Johanna I.P. de Vries

Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials

BACKGROUNDnPlacenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and birth of a small-for-gestational-age (SGA) neonate. These complications are leading causes of maternal, fetal, and neonatal morbidity and mortality in high-income countries. Affected women are at high risk of recurrence in subsequent pregnancies; however, effective strategies to prevent recurrence are absent. Findings from our previous study-level meta-analysis suggested that low-molecular-weight heparin reduced the risk of recurrent placenta-mediated pregnancy complications. However, we identified significant heterogeneity in the results, possibly due to trial design or inclusion criteria. To identify which patients benefit from, and which outcomes are prevented by, low-molecular-weight heparin, we did an individual patient data meta-analysis.nnnMETHODSnWe did a systematic review in May, 2013, which identified eight eligible randomised trials done between 2000 and 2013 of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. We excluded studies on the basis of the wrong population, the study being ongoing, inability to confirm eligibility of participants, intervention stopped too early, and no response from the principal investigator. We requested individual patient data from the study authors for eligible women (women pregnant at the time of the study with a history of previous pregnancy that had been complicated by one or more of the following: pre-eclampsia, placental abruption, birth of an SGA neonate [<10th percentile], pregnancy loss after 16 weeks gestation, or two losses after 12 weeks gestation) and recoded, combined, and analysed the data for our meta-analysis. The primary outcome was a composite of early-onset (<34 weeks) or severe pre-eclampsia, birth of an SGA neonate (<5th percentile), late pregnancy loss (≥20 weeks gestation), or placental abruption leading to delivery, assessed on an intention-to-treat basis. We assessed risk of bias with the Cochrane Risk of Bias tool. This study is registered with PROSPERO, number CRD42013006249.nnnFINDINGSnWe analysed data from 963 eligible women in eight trials: 480 randomly assigned to low-molecular-weight heparin and 483 randomly assigned to no low-molecular-weight heparin. Overall, the risk of bias was not substantial enough to affect decisions regarding trial inclusion. Participants were mostly white (795/905; 88%) with a mean age of 30·9 years (SD 5·0) and 403/963 (42%) had thrombophilia. In the primary analysis, low-molecular-weight heparin did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications (low-molecular-weight heparin 62/444 [14%] versus no low-molecular-weight heparin 95/443 (22%) absolute difference -8%, 95% CI -17·3 to 1·4, p=0·09; relative risk 0·64, 95% CI 0·36-1·11, p=0·11). We noted significant heterogeneity between single-centre and multicentre trials. In subgroup analyses, low-molecular-weight heparin in multicentre trials reduced the primary outcome in women with previous abruption (p=0·006) but not in any of the other subgroups of previous complications.nnnINTERPRETATIONnLow-molecular-weight heparin does not seem to reduce the risk of recurrent placenta-mediated pregnancy complications in at-risk women. However, some decreases in event rates might have been too small for the power of our study to explore.nnnFUNDINGnCanadian Institutes of Health Research.

Low-molecular-weight heparin for prevention of placenta-mediated pregnancy complications: protocol for a systematic review and individual patient data meta-analysis (AFFIRM).

BackgroundPlacenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and the small-for-gestational age newborn. They are leading causes of maternal, fetal, and neonatal morbidity and mortality in developed nations. Women who have experienced these complications are at an elevated risk of recurrence in subsequent pregnancies. However, despite decades of research no effective strategies to prevent recurrence have been identified, until recently. We completed a pooled summary-based meta-analysis that strongly suggests that low-molecular-weight heparin reduces the risk of recurrent placenta-mediated complications. The proposed individual patient data meta-analysis builds on this successful collaboration. The project is called AFFIRM, A n individual patient data meta-analysis oF low-molecular-weight heparin F or prevention of placenta-medI ated pR egnancy coMplications.Methods/DesignWe conducted a systematic review to identify randomized controlled trials with a low-molecular-weight heparin intervention for the prevention of recurrent placenta-mediated pregnancy complications. Investigators and statisticians representing eight trials met to discuss the outcomes and analysis plan for an individual patient data meta-analysis. An additional trial has since been added for a total of nine eligible trials. The primary analyses from the original trials will be replicated for quality assurance prior to recoding the data from each trial and combining it into a common dataset for analysis. Using the anonymized combined data we will conduct logistic regression and subgroup analyses aimed at identifying which women with previous pregnancy complications benefit most from treatment with low-molecular-weight heparin during pregnancy.DiscussionThe goal of the proposed individual patient data meta-analysis is a thorough estimation of treatment effects in patients with prior individual placenta-mediated pregnancy complications and exploration of which complications are specifically prevented by low-molecular-weight heparin.Systematic review registrationPROSPERO (International Prospective Registry of Systematic Reviews) 23 December 2013, CRD42013006249

Serial postural and motor assessment of Fetal Akinesia Deformation Sequence (FADS)

BACKGROUNDnFetal Akinesia Deformation Sequence (FADS) is a rare, in most cases autosomal recessive, disorder. Its heterogeneous origin results in variable onset and expression of motor and postural anomalies. DNA-diagnostic possibilities are limited, thus prenatal diagnosis is chiefly dependent on sonographic examinations.nnnAIMnTo explore postural and motor development from a systematic sonographic protocol for fetuses at high risk for FADS. Specific questions are: which motor (i.e., specific movement patterns, quality and quantity of general movements) and postural aspects are most informative about emerging FADS and is the gestational age of onset range of FADS more limited for siblings?nnnMETHODSnTen families underwent 45, 15-minute sonographic assessments for motility and posture for ten index fetuses with FADS and nine subsequent pregnancies from five families.nnnRESULTSnFADS was diagnosed between 18 and 33 weeks gestation in ten index pregnancies and between 11 and 18 weeks gestation in 4/9 subsequent pregnancies, 1-12 weeks earlier than their index pregnancies. From the four assessment aspects, posture and movement quality were always abnormal, movement quantity in 7/14 and differentiation into specific movement patterns were reduced in comparison with healthy siblings (p<0.01). Deterioration occurred in a 2 week period.nnnCONCLUSIONSnSerial postural and qualitative assessments were most informative diagnosing FADS. Quantity and differentiation into specific movement patterns contributed substantially. Onset range of FADS within siblings was suggested to be more limited than between families.

Low-molecular-weight heparin and aspirin in the prevention of recurrent early-onset pre-eclampsia in women with antiphospholipid antibodies: the FRUIT-RCT

OBJECTIVEnTo examine whether combined treatment with low-molecular-weight heparin (LMWH) and aspirin reduces recurrent hypertensive disorders of pregnancy (HD: pre-eclampsia, eclampsia or HELLP syndrome) in women with antiphospholipid antibodies (aPLA) and a previous delivery for HD and/or small-for-gestational-age (SGA) birthweight before 34 weeks gestation.nnnSTUDY DESIGNnThis multicentre randomised controlled trial was performed between December 2000 and December 2009. Women were recruited from all eight university and six non-university/teaching hospitals in The Netherlands, two university hospitals in Australia and one university hospital in Sweden. Thirty two women with a previous delivery <34 weeks gestation with HD and/or SGA and aPLA were included before 12 weeks gestation. The intervention was daily LMWH with aspirin or aspirin alone.nnnPRIMARY OUTCOMESnrecurrent HD onset <34 weeks and recurrent HD irrespective of gestational age. Analysis by intention-to-treat.nnnRESULTSnAfter an interim analysis, recruitment was ceased: accrual was low and the incidence of recurrent HD was far lower (3%) than expected (60%). The final analysis, performed on 32 women, shows no difference in the primary outcomes (LMWH and aspirin 0/16 versus aspirin only 1/16, risk difference 6.25% [CI -17 to 27%] for recurrent HD onset <34 weeks and 0/16 for LMWH and aspirin versus 2/16 for aspirin only, risk difference 12.5% [CI -15 to 35%] for HD irrespective of gestational age).nnnCONCLUSIONnIn this population of women with aPLA, who had previously had an early delivery for HD and/or SGA prior to 34 weeks gestation, combined LMWH and aspirin treatment started before 12 weeks gestation in a subsequent pregnancy did not show reduction of onset of recurrent HD either <34 weeks gestation or irrespective of gestational age, compared with aspirin alone.

Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence.

Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK-dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing.

Predicting complications in pre-eclampsia : external validation of the fullPIERS model using the PETRA trial dataset

OBJECTIVEnThe internally validated fullPIERS model predicts adverse maternal outcomes in women with pre-eclampsia within 48h after eligibility. Our objective was to assess generalizability of this prediction model.nnnSTUDY DESIGNnExternal validation study using prospectively collected data from two tertiary care obstetric centers.nnnMETHODSnThe existing PETRA dataset, a cohort of women (n=216) with severe early-onset pre-eclampsia, eclampsia, HELLP syndrome or hypertension-associated fetal growth restriction was used. The fullPIERS model equation was applied to all women in the dataset using values collected within 48h after inclusion. The performance (ROC area and R-squared) of the model, risk stratification and calibration were assessed from 48h up to a week after inclusion.nnnRESULTSnOf 216 women in the PETRA trial, 73 (34%) experienced an adverse maternal outcome(s) at any time after inclusion. Adverse maternal outcome was observed in 32 (15%) cases within 48h and 62 (29%) within 7 days after inclusion. The fullPIERS model predicted adverse maternal outcomes within 48h (AUC ROC 0.97, 95% CI: 0.87-0.99) and up to 7 days after inclusion (AUC ROC 0.80, 95% CI: 0.70-0.87).nnnCONCLUSIONSnThe fullPIERS model performed well when applied to the PETRA dataset. These results confirm the usability of the fullPIERS prediction model as a rule-in test for women admitted with severe pre-eclampsia, eclampsia, HELLP syndrome or hypertension-associated fetal growth restriction. Future research should focus on intervention studies that assess the clinical impact of strategies using the fullPIERS model.

Transient Neonatal Myelosuppression after Fetal Exposure to Maternal Chemotherapy

Transient neonatal myelosuppression (TNM) is a rare but potentially life-threatening adverse effect of fetal exposure to maternal chemotherapy during pregnancy. We report a case of TNM in a preterm infant born to a mother diagnosed with acute lymphoblastic leukemia during pregnancy. The mother received chemotherapy during the second and third trimester. The neonate was successfully treated with supportive care. In addition, we also conducted a medical literature review and identified another 14 cases of TNM. Although the long-term outcome of these children is not known, short-term survival is relatively good. Prompt recognition and aggressive treatment of infants at risk for TNM is mandatory.

General movements in the perinatal period and its relation to echogenicity changes in the brain

BACKGROUNDnIn preterm born infants abnormal general movements (GMs) generally normalize before three months post term, but may persist when perinatal brain injury is present.nnnAIMSnTo assess the continuity of GM quality from fetal to early neonatal period and its relation to brain echogenicity changes.nnnSTUDY DESIGNnProspective study examining GMs and three vulnerable brain areas before and 7days after birth. The quality of GMs was classified as normal or abnormal by Gestalt-perception. The brain was examined for moderate echogenicity changes (periventricular: brighter than choroid plexus, intraventricular: filling equal or more than 50% of the ventricle, and locally increased basal ganglia/thalami).nnnSUBJECTSn94 fetuses from pregnancies complicated by preterm hypertensive disorders or labour at a gestational age between 26 and 34weeks.nnnOUTCOMES MEASURESnCorrelations of fetal GMs, echogenicity changes, and clinical parameters (e.g. gestational age, parity, hypertensive disorders or preterm labour, oligohydramnios and fetal growth restriction) with neonatal GMs.nnnRESULTSnFetal GMs were abnormal in 64%, normalizing in 68% within 7days after birth. Fetal GMs were significantly related to postnatal GMs (p=0.045). Moderate fetal brain echogenicity changes and clinical parameters were not significantly related to neonatal GM.nnnCONCLUSIONSnIn this population of pregnancies compromised by hypertensive disorders or preterm labour fetal GMs correlated with neonatal GMs. Presence of moderate echogenicity changes in the fetal brain was not related to neonatal GMs.

Catch-up growth in children born growth restricted to mothers with hypertensive disorders of pregnancy

Background In preterm hypertensive disorders of pregnancy, fetal growth restriction (FGR) occurs frequently. The timing and severity of FGR impacts childhood growth and is associated with metabolic changes later in life. Aim To examine growth and the impact of FGR in early childhood. Design Prospective cohort study. Participants Children (n=135) born to mothers who were admitted before 34u2005weeks’ gestational age with a severe hypertensive disorder of pregnancy. Outcome measures Height, weight, body mass index (BMI), head circumference (HC), SD scores (SDS) at 3u2005months, and 1 and 4.5u2005years of age, and complete catch-up growth (height SDS−target height SDS >−1.6). Results Growth scores were lower compared to Dutch growth curves, except for BMI at 3u2005months and girls’ HC at all ages. Mean height SDS increased over time from −1.4 to −0.5 at 4.5u2005years, with 94% having complete catch-up growth. Mean BMI SDS decreased from −0.2 at 3u2005months to −1.0 at 1u2005year, and was −0.8 at age 4.5. Mean HC SDS was stable over time and −0.3 at 4.5u2005years. The customised birth weight ratio, as a measure of the degree of FGR, was related to all growth SDS at 4.5u2005years, while gestational age at birth was not. Conclusions Although the majority of children born growth restricted had catch-up growth of height within the normal range at 4.5u2005years of age, they were smaller, but especially lighter compared to Dutch growth charts. The degree of FGR was associated with all growth outcomes.

Saved from a fatal flight: A ruptured splenic artery aneurysm in a pregnant woman

Highlights • Although rupture of a splenic artery aneurysm is rare, its consequences can be devastating for both mother and child.• Early recognition and prompt multidisciplinary treatment might save the life of mother and child.• There is a difficulty in recognizing hemodynamic instability in pregnancy due to the increase in circulating volume.