Jan Helge Seglem Mortensen

Genetic Aspects of Preeclampsia and the HELLP Syndrome

Both preeclampsia and the HELLP syndrome have their origin in the placenta. The aim of this study is to review genetic factors involved in development of preeclampsia and the HELLP syndrome using literature search in PubMed. A familial cohort links chromosomes 2q, 5q, and 13q to preeclampsia. The chromosome 12q is coupled with the HELLP syndrome. The STOX1 gene, the ERAP1 and 2 genes, the syncytin envelope gene, and the −670 Fas receptor polymorphisms are involved in the development of preeclampsia. The ACVR2A gene on chromosome 2q22 is also implicated. The toll-like receptor-4 (TLR-4) and factor V Leiden mutation participate both in development of preeclampsia and the HELLP syndrome. Carriers of the TT and the CC genotype of the MTHFR C677T polymorphism seem to have an increased risk of the HELLP syndrome. The placental levels of VEGF mRNA are reduced both in women with preeclampsia and in women with the HELLP syndrome. The BclI polymorphism is engaged in development of the HELLP syndrome but not in development of severe preeclampsia. The ACE I/D polymorphism affects uteroplacental and umbilical artery blood flows in women with preeclampsia. In women with preeclampsia and the HELLP syndrome several genes in the placenta are deregulated. Preeclampsia and the HELLP syndrome are multiplex genetic diseases.

Capillary zone electrophoresis with laser-induced fluorescence detection for analysis of methylmalonic acid and other short-chain dicarboxylic acids derivatized with 1-pyrenyldiazomethane

Methylmalonic acid (MMA) and other short-chain dicarboxylic acids react with 1-pyrenyldiazomethane (PDAM) in aqueous matrices and form stable, highly fluorescent 1-pyrenylmethyl monoesters [Schneede and Ueland, Anal. Chem., 64 (1992) 315-319]. We investigated the migration behaviour of these derivatives in capillary zone electrophoresis in fused-silica capillaries. The 1-pyrenyldiazomethane derivatives were detected with a laser-induced fluorescence detector that was connected to a helium-cadmium laser, delivering light at a wavelength of 325 nm, which exactly matched an excitation maximum of the 1-pyrenylmethyl monoesters. These esters have one free carboxylic acid group, which carries negative charge at pH > 4.0. The electrophoretic mobility varied according to pH, and the pH effect was most pronounced at values close to the pKa value (5.2–5.8) of the esters. The effects of the composition of the running buffer (pH, organic modifier concentration, ionic strength) and some operational parameters (voltage, temperature and capillary length) were tested, and were largely found to comply with validated theoretical models for capillary zone electrophoresis. In an optimal system, as judged by high number of theoretical plates, high resolution and short run times, the MMA derivative was separated from related 1-pyrenylmethyl monoesters. The laser-induced fluorescence detection afforded a limit of detection of about 40 nmol/1 (signal-to-noise ratio of 5) for the MMA derivative. Under optimal conditions, we were able to detect <1 μmol/1 endogenous MMA in human serum.

Tocolysis for acute preterm labor: does anything work.

Abstract The central rationale of tocolysis for preterm labor (PTL) is to delay delivery for at least 48 h to allow for transfer of the mother to a tertiary facility and for corticosteroids to induce surfactant production in fetal lungs. Beta-mimetics decrease the number of women in preterm labor giving birth within 48 h without reducing adverse neonatal outcomes. Calcium channel blockers inclusive of nifedipine decrease the adverse neonatal outcomes by significantly delaying delivery. Atosiban has the best maternal and fetal safety profile but does not seem to reduce neonatal complications. Magnesium sulfate is controversial as a tocolytic, but is valuable as a neuroprotective agent and for treatment of eclamptic seizures. Indomethacin may be a reasonable first choice for acute tocolytsis in gestational ages less than 32 weeks’ gestation. Prolonged use (>48 h) should be avoided. Transdermal nitroglycerin can reduce neonatal morbidity and mortality as a result of decreased risk of birth before 28 weeks’ gestation. Nifedipine may be a reasonable first choice because it is easy to administer and also of limited side effects relative to β2-mimetics. Tocolysis does not appear to significantly lengthen the gestational age beyond seven days.

Supplemental folic acid in pregnancy and childhood cancer risk

Background:We investigated the association between supplemental folic acid in pregnancy and childhood cancer in a nation-wide study of 687 406 live births in Norway, 1999–2010, and 799 children diagnosed later with cancer.Methods:Adjusted hazard ratios (HRs) compared cancer risk in children by approximated periconceptional folic acid levels (folic acid tablets and multivitamins (0.6 mg), only folic acid (0.4 mg), only multivitamins (0.2 mg)) and cancer risk in unexposed.Results:Any folic acid levels were not associated with leukemia (e.g., high-level folic acid HR 1.25; 95% CI 0.89–1.76, PTrend 0.20), lymphoma (HR 0.96; 95% CI 0.42–2.21, PTrend 0.51), central nervous system tumours (HR 0.68; 95% CI 0.42–1.10, PTrend 0.32), neuroblastoma (HR 1.05; 95% CI 0.53–2.06, PTrend 0.85), Wilms’ tumour (HR 1.16; 95% CI 0.52–2.58, PTrend 0.76), or soft-tissue tumours (HR 0.77; 95% CI 0.34–1.75, PTrend 0.90).Conclusions:Folic acid supplementation was not associated with risk of major childhood cancers.

Disseminated intravascular coagulation in the HELLP syndrome: how much do we really know?

Abstract The rate of disseminated intravascular coagulation (DIC) during pregnancy varies among nations from 0.03% to 0.35%. The existing reports suggest dissimilarity in the underlying mechanisms leading to DIC during gestation. While in developing countries preeclampsia and the HELLP syndrome are prevalent causes of DIC, the leading causes in the developed countries are placental abruption and postpartum hemorrhage. In different cohort studies, DIC is reported in about 12–14% of women with preeclampsia. Nevertheless, it has been suggested that in most cases these women also had a HELLP syndrome and that the occurrence of DIC in women who had only preeclampsia without manifestations of the HELLP syndrome is rare. The aims of this review are to: (1) highlight the mechanisms leading to DIC; (2) describe the changes in the coagulation system during this complication; and; (3) discuss the diagnostic tool and treatment modalities of DIC, in women who develop a HELLP syndrome.

Antenatal corticosteroid treatment: factors other than lung maturation

Abstract Antenatal corticosteroid (CS) therapy improves both fetal lung mechanism and gas exchange due to accelerated morphologic development of type one and two pneumocytes. This therapy also enhances the production of surfactant binding proteins and fetal lung antioxidant enzymes. In women with threatening preterm delivery, a single course is advocated between 24 and 34 weeks’ gestation with either betamethasone (two doses of 12 mg 24 h apart) or dexamethasone (four doses of 6 mg at 12-h intervals). Such treatment reduces the rate of respiratory distress syndrome, comorbidity, and mortality in neonates in the first 48 h of life. The optimal time interval between CS administration and delivery is reported to be 1–7 days. Weekly repeat courses reduce the occurrences and severity of respiratory diseases but are associated with reduce fetal growth. Multiple courses should be avoided. However, a repeat course should be considered in women at risk of preterm birth 7 or more days after an initial course in women who remain at risk of preterm birth <34 weeks’ gestation. CS may be harmful in growth restricted fetuses associated with an absent or reversed end-diastolic UA flow since they are at increased risk of acidosis and perinatal death. The purpose of this publication is to update and highlight antenatal CS therapy.

Use of antenatal corticosteroids in special circumstances: a comprehensive review

The aim of this study was to determine, in pregnancies complicated by preterm premature rupture of membranes (PPROM), hypertension, intrauterine growth restriction, multi‐fetal gestations and pregnancies 23–26 weeks and ≥34 weeks’ gestation, whether antenatal corticosteroids benefit the fetus.

Cerclage, progesterone and α-hydroxyprogeterone caproate treatment in women at risk for preterm delivery

Abstract The most significant action of progesterone appears to be on the cervix and in prevention rather than on treatment of preterm delivery. In women with singleton gestations, no prior PTB, and CL <20 mm at <24 weeks, vaginal progesterone, either 90 mg gel or 200 mg suppository, is associated with reduction of both preterm birth (PTB) and perinatal morbidity/mortality. Cerclage is as effective as vaginal progesterone in women with CL <25 mm. Treatment of women with previous PTB with 17OHP-C from 16 to 20 weeks’ gestation until 36 weeks could reduce significantly both the risk of delivery at <37, <35 and <32 weeks’ gestation, as well as the rates of NEC, the need for supplemental oxygen and IVH. In women successfully treated with tocolytics progesterone combined with corticosteroid therapy lengthens pregnancy, reduces occurrence of respiratory distress syndrome and low birth weight. However, there is currently insufficient evidence on the role of progesterone after arrested preterm labor. It is reasonable to support an approach with CL screening of women with prior PTB starting at 16 to 19 weeks and administration of progesterone to women with a short cervix. Cerclage may be offered to those with a CL<25 mm. A combination of traditional tocolytics, corticosteroids and progesterone might be beneficial.

Supplemental folic acid in pregnancy and maternal cancer risk

BACKGROUND There is evidence that increased intake of folate protects against the development of several types of cancer. Some studies have, however, raised concern about the safety of folate in relation to cancer risk. Here we examined the risk of maternal cancer after intake of supplemental folic acid in pregnancy. METHODS This is a population-based cohort study comprising 429,004 women with data from the Medical Birth Registry of Norway, the Cancer Registry of Norway, and other national registries from 1999 to 2010. Altogether 3781 cancer cases were identified during follow-up (average 7 years). Cox proportional hazards regression models were used to estimate hazard ratios of maternal cancer according to folic acid use prior to and during one or two or more pregnancies as compared to no supplement use. RESULTS Folic acid supplementation use had no overall effect on cancer risk in women using folic acid supplementation in one (HR 1.08; 95% CI 1.00-1.18) or two or more pregnancies (HR 1.06; 95% CI 0.91-1.22) (ptrend=0.12). Analyses of 13 cancer types revealed no associations between folic acid and cancer. CONCLUSION Folic acid supplementation before and during pregnancy had no overall effect on maternal cancer risk. IMPACT Folic acid substitution before and/or during pregnancy does not increase the short-term overall maternal cancer risk.