Karin J. Blakemore

Acquired spinal cord injury in human fetuses with myelomeningocele.

Experimental studies have shown that there is a potential to attempt in utero repair of myelomeningocele in human fetuses. To provide a better understanding of the pathology of these lesions we prospectively studied eight stillborn human fetuses with myelomeningocele autopsied at The Johns Hopkins Hospital. The intact vertebral column with surrounding structures was removed, processed as a single block, and prepared as serial histologic sections. Study of the slides showed in all cases that in the center of the myelomeningocele the vertebral arch was open, the arrangement of meninges was such that the dura mater was open and in continuity with the deep layers of the dermis, and the pia mater was open and in continuity with a layer consisting of the superficial dermis and the epidermis. These meningeal relationships created an abnormally configured arachnoid space containing cerebrospinal fluid ventral to the spinal cord, which rested on the open pia mater and was exposed on the dorsal aspect of the sac. At the level of the myelomeningocele the naked cord had undergone varying degrees of injury up to complete loss of neural tissue. Where ventral remnants of the cord remained it was evident that a large degree of normal development of the cord had occurred. In most instances it appeared that the injury or destruction of the dorsal spinal cord was recent and consistent with occurrence during delivery. The results of this study support the concept that in utero surgery could preserve and protect the exposed spinal cord in a myelomeningocele of a human fetus and thus could reduce the severity of the neurologic deficit at birth.

Gene frequencies of the five major human platelet antigens in African American, white, and Korean populations

BACKGROUND: The study of the immunogenetics of the human platelet antigens is important to the improvement of diagnosis and genetic counseling and to the development of screening programs for women at risk of having babies with neonatal alloimmune thrombocytopenia. Description of the immunogenetics of the human platelet antigens in some racial groups has been incomplete.

Preterm Labor, Placental Abruption, and Premature Rupture of Membranes in Relation to Maternal Violence or Verbal Abuse

OBJECTIVE The prevalence of preterm labor (PTL) in prenatal populations has been estimated to be from 6.9 to 10.0%. It has been suggested that violence during pregnancy may be associated with an increase in antenatal complications. The hypothesis is that physical violence and verbal abuse in pregnancy lead to increased risk of PTL. METHODS A cohort of 636 women attending the Adult Obstetrical Clinic for their first prenatal visit, between December 1989 and September 1990, were approached; 567 women enlisted as study participants. Study participants were interviewed 3 times during the course of their prenatal care, and 401 participants successfully completed their third prenatal interviews. Violence data were obtained during the third interview. Obstetrical and neonatal outcome data were obtained by abstracting the maternal and neonatal medical records. RESULTS When stratified by levels of violence, women who experienced moderate or severe violence had incidences of PTL of 15.4 and 17.2%, respectively. Chi-square test for homogeneity revealed a significant difference among these groups. CONCLUSIONS In our cohort of women, serious acts of verbal abuse and physical violence occurred with significant frequency. PTL was strongly correlated with increasing acts of violence with 4.1 times greater risk of PTL in women who experienced severe violence as compared to those who experienced no maternal abuse.

Engraftment following in utero bone marrow transplantation for globoid cell leukodystrophy

To date, in utero bone marrow transplantation (BMT) has had limited success, largely because of poor donor engraftment. The poor engraftment is probably the result of performing the procedure late in gestation after significant fetal immunocompetence has developed and/or transplanting insufficient numbers of donor hematopoietic stem cells for competing successfully with ongoing fetal hematopoiesis. To overcome these problems, we performed in utero BMT on a fetus with globoid cell leukodystrophy during the first trimester of gestation using selected paternal bone marrow stem (CD34+) cells. CD34 selection allowed a substantially greater number of stem cells to be transplanted. Although the fetus died 7 weeks after the procedure (during the 20th week of gestation), full donor engraftment was established. Moreover, the cause of death appeared to be overwhelming donor engraftment and leukostasis with paternal myeloid cells infiltrating most tissues. The ability of in utero BMT to produce this degree of engraftment provides great promise for the use of this approach in the treatment of a variety of inherited disorders that can be diagnosed prenatally.

The degree of antenatal ventriculomegaly is related to pediatric neurological morbidity

Objective: Our hypothesis was that the degree of antenatally diagnosed cerebral ventriculomegaly is related to aneuploidy, perinatal mortality and long-term neurological morbidity. Methods: Ninety-one cases of ventriculomegaly identified from 1 June 1994 to 1 July 1999 were examined for prenatal, intrapartum and neonatal complications. Pediatric follow-up was reviewed for infants with ventriculomegaly from birth up to as long as 4 years. Minor neurological morbidity was defined as a score of 70-80 on the clinical adaptive test/clinical linguistic and auditory milestone scale and included mild motor or language delay. Major morbidity included a score of < 70, evidence of cerebral palsy, or seizure disorder. The incidence of neurological complications was compared, on the basis of the degree of ventriculomegaly, with group 1 being > 10-15 mm and group 2 being > 15 mm. Results: Twenty-seven cases (18 with neural tube defects and nine with holoprosencephaly) were excluded. Among the remaining 64 patients, 39 had a ventricular diameter of > 10-15 mm and comprised group 1. Five of the 39 cases (12.8%), all with other ultrasound anomalies, elected to terminate. The incidence of aneuploidy in group 1 was 14.2%. Among the 19 cases with isolated ventriculomegaly, 17 (89%) were normal and two (11%) had minor neurological morbidity. In group 1 there were two cases associated with cytomegalovirus (CMV) infection. Of the 25 cases in group 2, eight (32%), all with other ultrasound anomalies, elected to terminate. The incidence of aneuploidy in group 2 was 17.4%. For the nine cases with isolated ventriculomegaly of > 15 mm, one (11%) was normal ( p < 0.001), five (56%) had minor neurological morbidity requiring a ventriculoperitoneal shunt ( p = 0.035), and three (33%) had major neurological morbidity ( p = 0.045) when compared to cases of isolated ventriculomegaly in group 1. There was one case of CMV infection in group 2. All perinatal deaths in both groups were associated with other anomalies. Conclusions: Amniocentesis to determine karyotype and the presence of CMV is warranted for all cases of ventriculomegaly of > 10 mm. The degree of antenatal ventriculomegaly is related to pediatric neurological morbidity and, when it is > 15 mm, it is associated with an increase in abnormal neurological development.

Multiple anomalies in a fetus exposed to low-dose methotrexate in the first trimester

BACKGROUND Methotrexate has multiple therapeutic uses in women of reproductive age including treatment for ectopic pregnancy, neoplastic disease, autoimmune disorders, and inflammatory conditions. More frequent use of methotrexate may result in an increased number of exposures in pregnant women and their fetuses. CASE A 16‐year‐old gravida 1, para 0 used oral methotrexate treatment of 7.5 mg per day for psoriasis for 2 days at 3.5 weeks postconception. Multiple anomalies were noted on an 18‐week ultrasound. Fetopsy revealed craniofacial, axial skeletal, cardiopulmonary, and gastrointestinal abnormalities. CONCLUSION A minimal, low‐dose, brief exposure to methotrexate in the first trimester resulted in a fetus with multiple internal and external malformations. Some of the anomalies (craniofacial and skeletal) have been previously reported with first‐ trimester methotrexate exposure. This case depicts the association of cardiopulmonary and gastrointestinal abnormalities with methotrexate exposure.

Reevaluating confined placental mosaicism

Chromosomal mosaicism was found in 38 of 4,000 chorionic villus samples examined from 1998 to 2003. A small fraction of these (5/38) were confirmed as true mosaics by analysis of amniotic fluid. Twenty‐nine cases that fit the definition of confined placental mosaicism were followed with clinical and cytogenetic analysis throughout the pregnancy, at birth and in a few cases into infancy. This was done to determine the prognostic interpretation of prenatal cytogenetic results from multiple specimens in a single pregnancy and thus allow for reevaluation of the genetic counseling. In 2 of these 29 cases, low‐level mosaicism was found in the neonate, and in 1 of these the chromosome abnormality is probably the cause of the resulting minor phenotypic abnormalities. Families face unique difficulties when confined placental mosaicism is the prenatal diagnosis, and it is extremely important that the counseling they receive takes into consideration the unlikely possibility of the placental abnormality appearing in fetal tissues.

Demonstration of myc and ras oncogene expression by hybridization in situ in hydatidiform mole and in the BeWo choriocarcinoma cell line

With the use of hybridization in situ, c-myc and c-ras oncogene expression has been identified in the cytotrophoblast of hydatidiform mole and in the malignant trophoblast cell line BeWo. Expression was also found in early villous placenta. No expression of these two oncogenes was found in the cytotrophoblast of an 11-week conceptus, nor was it found in term placenta. The significance of these findings is discussed.

Second-trimester maternal serum analyte levels associated with fetal trisomy 13 †

The aim of this study was to determine whether pregancies affected by fetal trisomy 13 are associated with second‐trimester maternal serum analyte levels different from those typical of the unaffected population. Pregnancies with trisomy 13 were identified through cytogenetics laboratories. Those which had second‐trimester maternal serum screening analyte measurements were further evaluated. Maternal serum analyte levels for each case and five matched controls were statistically analysed by matched ranked‐sum analysis. 28 cases of fetal trisomy 13 were identified. The median AFP, uE3 and hCG levels were 1.35 MoM, 0.71 MoM and 0.90 MoM, respectively. Only uE3 levels were statistically different (p<0.01) from those for the unaffected population. These data suggest that second‐trimester maternal serum AFP, uE3 and hCG levels are not useful in detecting fetal trisomy 13 and protocols already existing for Down syndrome or trisomy 18 screening will not detect the majority of cases of this aneuploidy. Copyright

Association of prematurity and neonatal infection with neurologic morbidity in very low birth weight infants

OBJECTIVE To identify risk factors predictive of neurologic morbidity in very low birth weight (VLBW) infants. METHODS This is a case–control study of all infants weighing 1500 g or less admitted to a single tertiary neonatal intensive care unit between April 1999 and December 2001. The case group were those neonates with neurologic morbidity including intraventricular hemorrhage, seizures, hydrocephalus, and periventricular leukomalacia. The control group were those without neurologic morbidity. Wilcoxon rank-sum, Fisher exact test, χ2, and univariate and stepwise multiple logistic regression were performed, with P < 0.05 considered significant. RESULTS Of 213 VLBW infants, 77 had neurologic morbidity: 61 had intraventricular hemorrhage, eight had seizures, 13 had hydrocephalus, and nine had periventricular leukomalacia. Several infants had more than one morbidity. Gestational age (odds ratio [OR] 0.95; 95% confidence interval [CI] 0.94, 0.96; P < .005), birth weight (OR 0.62; 95% CI 0.49, 0.79; P < .005), and neonatal infection (OR 1.36; 95% CI 1.17, 1.58; P < .005) were highly associated with neurologic morbidity. There was no difference in mean umbilical arterial cord pH (7.25 ± 0.15, 7.28 ± 0.09, P = .45) or base excess (−3.8 ± 4.8 mEq/L, −2.3 ± 3.0, P = .10). Only three of 52 infants (5.8%) in the case group had an umbilical arterial pH of less than 7. CONCLUSION Prematurity and neonatal infection were the dominant factors associated with neurologic morbidity in VLBW infants. Intrapartum acidosis occurred in less than 6% of those with neurologic morbidity.