Search

Summary Background Use of free fetal DNA to diagnose fetal chromosomal abnormalities has been hindered by the inability to distinguish fetal DNA from maternal DNA. Our aim was to establish whether single nucleotide polymorphisms (SNPs) can be used to distinguish fetal DNA from maternal DNA—and to determine the number of fetal chromosomes—in maternal blood samples. Methods Formaldehyde-treated blood samples from 60 pregnant women and the stated biological fathers were analysed. Maternal plasma fractions were quantified at multiple SNPs, and the ratio of the unique fetal allele signal to the combined maternal and fetal allele signal calculated. The mean ratios of SNPs on chromosomes 13 and 21 were compared to test for potential fetal chromosomal abnormalities. Findings The mean proportion of free fetal DNA was 34·0% (median 32·5%, range 17·0–93·8). We identified three samples with significant differences in the fetal DNA ratios for chromosome 13 and chromosome 21, indicative of trisomy 21; the remaining 57 samples were deemed to be normal. Amniocentesis or newborn reports from the clinical sites confirmed that the copy number of fetal chromosomes 13 and 21 was established correctly for 58 of the 60 samples, identifying 56 of the 57 normal samples, and two of the three trisomy 21 samples. Of the incorrectly identified samples, one was a false negative and one was a false positive. The sensitivity and positive predictive value were both 66·7% (95% CI 12·5–98·2) and the specificity and negative predictive values were both 98·2% (89·4–99·9). Interpretation The copy number of chromosomes of interest can be directly established from maternal plasma. Such a non-invasive prenatal test could provide a useful complement to currently used screening tests.

Fetal cells enter maternal blood during pregnancy and persist in women with autoimmune disease. The frequency of subsequent fetomaternal microchimerism in healthy women and its cell type is unknown. To test the hypothesis that fetal mesenchymal stem cells persist in maternal organs, we studied female bone marrow and ribs. Male cells were identified by XY fluorescence in-situ hybridisation in marrow-derived mesenchymal stem cells and in rib sections from all women with male pregnancies, but not in controls (9/9 vs 0/5, p=0.0005). We conclude that fetal stem cells transferred into maternal blood engraft in marrow, where they remain throughout life. This finding has implications for normal pregnancy, for obstetric complications that increase fetomaternal trafficking, and for graft survival after transplantation.

Summary Background During pregnancy, maternal cells pass into the fetus, where they can persist for many years after birth. We investigated the presence of maternal cells in neonatal lupus syndrome (NLS), an autoimmune disease that develops in utero. The most serious complication of NLS is inflammation of the atrioventricular node leading to congenital heart block (CHB). Methods In a blinded case-control study, maternal (female) cells were detected and quantified in male NLS and control heart-tissue samples. We used fluorescence in-situ hybridisation to label X and Y chromosomes. Studies in transplantation suggest that donor cells can differentiate into somatic tissue cells. Therefore, we asked whether maternal cells transferred in utero have cellular plasticity. To simultaneously identify and characterise maternal cells, we developed a technique by which multiple phenotypic markers could be detected concurrently with fluorescence in-situ hybridisation in the same cells of a tissue section. Findings Maternal cells were found in 15 of 15 sections of NLS heart tissue, ranging from 0·025% to 2·2% of total cells. By contrast, maternal cells were found in two of eight control sections (0–0·1%). Very few maternal cells expressed the haemopoietic cell marker CD45. Most expressed sarcomeric α actin, a specific marker for cardiac myocytes. Interpretation Our findings suggest that differentiated tissue-specific maternal microchimerism can occur in neonates. Thus, semiallogeneic maternal cells could be the target of an immune response. Alternatively, maternal cells could contribute to a secondary process of tissue repair.

Summary Mononuclear cells in umbilical-cord blood display allergen-specific reactivity, but how allergen exposure occurs in utero is unknown. We investigated the presence of a common inhalant allergen (Der p 1), to which mothers are exposed throughout pregnancy, by ELISA in matched maternal blood and amniotic fluid samples at 16–17 weeks of gestation, and in matched maternal and umbilical-cord blood at term (≥37 weeks of gestation). Der p 1 was detectable in 24 of 43 amniotic fluid samples where it was also present in maternal blood, and in 15 of 24 cord-plasma samples at significantly higher concentrations than in the maternal plasma (p=0·022). The detection of Der p 1 in the amniotic fluid and the fetal circulation provides direct evidence of transamniotic and transplacental allergen exposure.

Juvenile dermatomyositis is a disease with similarities to chronic graft-versus-host disease. To identify whether chimerism is present in juvenile dermatomyositis, we investigated the families of 15 children with the disorder. Chimerism was identified by PCR in 13 of the 15 affected children, compared with five of 35 siblings (p0.0001). Maternal cells among peripheral-blood mononuclear cells were detected in 11 of the 15 boys, compared with five of 17 unaffected controls (p=0.02), and in muscle tissue of 12 of 15 compared with two of ten unaffected siblings (p=0.005). These results suggest that chimerism may be involved in juvenile dermatomyositis.

Studies assessing the risk of congenital malformations associated with the treatment of asthma during the first trimester of pregnancy are few, have limited power and support continuation of treatment.