Malaria in Early Pregnancy and the Development of the Placental Vasculature.

BACKGROUND: Pregnancy malaria has a negative impact on fetal outcome. It is uncertain whether infections in early pregnancy have a clinical impact by impeding the development of the placental vasculature. METHODS: Tanzanian women (n = 138) were closely monitored during pregnancy. Placentas collected at birth were investigated using stereology to establish the characteristics of placental villi and vessels. Placental vasculature measures were compared between women infected with malaria and controls. RESULTS: Compared with controls, placentas from women infected with malaria before a gestational age (GA) of 15 weeks had a decreased volume of transport villi (mean decrease [standard deviation], 12.45 [5.39] cm3; P = .02), an increased diffusion distance in diffusion vessels (mean increase, 3.33 [1.27] µm; P = .01), and a compensatory increase in diffusion vessel surface area (mean increase, 1.81 [0.74 m2]; P = .02). In women who had malaria before a GA of 15 weeks diffusion vessel surface area and transport vessel length distance were positive predictors for birth weight (multilinear regression: P = .007 and P = .055 for diffusion surface area and transport length, respectively) and GA at delivery (P = .005 and P = .04). CONCLUSIONS: Malaria infection in early pregnancy impedes placental vascular development. The resulting phenotypic changes, which can be detected at delivery, are associated with birth weight and gestational length. CLINICAL TRIALS REGISTRATION: NCT02191683.

Partial duplication of 13q31.3-q34 and deletion of 13q34 associated with diaphragmatic hernia as a sole malformation in a fetus.

Partial duplications and deletions of chromosome 13 are rare and the phenotypic expressions of both aneuploidies are highly variable. Here we report on a fetus diagnosed prenatally with partial trisomy of 13q and a diaphragmatic hernia as a sole malformation. The parents had decided to terminate the pregnancy after the finding of diaphragmatic hernia by ultrasound scan, which was also confirmed by autopsy of the fetus. Subsequently chromosome analysis, fluorescence in situ hybridization (FISH), and array comparative genomic hybridization (array CGH) was carried out on fetal tissue. The chromosome analysis revealed additional material on chromosome 13, which was shown to be from the same chromosome, by FISH analysis. Array CGH demonstrated a partial duplication and a small deletion at the distal long arm of chromosome 13. The parents had normal karyotypes. This is the first case of a de novo pure partial duplication of 13q31.3-q34 and distal deletion of 13q34 with a phenotype apparently only involving a diaphragmatic hernia and three lung lobes on both sides. Microarray analysis was useful in refining the chromosomal imbalance and suggesting a candidate region for diaphragmatic hernia.

Anemia in late pregnancy induces an adaptive response in fetoplacental vascularization.

INTRODUCTION: Anemia during pregnancy may compromise fetal and newborn's health, however, little is known about how and when the fetoplacental vascularization is most vulnerable to anemia. METHODS: Using systematic and isotropic uniform random sampling, placental samples were collected from 189 placentas in a cohort study of Tanzanian women whose hemoglobin concentration was measured throughout pregnancy. Fetoplacental vessels and villi were defined as exerting either a transport or diffusion function. The vascularization patterns for transport and diffusion vessels and villi were assessed by stereology. Blood vessel length, surface area and diffusion distance as well as placental villi volume were calculated. RESULTS: Anemia from a gestational age of 23 weeks was significantly associated with increased fetoplacental vascularization in vessels and villi compared to women who were non-anemic throughout pregnancy. Transport surface vessel area: 0.31 m2 [95% CI: 0.18-0.55], P = 0.01; Transport villi volume 19.8 cm3 [95% CI: 6.37-33.2], P = 0.004, Transport vessel diameter 7.23 µm [95% CI: 1.23-13.3], P = 0.02. Diffusion vessel surface: 3.23 m2 [95% CI: 1.55-4.91], P < 0.001 and diffusion villi volume: 29.8 cm3 [95% CI: 10.0-49.5], P = 0.003). Finally, all the measured transport vessel and villi significantly parameters and diffusion vessel surface, vessel diameter and diffusion distance were associated with birth weight. DISCUSSION: Increased fetoplacental vascularization related to anemia from a gestational age of 23 weeks in pregnancy together with the association between fetoplacental vascularity and birth weight suggest that the timing of anemia determines the effect on fetoplacental vascularization and underlines the clinical relevance for proper development of fetoplacental vasculature.

Transient neonatal diabetes, ZFP57, and hypomethylation of multiple imprinted loci: a detailed follow-up.

OBJECTIVE: Transient neonatal diabetes mellitus 1 (TNDM1) is the most common cause of diabetes presenting at birth. Approximately 5% of the cases are due to recessive ZFP57 mutations, causing hypomethylation at the TNDM locus and other imprinted loci (HIL). This has consequences for patient care because it has impact on the phenotype and recurrence risk for families. We have determined the genotype, phenotype, and epigenotype of the first 10 families to alert health professionals to this newly described genetic subgroup of diabetes. RESEARCH DESIGN AND METHODS: The 10 families (14 homozygous/compound heterozygous individuals) with ZFP57 mutations were ascertained through TNDM1 diagnostic testing. ZFP57 was sequenced in probands and their relatives, and the methylation levels at multiple maternally and paternally imprinted loci were determined. Medical and family histories were obtained, and clinical examination was performed. RESULTS: The key clinical features in probands were transient neonatal diabetes, intrauterine growth retardation, macroglossia, heart defects, and developmental delay. However, the finding of two homozygous relatives without diabetes and normal intelligence showed that the phenotype could be very variable. The epigenotype always included total loss of methylation at the TNDM1 locus and reproducible combinations of differential hypomethylation at other maternally imprinted loci, including tissue mosaicism. CONCLUSIONS: There is yet no clear genotype-epigenotype-phenotype correlation to explain the variable clinical presentation, and this results in difficulties predicting the prognosis of affected individuals. However, many cases have a more severe phenotype than seen in other causes of TNDM1. Further cases and global epigenetic testing are needed to clarify this.

Stereologic examination of placentas from mothers who smoke during pregnancy.

OBJECTIVE: Structural changes in the placenta might contribute to the lower birth weight seen among infants born to mothers who smoke cigarettes. In this study, a morphologic examination and a stereologic quantitation of placentas from mothers who smoked cigarettes and who did not smoke cigarettes during pregnancy were performed. STUDY DESIGN: Twenty-five placentas from mothers who did not smoke cigarettes, 15 placentas from mothers who smoked 5 to 10 cigarettes per day, 16 placentas from mothers who smoked 11 to 20 cigarettes per day, and 16 placentas from mothers who smoked >20 cigarettes per day were delivered at term after normal pregnancies and were fixed by dual perfusion. The volume and the surface area of villi, the trophoblast volume, and the volume and the surface area and length of villous capillaries were estimated. A measurement of the concentration of cadmium in serum was used to assess the validity of information concerning smoking habits. RESULTS: No differences were shown in the total volume of placenta between the groups. The estimated volume and surface area and the calculated lengths for villous capillaries were significantly reduced in all 3 groups of smokers. A significant increase of the trophoblast volume was observed in the mothers who smoked cigarettes. CONCLUSION: Cigarette smoking during pregnancy influences the placental vasculature. The reduced dimensions of fetal capillaries in villi may affect the placental blood flow, and the diminished area for exchange of gases and nutrients between the mother and the fetus will increase the risk of fetal undernourishment.