Predicting the risks and recognizing the signs: a two-year prospective population-based study on pregnant women with uterine rupture in The Netherlands.

OBJECTIVE: To estimate the incidence of uterine rupture in the Netherlands and evaluate risk indicators prelabour and during labor of women with adverse maternal and/or perinatal outcome. METHODS: This is a population-based nationwide study using the Netherlands Obstetrics Surveillance System (NethOSS). We performed a two-year registration of pregnant women with uterine rupture. The first year of registration included both women with complete uterine rupture and women with incomplete (peritoneum intact) uterine rupture. The second year of registration included women with uterine rupture with adverse maternal and/or perinatal outcome. We collected maternal and obstetric characteristics, clinical signs, and symptoms during labor and CTG abnormalities. The main outcome measures were incidence of complete uterine rupture and uterine rupture with adverse outcome and adverse outcome defined as major obstetric hemorrhage, hysterectomy, embolization, perinatal asphyxia and/or (neonatal) intensive care unit admission. RESULTS: We registered 41 women with a complete uterine rupture (incidence: 2.5 per 10,000 births) and 35 women with uterine rupture with adverse outcome (incidence: 0.9 per 10,000 births). No adverse outcomes were found among women with incomplete uterine rupture. Risk indicators for adverse outcome included previous cesarean section, higher maternal age, gestational age <37 weeks, augmentation of labor, migration background from Sub-Saharan Africa or Asia. Compared to women with uterine rupture without adverse outcomes, women with adverse outcome more often expressed warning symptoms during labor such as abdominal pain (OR 3.34, 95%CI 1.26-8.90) and CTG abnormalities (OR 9.94, 95%CI 2.17-45.65). These symptoms were present most often 20 to 60 min prior to birth. CONCLUSION: Uterine rupture is a rare condition for which several risk indicators were identified. Maternal symptoms and CTG abnormalities are associated with adverse outcomes and time dependent. Further analysis could provide guidance to expedite delivery.

SARS-CoV-2 infection in pregnancy during the first wave of COVID-19 in the Netherlands: a prospective nationwide population-based cohort study (NethOSS).

OBJECTIVE: To describe characteristics, risk factors and maternal, obstetric and neonatal outcomes of pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). DESIGN: Multi-centre prospective population-based cohort study. SETTING: Nationwide study in the Netherlands. POPULATION: Pregnant women with confirmed SARS-CoV-2 infection admitted to hospital or in home-isolation: 1 March 2020 to 31 August 2020. METHODS: Pregnant women with positive polymerase chain reaction or antibody tests were registered using the Netherlands Obstetrics Surveillance System (NethOSS). (Selective) testing occurred according to national guidelines. Data from the national birth registry (pregnant pre-coronavirus disease 2019 [COVID-19] cohort) and an age-matched cohort of COVID-19-positive women (National Institute for Public Health and the Environment; fertile age COVID-19 cohort) were used as reference. MAIN OUTCOME MEASURES: Incidence of SARS-CoV-2 infection in pregnant women. Maternal, obstetric and neonatal outcomes including hospital and intensive care admission. RESULTS: Of 376 registered pregnant women with confirmed SARS-CoV-2 infection, 20% (74/376) were admitted to hospital, of whom 84% (62/74) were due to SARS-CoV-2; 10% (6/62) were admitted to intensive care and 15% (9/62) to obstetric high-care units. Risk factors for admission were non-European country of origin (odds ratio [OR] 1.73, 95% CI 1.01-2.96) and being overweight/obese (OR 1.86, 95% CI 1.51-3.20). No maternal or perinatal deaths occurred. Caesarean section after labour-onset was increased (OR 1.58, 95% CI 1.09-2.28). Hospital and intensive care admission were higher compared with the fertile age COVID-19 cohort (OR 6.75, 95% CI 5.18-8.81 and OR 2.52, 95% CI 1.11-5.77, respectively). CONCLUSIONS: Non-European country of origin and being overweight/obese are risk factors for severe course of SARS-CoV-2 infection in pregnancy, risk of caesarean section and hospital and intensive care unit admission are increased. TWEETABLE ABSTRACT: Pregnant women with SARS-CoV-2 in the Netherlands show increased hospital/ICU admission and caesarean section.

Defining definitions: a Delphi study to develop a core outcome set for conditions of severe maternal morbidity.

OBJECTIVE: Develop a core outcome set of international consensus definitions for severe maternal morbidities. DESIGN: Electronic Delphi study. SETTING: International. POPULATION: Eight expert panels. METHODS: All 13 high-income countries represented in the International Network of Obstetric Surveillance Systems (INOSS) nominated five experts per condition of morbidity, who submitted possible definitions. From these suggestions, a steering committee distilled critical components: eclampsia: 23, amniotic fluid embolism: 15, pregnancy-related hysterectomy: 11, severe primary postpartum haemorrhage: 19, uterine rupture: 20, abnormally invasive placentation: 12, spontaneous haemoperitoneum in pregnancy: 16, and cardiac arrest in pregnancy: 10. These components were assessed by the expert panel using a 5-point Likert scale, following which a framework for an encompassing definition was constructed. Possible definitions were evaluated in rounds until a rate of agreement of more than 70% was reached. Expert commentaries were used in each round to improve definitions. MAIN OUTCOME MEASURES: Definitions with a rate of agreement of more than 70%. RESULTS: The invitation to participate in one or more of eight Delphi processes was accepted by 103 experts from 13 high-income countries. Consensus definitions were developed for all of the conditions. CONCLUSION: Consensus definitions for eight morbidity conditions were successfully developed using the Delphi process. These should be used in national registrations and international studies, and should be taken up by the Core Outcomes in Women's and Newborn Health initiative. TWEETABLE ABSTRACT: Consensus definitions for eight morbidity conditions were successfully developed using the Delphi process.

Proprioceptively guided reaching movements in 3D space: effects of age, task complexity and handedness.

Aging is associated with impaired upper limb proprioceptive acuity, as reflected by decreased position matching accuracy with increasing task complexity and movement extent. Most studies have primarily used single-joint or planar paradigms to examine age-related changes in proprioception. It is unclear whether these changes can be generalized to more complex multi-joint movements, where additional sensory feedback may affect performance. Since age-related declines in cognitive function may impair the ability to integrate multiple sources of sensory feedback, deficits in position matching ability in older adults may persist when tasks are performed in three-dimensional space. The accuracy with which young and older participants reproduced remembered reference hand positions was assessed under different experimental conditions. Participants matched target locations located directly to the front or 45° to the side relative to the midline using the preferred and non-preferred arms. Either the same (i.e., ipsilateral matching) or the opposite (i.e., contralateral matching) arm was used to reproduce the target location. No differences in matching accuracy were found between young and older participants when matching ipsilaterally. When matching contralaterally, accuracy was worse in older participants for target locations located to the side, which may reflect age-related changes in the perception of peripersonal space. In contrast to previous studies, accuracy did not differ between the preferred and non-preferred arms in either group. These results extend previous findings demonstrating age-related impairments in proprioceptively guided arm movements when interhemispheric transfer is required.

Eclampsia, a comparison within the International Network of Obstetric Survey Systems.

OBJECTIVE: To compare incidences, characteristics, management and outcome of eclampsia in the Netherlands and the UK. DESIGN: A comparative analysis of two population-based prospective cohort studies. SETTING: All hospitals with consultant-led maternity units. POPULATION: Women with eclampsia in the Netherlands (226) and the UK (264). METHODS: Comparison of individual level data from national studies in the Netherlands and the UK (LEMMoN 2004-06; UKOSS 2005/06). MAIN OUTCOME MEASURES: Incidence, maternal complications and differences in management strategies. RESULTS: Incidences of eclampsia differed significantly between both countries: the Netherlands 5.4/10,000 deliveries versus UK 2.7/10,000 (relative risk [RR] 1.94, 95% confidence intervals [95% CI] 1.6-2.4). The proportion of women with a preceding diagnosis of pre-eclampsia was comparable between both countries (the Netherlands 42%; UK 43%), as was the proportion who received magnesium sulphate prophylaxis. Women in the Netherlands had a significantly higher maximum diastolic blood pressure (111 mmHg versus 95 mmHg, P < 0.001); significantly fewer received anti-hypertensive medication (16% versus 71%; RR 0.2, 95% CI 0.1-0.3) and were treated less often with magnesium sulphate after their first fit (95% versus 99%; RR 0.96, 95% CI 0.92-0.99). Maternal death occurred in three cases in the Netherlands compared with zero in the UK. CONCLUSIONS: The incidence of eclampsia in the Netherlands was twice as high compared with the UK when using uniform definitions. Women with eclampsia in the Netherlands were not managed according to guidelines, particularly with respect to blood pressure management. Changes in management practice may reduce both incidence and poor outcomes.

CT, MRI and laparoscopy findings of a retroperitoneally herniated ovary causing acute abdominal pain.

We report a case of a young woman presenting with abdominal pain due to a rare and recurrent herniation of the ovary, to a retroperitoneal location lateral to the external iliac artery and directly dorsal to the iliopsoas muscle. Correlation between computed tomography, magnetic resonance imaging and laparoscopy is presented. The patient's complaints subsided after right oophoropexy. When aware, this diagnosis is easy to make and may allow symptomatic patients to be treated with laparoscopic oophoropexy.

Fatal meningitis during pregnancy in the Netherlands: a nationwide confidential enquiry.

OBJECTIVE: To determine the incidence of maternal deaths attributable to meningitis in the Netherlands, and to assess clinical features and risk factors. DESIGN: Confidential enquiry into the causes of maternal deaths. SETTING: Nationwide in the Netherlands. POPULATION: A total of 4 784 408 live births. METHODS: Analysis of all maternal deaths due to meningitis in pregnancy and puerperium from 1983 up to and including 2007 reported to the Maternal Mortality Committee of the Dutch Society of Obstetrics and Gynaecology. MAIN OUTCOME MEASURES: Incidence, clinical features and risk factors. RESULTS: Fifteen maternal deaths occurred due to meningitis, representing 4.4% of all maternal deaths. Twelve women (80%) presented with meningitis during pregnancy, 8 (66%) of them in the third trimester. Presenting symptoms were altered mental status (11; 73%), fever (9; 60%), nuchal rigidity (5; 33%) and headache (13; 87%). Nine women (60%) had otolaryngological infection at presentation or in the previous days or weeks. Twelve women (80%) underwent radiological examination, of which 5 (33%) showed distinct abnormalities. Cerebrospinal fluid (CSF) examination showed infected CSF in 8 (53%) women. In ten women (67%) Streptococcus pneumoniae was isolated. Substandard care was identified in 4 (27%) women. CONCLUSION: Pregnant or puerperal women presenting with classical symptoms of meningitis, particularly those with a history of otolaryngological infection or headache, should undergo thorough investigation and radiological and CSF examinations. Early diagnosis and immediate antibiotic treatment are imperative because of rapid deterioration in pregnant women. In case of doubt, the threshold for antibiotic treatment should be low and close monitoring is warranted.

Evidence for a major gene affecting the transition from normoglycaemia to hyperglycaemia in Psammomys obesus.

We investigated the mode of inheritance of nutritionally induced diabetes in the desert gerbil Psammomys obesus (sand rat), following transfer from low-energy (LE) to high-energy (HE) diet which induces hyperglycaemia. Psammomys selected for high or low blood glucose level were used as two parental lines. A first backcross generation (BC(1)) was formed by crossing F(1) males with females of the diabetes-prone line. The resulting 232 BC(1) progeny were assessed for blood glucose. All progeny were weaned at 3 weeks of age (week 0), and their weekly assessment of blood glucose levels proceeded until week 9 after weaning, with all progeny maintained on HE diet. At weeks 1 to 9 post weaning, a clear bimodal distribution statistically different from unimodal distribution of blood glucose was observed, normoglycaemic and hyperglycaemic at a 1:1 ratio. This ratio is expected at the first backcross generation for traits controlled by a single dominant gene. From week 0 (prior to the transfer to HE diet) till week 8, the hyperglycaemic individuals were significantly heavier (4--17%) than the normoglycaemic ones. The bimodal blood glucose distribution in BC(1) generation, with about equal frequencies in each mode, strongly suggests that a single major gene affects the transition from normo- to hyperglycaemia. The wide range of blood glucose values among the hyperglycaemic individuals (180 to 500 mg/dl) indicates that several genes and environmental factors influence the extent of hyperglycaemia. The diabetes-resistant allele appears to be dominant; the estimate for dominance ratio is 0.97.

Distinctive genetic signatures in the Libyan Jews.

Unlinked autosomal microsatellites in six Jewish and two non-Jewish populations were genotyped, and the relationships among these populations were explored. Based on considerations of clustering, pairwise population differentiation, and genetic distance, we found that the Libyan Jewish group retains genetic signatures distinguishable from those of the other populations, in agreement with some historical records on the relative isolation of this community. Our methods also identified evidence of some similarity between Ethiopian and Yemenite Jews, reflecting possible migration in the Red Sea region. We suggest that high-resolution statistical methods that use individual multilocus genotypes may make it practical to distinguish related populations of extremely recent common ancestry.

Intensive plasmapheresis for severe thrombotic thrombocytopenic purpura: long-term clinical outcome.

Plasma exchange is of proven efficacy in the treatment of thrombotic thrombocytopenic purpura (TTP). In most series, less than 40 plasma exchanges (PE) were required for treatment and as many as two thirds of patients had permanent residual organ damage. We report on 4 patients who required very intensive PE for the resolution of TTP (37, 68, 102 and 108 procedures, respectively). The maximum number of PE procedures per attack was 102. None of these patients has any permanent sequellae of TTP (other than those associated with splenectomy, which was performed on all patients). Two of the female patients had uncomplicated pregnancies since resolution of the disease. We conclude that even highly refractory cases of TTP can have an excellent clinical outcome with intense PE therapy.

Confidentiality in counseling for X-linked conditions.

Genetic counseling in a synthetic fragile-X family is used to illustrate some dilemmas which may arise from the genetic counselor's wish to respect the patient's confidence. What is the counselor's obligation towards family members who are unaware that they are carriers? Should the counselor try to avoid disclosing information concerning such family members to the patient, and if so-how? May the future father of an affected fetus be prevented from participating in the reproductive decisions concerning that fetus, out of respect for the mother's wishes?

Hunter syndrome in Jews in Israel: further evidence for prenatal selection favoring the Hunter allele.

Among all the Jewish families with Hunter patients in Israel, 10 were Ashkenazi or Moroccan in origin. In those families, there was a paucity of new mutations. In addition, a significant deviation of the segregation ratio between the Hunter gene and the normal allele was demonstrated among the offspring of heterozygous mothers or siblings of affected children in these families. These results confirm and extend our previous observations suggesting selection in favor of the X chromosome carrying the Hunter allele among Ashkenazi and Moroccan Jews.

Endoreduplication and polyploidy in fragile X cells induced by methotrexate and fluorodeoxyuridine: implications for diagnosis.

Lymphoblastoid cell lines from fragile X patients and amniotic cells from fragile X embryos, when cultured with methotrexate (MTX) or fluorodeoxyuridine (FUdR), showed a significant increase in endoreduplication and polyploidy. This phenomenon was not observed in fragile X lymphocytes or in lymphoblastoid cell lines and amniotic cells of normal control individuals. The relationship between the inducible fragile site at Xq27.3 and the inducible endoreduplication is discussed. The induction of endoreduplication and polyploidy in fragile X lymphoblasts and amniocytes is evaluated as a possible diagnostic test.

Genetic factors accountable for line-specific DNA fingerprint bands in quail.

DNA fingerprints, prepared from mixes of DNA of individuals sampled from lines of Japanese quail selected for high or low 4-week body weight, were used to evaluate the relative contribution of several evolutionary forces to genetic diversity among populations. Comparisons between lines--two replicates of each selection direction and a control unselected line--were used to determine the frequency of line-specific DNA fingerprint bands produced by each of three major evolutionary forces: 1) mutation; 2) genetic drift; 3) selection. The latter force is expected to generate line-specific bands only if there is linkage disequilibrium between DNA fingerprint loci and quantitative loci (QTLs) controlling body weight. Using probes 33.6 and R18.1, an average of 48.4 DNA fingerprint bands in each line were analyzed. On average, 27.8 bands were found to be line-specific among the 96.8 (2 x 48.4) bands analyzed in an average comparison between pairs of lines. Based on the frequencies of line-specific bands in each particular comparison, it was calculated that 21% of the line-specific bands were due to mutation, 11% due to a single genetic drift event, 11% due to selection, 21% due to the combined effects of genetic drift and selection, 22% due to double independent events of genetic drift, and 14% due to undefined factors. Although evidence was found for a high frequency of genetic changes attributable to genetic drift, and a higher than expected frequency of linkage disequilibrium, the emphasis of this report is on the methodology suggested rather than on the particular results.

DNA fingerprints applied to gene introgression in breeding programs.

An application of DNA fingerprints (DFP) for gene introgression in breeding programs of both farm animals and plants is proposed. DFP loci, detectable by minisatellite probes, are extremely polymorphic. Individuals have unique patterns of DFP and thus can be selected for maximal genomic similarity to the recipient line, and minimal similarity to the donor line, using their DFP patterns as the criterion for similarity. This genomic selection (GS) can be performed at generations BC1, BC2 or both, and thus significantly reduce the required number of backcross generations in introgression breeding programs. The association between genomic and DFP similarity is demonstrated. Theoretical distributions and variances of the relative percentages of the donor and recipient genomes as the basis for the GS approach are presented.

The role of recombination in the evolvement of the fragile X mutation.

The frequency of recombination in the regions adjacent to the fragile X locus was studied in two groups of carriers: daughters of transmitting males and transmitters of maternally inherited fragile X chromosomes. Approximately one-half of the offspring of the former and one quarter of the offspring of the latter are recombinant. Recombinants and parentals are equally distributed among affected and normal offspring in the two groups. These results indicate that crossing-over at or around the fragile X locus occurs in every meiosis in daughters of transmitting males, although the recombinant chromatids do not necessarily carry the fragile X mutation. Hence, crossing-over is unequivocally associated with, but is not the direct cause of, the transition from the primary genetic lesion to the final mutation.

Cytological evidence of defective template in the fragile X chromosome.

In cells of fragile X patients, the changed X segment may appear as a poorly staining region or a gap, or as a deletion, involving one or both chromatids. To find out whether the fragile site represents an incompletely replicated DNA sequence, as has been suggested recently, we analyzed the four chromatids of methotrexate-induced endoreduplicated fragile X chromosomes. Our main observations were: (1) a deleted chromatid was never internal to a poorly staining one; (2) an endoreduplicated X chromosome with a fragile site never included a normal chromatid. These results can be explained by assuming that DNA at the fragile site, when replicated in the presence of methotrexate, may undergo defective replication and give rise to improperly packaged chromatin, appearing as a chromatid with a poorly staining region or a gap in the following metaphase. The same DNA may fail to function as a template in the following S-phase and give rise to a chromatid with a single-stranded segment, appearing as a deleted chromatid in the following metaphase.

Proximal and distal regulatory elements that influence in vivo expression of a cell cycle-dependent human H4 histone gene.

We have examined the sequences required in vivo to promote transcription of a cell cycle-regulated human H4 histone gene. Deletion mutants of the 5' flanking region were assayed in mouse cells or fused with the chloramphenicol acetyltransferase (CAT) gene for assay in HeLa cells. The functional limits of the regulatory sequences were shown to extend at least 6.5 kilobases (kb) upstream. Sequences sufficient for correctly initiated transcription were found in the 70 base pairs (bp) immediately 5' to the cap site. A proximal element located 200-400 bp upstream increased the level of transcription several times above the basal level, although not to maximal levels. Maximal levels of expression were achieved with 6.5 kb of 5' flanking sequence adjacent to the proximal promoter sequences or when a distal enhancer element with both position- and orientation-independent function was moved proximal to the promoter. Our results indicate that a series of 5' cis-acting sequences are functionally related to the fidelity and level of expression of this human H4 histone gene.