypoplastic kidney, hypoplastic right lower lobe of the lung, and displacement of the larynx to the right; these anomalies have not been described previously in this syndrome. A summary of the clinical manifestations of the previously reported patients is presented.

Body stalk anomaly: congenital absence of the umbilical cord.

On ultrasound examination, a 20-year-old pregnant woman was found to have a fetus with a large ventral abdominal wall defect diagnosed as a fetal omphalocele. The neonate was delivered by cesarean; the abdominal viscera including liver, stomach, spleen, pancreas, intestine, and uterus were contained in an extraembryonic sac directly attached to the placenta without an umbilical cord. Body stalk anomaly (also known as absence of the umbilical cord syndrome) is a fatal condition resulting from maldevelopment of embryonic body folding and is associated with multiple congenital defects. Prenatal ultrasonographic recognition of the absence of an umbilical cord and direct apposition of the membranous sac to the amniochorionic membrane would permit early termination of pregnancy or avoidance of operative intervention.

Congenital herpes infection: placental and umbilical cord findings.

BACKGROUND: Herpes simplex virus (HSV) fetal infections are rare, and the routes through which the virus reaches the fetus are insufficiently documented. CASE: We describe a case of congenital HSV ascending infection in an infant whose membranes were intact until cesarean delivery. The pathologic findings were remarkable for a mild lymphoplasmocytic funisitis and the presence of positive viral staining of cells in the subamniotic connective tissue, amniotic epithelium, and umbilical cord. Antigen-positive cells within the extraplacental membranes were mostly located in an area presumably adjacent to the cervix before birth. In the umbilical cord, positive viral staining was confined to cells in the subamniotic mesenchyma away from the perivascular mesenchyma of the central portion of the cord. CONCLUSION: Immunohistochemistry using herpes-specific antibodies, coupled with routine histologic examination, allows early diagnosis of congenital HSV infection and documentation of the ascending route of infection when the membranes are intact.

Reproductive hazards in the workplace.

The growing public concern about the presence of toxic substances in the working and living environments has increased the awareness of prospective parents on the potential reproductive damage that may occur as a result of occupational exposure. The obstetrician or gynecologist attempting to counsel a couple about reproductive damage of specific occupational exposure faces a dilemma because of conflicting factors that need to be taken into account. Those factors include lack of a well-defined relationship between exposure at the worksite and reproductive damage, lack of information or conflicting data, economic concerns, and sex discrimination issues. This review describes pathogenic mechanisms of reproductive damage produced by occupational chemical exposure and details common weaknesses and problems in the interpretation and application to clinical practice of the burgeoning literature in the subject. A listing of different chemicals and physical agents suspected of producing reproductive impairment in either membrane of the reproductive dyad is presented. In addition, the legality of the so called "fetal protection policies" is also reviewed. Despite the current scientific uncertainty, knowledgeable health professionals can help parents reach an informed decision about the reproductive risks that they are willing to take when a "zero exposure" environment cannot be guaranteed and allay unfounded fears.

Severe fetomaternal hemorrhage: a review.

The etiology, clinical presentation, obstetrical antecedents, and outcome of pregnancies complicated by large fetomaternal hemorrhage (FMH) were reviewed by doing a MEDLINE search from 1966 to the present and manual search before 1966. One hundred thirty-four infants with FMH > 50 dl were reported in the literature. The primary variables: birth weight, gestational age, presence of sinusoidal fetal heart rate pattern, decrease or absent fetal body movements (FBM) estimated the amount of fetomaternal bleeding and the pretransfusion hemoglobin. Other variables included the condition of the infants at birth, erythroblasts, and reticulocyte blood counts at birth, as well as the year of publication. Thirty-five of the 134 cases were preterm. Twenty infants born to mothers reporting decreased or absent FBM survived. FBM was absent in 17 cases for a period ranging between 24 hours and 7 days. In this group, six infants survived, five were stillborn, and five died in the neonatal period. A sinusoidal heart rate (SHR) pattern was reported in 21 cases. A SHR pattern was associated with decreased FBM in 13 cases (39.3 percent). Fifteen cases with sinusoidal fetal heart rate pattern survived (71.4 percent). Both decreased or absent FBM and SHR patterns were reported more often in 1990 or later than before 1990 (P < .0017 and P < .008, respectively). The cause of FMH was not known in 82 percent of the cases. The most common presenting symptoms of FMH were anemia at birth (35.2 percent), decreased or absent FBM (26.8 percent), and unexpected stillbirths (12.5 percent). Seventeen intrauterine transfusions were performed in nine cases (eight survived). A negative correlation was found between pretransfusion hemoglobin and FMH (r = -0.35; P = .0019). No significant difference was found between the cases with FMH of > 200 ml or < 200 ml. Thus, decreased or absent FBM, SHR pattern, or hydrops fetalis are late signs of FMH. Other means of early detection are needed. The role of intrauterine transfusion (IUT) needs to be better defined. The inadequate outcome data indicate the need to follow infants born with large FMH into childhood to document the effect on the central nervous system.

Autoimmune diseases in pregnancy: their effect on the fetus and newborn.

A variegated group of autoimmune disorders tend to occur in women during childbearing years. Autoantibodies, often of IgG type, directed against the mother's (self) antigens has been well characterized in a number of these disorders. Transplacental transfer of IgG autoantibodies has been frequently demonstrated without demonstrable ill effects of offspring of affected mothers. However, transient neonatal autoimmune syndromes have been described in a subset of infants born with circulating autoantibodies. The time course of clinical symptomatology often parallels the presumed half life IgG immunoglobulins. This review details the clinical manifestations of different transient neonatal autoimmune syndromes and describes possible pathogenic mechanisms. Autoimmune disorders reviewed include connective tissue disorders, thyroid autoimmune disorders, myasthenia gravis, idiopathic thrombocytopenic purpura, and other uncommon disorders.

Cardiac tamponade and hydrothorax as complications of central venous parenteral nutrition in infants.

The recent use of soft catheters made of silastic polymeric silicone or polyurethane has decreased the incidence of perforation of great veins or right-sided heart chambers but has not eliminated it as had been hoped. Two premature infants who presented with cardiac tamponade more than 24 hr after the insertion of a 23-gauge silastic catheter for total parenteral nutrition (TPN) administration are described. In one infant, bilateral hydrothorax preceded the occurrence of cardiac tamponade. Osmotic injury to great vessels and/or myocardium seems to be the common mechanism but which these complications of intraluminal catheters are produced. Review of the pediatric literature revealed a proportion of low birth weight infants among the reported cases. Despite a prohibitively high mortality rate, early recognition can prevent a fatal outcome.

The use of a computer in parenteral alimentation of low birth weight infants.

A computer program which aids in the formulation and preparation of parenteral nutrition fluids for low birth weight infants is described. The program performs a number of calculations for fluid and specific nutrient requirements taking into account environmental conditions, potential renal solute load, deficits, and surpluses. Safety and precipiation checks are also included in the calculations. Its use has considerably reduced the workload on both physician and pharmacy personnel involved in the formulation and preparation of individualized parenteral nutrition solutions for low birth weight infants. A controlled study in 15 very low birth weight infants utilizing this program revealed a reduced incidence of hyperglycemia, decrease in fluctuations in serum sodium, a more physiologic urine osmolality, and a reduction of weight loss in the first days of life.

Rapid turnover transport proteins, plasma albumin, and growth in low birth weight infants.

The purpose of this investigation was to establish normative data and to determine the value of measuring rapid plasma turnover proteins in low birth weight infants during the neonatal period. Forty-three premature, adequate for gestational age infants were divided in three groups according to their birth weight: group A less than 1000 g, group B 1001 to 1500 g, group C 1501 to 2000 g. Weekly anthropometric measurements and biochemical determinations were obtained. Anthropometric measurements included weight, crown heel length, midtricipital skinfold thickness, and midarm circumference. Biochemical studies in plasma included total proteins, albumin, prealbumin, and retinol-binding protein. A significant increase in prealbumin concentration preceded weight gain. The elevation in prealbumin concentration was statistically significant (p less than 0.02) for the combined data from all groups and for infants included in group B and C (p less than 0.05). No concomitant changes were demonstrated in plasma retinol-binding protein, or total proteins. The transient rise in prealbumin plasma concentrations remains unexplained, but may be related to the infant's nutritional status.

Uncommon pathogens in newborn infants.

Newborns, especially premature newborns, are immunocompromised and have increased susceptibility to infections by opportunistic organisms. Experience with these uncommon pathogens is limited to a handful of case reports and to several reports of neonatal intensive care nursery outbreaks. Many of these infections are misdiagnosed or diagnosed at autopsy because of the nonspecific features of their clinical presentation, difficulties in recovering the pathogen from body fluids, or because the microorganism is considered either a contaminant or nonpathogenic. This review summarizes the clinical characteristics of these uncommon pathogens and emphasizes the existence of dual and polymicrobial infections. The limited experience with many of these infections precludes the formulation of an optimal therapeutic approach.

The use of intravenous immunoglobulin (IVIG) to prevent infections in bronchopulmonary dysplasia: report of a pilot study.

The incidence and severity of pneumonia, sepsis, and other infections was evaluated in a group of 30 premature infants with moderate to severe bronchopulmonary dysplasia (BPD), half of whom were randomly treated with intravenous immunoglobulins (group A). The patients were treated until the age of 6 months. They were compared with an untreated control group (group B). The number of pneumonic episodes (5 in group A and 15 in group B) and other infections, excluding sepsis (1 in group A and 7 in group B), were significantly reduced in the treated group (P less than .05). The number of episodes of sepsis, suspected sepsis, and necrotizing enterocolitis were similar in the two groups. The decrease in the number of respiratory and other infections in BPD infants treated with IVIG requires verification by a larger trial.

Evaluation of a new glucose reflectance meter for use in the neonatal intensive care unit.

In this study, a new glucose reflective meter was compared with a conventional laboratory measure of glucose concentration. The excellent correlation found (r = 0.988) simplicity and economic cost make the new method suitable for use in the neonatal intensive care (NICU) environment. The authors believe that the physician dealing with premature or small-for-dates infants, or infants of diabetic mothers, can base emergency therapy on the results obtained by this bedside method of blood glucose measurement pending confirmation by the clinical laboratory.

Indomethacin and recurrent ileal perforations in a preterm infant.

This article reports a case of a very low birth weight infant who was given intravenous indomethacin for a symptomatic patent ductus arteriosus and subsequently had two isolated ileal perforations several days apart. Spontaneous or indomethacin-related ileal perforation appears to constitute a separate clinical and pathologic entity, different from necrotizing enterocolitis, with a benign clinical picture and good prognosis when promptly recognized.

Drugs and pollutants in breast milk.

Mechanisms of transport of environmental pollutants and ingested drugs in breast milk and their absorption in newborn nurslings are outlined. The authors urgently call for additional research to determine which maternal medications are safe for nursing infants.

High-dose urokinase therapy in newborn infants with major vessel thrombosis.

The effectiveness of urokinase therapy for thrombosis in children, particularly in newborn infants, has not been established. We report our experience with the local administration of high-dose intrathrombus urokinase in two newborn infants. One infant had aortic thrombosis and the other, thrombosis of the right femoral artery. The known abnormalities in the newborn's fibrinolytic mechanism provide the rational basis for the therapeutic use of high doses of plasminogen activators. No significant abnormalities of our patients' fibrinolytic systems were found, and effective thrombolysis was achieved. A literature review of the use of urokinase therapy for thrombosis in children reveals great disparities in dosage and outcome. We believe that fixed-dose regimens should be replaced by individually adjusted thrombolytic therapy and that the need for higher doses of urokinase in newborns should be studied further.

Intravenous drug therapy in premature infants: practical aspects.

Most decisions regarding the methods used for intravenous drug delivery are made by nurses. For this reason, neonatal nurses must recognize the unique problems associated with drug delivery to the low birth weight infant. A review of the associated problems is presented along with suggested solutions to aid the nurse in choosing a therapeutic method for intravenous drug administration.