J.I.P. de Vries

The emergence of fetal behaviour. I. Qualitative aspects

Abstract The emergence of spontaneous fetal motility during the first 20 weeks of gestation was studied longitudinally in 11 healthy nulliparae, using real-time ultrasound. The aim of this investigation was to study the onset and developmental course of spontaneously generated specific fetal movement patterns. 60-min observations were repeated weekly from 7 to 15 weeks and at 16/17 and 18/19 weeks. The qualitative aspects of fetal motility and posture were analyzed during video recording. Sixteen distinct movement patterns (just discernible movements; startle; general movements; hiccup; breathing; isolated arm or leg movements; isolated retroflexion/rotation and anteflexion of the head; jaw movements; sucking and swallowing; hand-facecontact; stretch; yawn; rotation), closely resembling those observed in preterm and fullterm newborn infants, could be distinguished and a detailed description is presented. The first movements were observed at 7.5 weeks postmenstrual age. A scatter of two weeks was found for the ages at which frequently occurring movement patterns could be observed for the first time. By the age of 15 weeks all 16 movement patterns could be observed. There were no major changes between 8 and 20 weeks in the appearance of the different movements, which meant that they were easy to recognize at all ages studied. A systematic assessment of position and posture showed a preference for the supine position before 16 weeks, and for the lateral position after 16 weeks. There was no consistent intra-individual preference for position or posture. Two specific motor patterns could be identified as causing either somersault or rotation around the longitudinal axis. The number of changes in fetal position increases from 10 weeks onwards, reaches a peak at 13–15 weeks and decreases after 17 weeks.

Underlying disorders associated with severe early-onset preeclampsia

OBJECTIVE Our purpose was to determine whether patients with severe early-onset preeclampsia have hemostatic or metabolic abnormalities that are associated with a tendency to vascular thrombosis. STUDY DESIGN A total of 101 patients with a history of severe early-onset preeclampsia were tested at least 10 weeks post partum for the presence of hyperhomocysteinemia (methionine loading test), protein C, protein S, and antithrombin III deficiency, activated protein C resistance, lupus anticoagulant, and immunoglobulin G and/or M anticardiolipin antibodies. RESULTS Of the 101 patients, 39 (38.6%) had chronic hypertension. Of the 85 patients tested for coagulation disturbances, 21 (24.7%) had protein S deficiency. Of the 50 patients tested for activated protein C resistance, 8 (16.0%) were positive. Of the 79 patients tested for hyperhomocysteinemia, 14 (17.7%) had a positive methionine loading test. Finally, 95 patients were tested for anticardiolipin antibodies; 27 (29.4%) had detectable immunoglobulin G and/or M anticardiolipin antibodies. CONCLUSION Patients with a history of severe early-onset preeclampsia should be screened for protein S deficiency, activated protein C resistance, hyperhomocysteinemia, and anticardiolipin antibodies, since these results may have an impact on counseling for and pharmacologic management in future pregnancies.

Severe maternal morbidity during pregnancy, delivery and puerperium in the Netherlands: a nationwide population-based study of 371,000 pregnancies.

Objective  To assess incidence, case fatality rate, risk factors and substandard care in severe maternal morbidity in the Netherlands.

Abnormal motor behaviour in anencephalic fetuses

In eight anencephalic fetuses ultrasound observations of movement patterns were made and correlated with the morphological findings at postmortem. In all fetuses the movements were qualitatively abnormal: they were forceful, jerky in character and of large amplitude. In some of the most defective cases classification of the movements was hardly possible as they showed little similarity to those observed in normal fetuses. In these cases movements tended to occur in burst-pause patterns in contrast to being scattered over the record. Excessive activity occurred also only in the more defective cases. In fetuses with no evident cervical cord present isolated arm movements were observed. Fetal lung hypoplasia occurred as early as 16 weeks and in a fetus which showed both hiccups and breathing movements. It is concluded that with a severely defective fetal central nervous system, already in the first half of pregnancy movement patterns are abnormal. This abnormality mainly concerns the quality of the different movements. Secondly, movements can occur despite severe reduction in the amount and alteration in the organisation of the fetal central nervous system.

Low-molecular-weight heparin added to aspirin in the prevention of recurrent early-onset pre-eclampsia in women with inheritable thrombophilia: the FRUIT-RCT

Summary.  Background: Early‐onset hypertensive disorders (HD) of pregnancy and small‐for‐gestational age infants (SGA) are associated with placental vascular thrombosis, these often recur and are also associated with inheritable thrombophilia. Aspirin reduces the recurrence risk. Objectives: Adding low‐molecular‐weight heparin (LMWH) to aspirin at < 12 weeks gestation reduces the recurrence of HD in women with previous early‐onset HD (pre‐eclampsia, hemolysis, elevated liver enzymes and low platelets [HELLP] syndrome and eclampsia) and/or SGA, in the context of inheritable thrombophilia without antiphospholipid antibodies. Patients/methods: In a multicenter randomized control trial (RCT), 139 women included were < 12 weeks gestation. Inclusion criteria: previous delivery < 34 weeks gestation with HD and/or SGA; inheritable thrombophilia (protein C deficiency, protein S deficiency, activated protein C resistance, factor V Leiden heterozygosity and prothrombin gene G20210A mutation heterozygosity); and no antiphospholipid antibodies detected. Intervention: either daily LMWH (dalteparin, 5000 IU weight‐adjusted dosage) with aspirin 80 mg or aspirin 80 mg alone. Main outcome measures: Primary outcomes: recurrent HD onset (i) < 34 weeks gestation and (ii) irrespective of gestational age. Secondary outcomes: recurrent SGA, preterm birth, maternal/neonatal hospitalization, spontaneous abortion and individual HD. Analysis by intention‐to‐treat. Results: Low‐molecular‐weight heparin with aspirin reduced recurrent HD onset < 34 weeks gestation (risk difference [RD] 8.7%: confidence interval [CI] of RD 1.9–15.5%; P = 0.012; number needed to treat [NNT] 12). Recurrent HD irrespective of gestational age was not different between the arms. No women withdrew as a result of adverse effects. Trial Registration: http://www.isrctn.org) (isrctn87325378). Conclusions: Adding LMWH to aspirin at < 12 weeks gestation reduces recurrent HD onset < 34 weeks gestation in women with inheritable thrombophilia and prior delivery for HD/SGA <34 weeks. However, close monitoring of the mother and fetus remains important throughout pregnancy.

Normal fetal motility: an overview

After 35 years of real‐time two‐dimensional sonography, and now that 4D sonography is within our grasp, this article presents an overview of present‐day knowledge of normal fetal motility. A literature search was carried out on articles from 1970, using the keywords: ‘fetal’, ‘movements’, ‘motility’, ‘movement patterns’, ‘ultrasound’ and ‘sonography’. Inclusion criteria were human studies and use of real‐time sonography. Articles were screened for type of motor assessment procedure, in terms of whether they: specified movements for participating body parts (specific movement pattern, SMP), were qualitative (performance in terms of speed and amplitude), were quantitative, identified behavioral states, stated the duration of observation, and specified gestational age. We noted developmental milestones obtained for each study aim. One of four aims was identified for each article, depending on whether it focused on emergence, development, or continuity after birth of the movement patterns, or on the relationship of various motor aspects to other parameters that evaluate fetal condition, such as blood flow and fetal heart rate. A total of 109 relevant articles was identified, examining 9862 fetuses. Assessment was performed primarily with analysis of SMPs (89%); 52% also included non‐SMPs (NSMPs), 78% included quantification, 24% assessment of quality, and 32% behavioral states. The duration of observation was 1 h or longer in 50% of the studies. The focus in 28 studies was on emergence, in 44 it was on development, in five it was on continuity and in 32 it was on relationship of the movements with other parameters of fetal well‐being. A few milestones identified were determination of the strictly age‐related emergence of SMPs and behavioral states, the highly reproducible quality of SMPs throughout gestation, the age‐related trends in quantified SMPs, the continuity in quality and quantity after birth, and the close relationship between motility and heart‐rate variability, flow parameters, and behavioral states. Periods of longest inactivity recorded before 20 weeks were 13 min; after 30 weeks they were 45 min. Much insight was obtained into the development of motility and its relationship to other parameters from those articles applying comparable assessment procedures. An assessment procedure with well‐defined SMPs, qualitative and quantitative aspects of SMPs and NSMPs, and an observation period dependent on age are advocated for future research. Copyright

Diurnal and other variations in fetal movement and heart rate patterns at 20–22 weeks

It was investigated when diurnal and other variations in fetal movements and in heart rate pattern emerge during the course of pregnancy. Real-time ultrasound observations were made at 13 weeks of gestation in 7 nulliparous women and at 20-22 weeks in 10 nulliparous women. The observations took place at 0800, 1300 and 2200 and lasted 60 min/session at 13 weeks and 120 min at 20-22 weeks. The fetal heart rate was recorded for 24 h at 20-22 weeks using electrocardiographic electrodes. No diurnal variations were found for any of the movement patterns at 13 weeks. At 20-22 weeks, however, significant diurnal changes were observed in the total activity, the incidence of general movements and the breathing movements, with the lowest values in the morning and the highest during the evening. Fetal breathing movements already appeared to be related to maternal meals at 20-22 weeks as their incidence was significantly lower during the third hour after meals compared to the second hour. The rank order of the incidence of movements (from high to low incidence) was fairly constant over the course of the day both at 13 and at 20-22 weeks. This confirms earlier findings that the rank order of movements is strictly age dependent. Diurnal rhythms were observed for both the fetal heart rate and its variation. The fetal heart rate was lowest between 2400 and 0600 and the heart rate variation was lowest between 0600 and 1100. The incidence of accelerations and decelerations showed no systematic fluctuations over the 24-h period. Decelerations occurred more frequently than accelerations. Episodes of high heart rate variation were associated with an increased incidence of general movements. The various diurnal variations over 24 h at 20-22 weeks generally followed the same temporal sequence as those found near term, although the changes were considerably smaller.

The emergence of fetal behaviour. III. Individual differences and consistencies

Intra- and inter-fetal consistencies and differences in motor activity were studied in 12 healthy nulliparous women during the first half of gestation. Real-time ultrasound observations, lasting 60 min, were performed weekly from 7 to 15 weeks of gestation and at 17 and 19 weeks. The various types of movements were categorized according to a previously developed classification system. Data on general movements during the second half of gestation were carried out on the same group of women and these results are also included in this study. Intra-individually there appeared to be a relative week-to-week consistency in the amount of total motor activity, i.e. the sum of all the movement patterns. There was a slight tendency of intra-fetal consistency when the incidence of general movements during the first half of gestation was compared to that during the second half. The other movement patterns did not show these consistencies, namely, each fetus showed large fluctuations in the week-to-week incidences. Inter-individually there were large differences in the amount of the different types of movements at the various ages, which resulted in wide ranges. The sum of the rank orders which for total activity and general movements, were found weekly, were compared to those which could be expected to occur in a homogeneous population. Two fetuses appeared to be significantly different from the others on mathematical grounds. One consistently showed a high and one a low motor output. Week-to-week stability in the rank orders of the various movement patterns was studied by adding up a sum score of all the weekly changes in ranks. Three fetuses were found to be stable and three showed large fluctuations. The others were in between these extremes. The ranks of the movements from high to low frequency, appeared to be strictly age dependent, whereby all the fetuses followed the same developmental trend. There were no differences between female and male fetuses in any of the movement patterns.

Meta-analysis of low molecular weight heparin to prevent recurrent placenta-mediated pregnancy complications

A 35-year-old woman with recurrent severe placenta-mediated pregnancy complications in her 2 pregnancies asks: Will low-molecular-weight heparin help prevent recurrent placenta-mediated pregnancy complications in my next pregnancy? We performed a meta-analysis of randomized controlled trials (RCTs) comparing low-molecular-weight heparin (LMWH) vs no LMWH for the prevention of recurrent placenta-mediated pregnancy complications. We identified six RCTs that included a total of 848 pregnant women with prior placenta-mediated pregnancy complications. The primary outcome was a composite of pre-eclampsia (PE), birth of a small-for-gestational-age (SGA) newborn (<10th percentile), placental abruption, or pregnancy loss >20 weeks. Overall, 67 (18.7%) of 358 of women being given prophylactic LMWH had recurrent severe placenta-mediated pregnancy complications compared with 127 (42.9%) of 296 women with no LMWH (relative risk reduction, 0.52; 95% CI, 0.32 to 0.86; P = .01; I(2), 69%, indicating moderate heterogeneity). We identified similar relative risk reductions with LMWH for individual outcomes, including any PE, severe PE, SGA <10th percentile, SGA <5th percentile, preterm delivery <37 weeks, and preterm delivery <34 weeks with minimal heterogeneity. LMWH may be a promising therapy for recurrent, especially severe, placenta-mediated pregnancy complications, but further research is required.

The mechanism of prevention of paracetamol-induced hepatotoxicity by 3,5-dialkyl substitution: The roles of glutathione depletion and oxidative stress

Recently, we have reported that 3,5-dialkyl substitution of paracetamol, in contrast to 3-monoalkyl substitution, prevented the paracetamol-induced toxicity in freshly isolated rat hepatocytes without having any effect on its cytochrome P-450 mediated bioactivation to reactive N-acetyl-p-benzoquinone imines (NAPQI). In the present study the mechanism of this prevention of toxicity, with special emphasis on oxidative stress, was studied in more detail in freshly isolated rat hepatocytes, using paracetamol, 3-methyl-, 3,5-dimethyl-paracetamol, synthetic NAPQI and 3,5-dimethyl-NAPQI. 3-Methyl-paracetamol was found to induce glutathione (GSH) depletion, lipid-peroxidation and cytotoxicity in hepatocytes to the same extent as paracetamol. 3,5-Dimethyl-paracetamol, however, even when added in a ten-fold higher concentration when compared to paracetamol, did not induce any of these effects. Similar differences of toxicity were observed between NAPQI and 3,5-dimethyl-NAPQI; 3,5-dimethyl-NAPQI, in contrast to NAPQI, did not reduce protein thiol levels, did not induce GSH depletion, lipid-peroxidation nor cytotoxicity. Only after artificial depletion of GSH levels in the hepatocytes by DEM or BCNU, 3,5-dimethyl-NAPQI was cytotoxic. This effect was accompanied by depletion of protein thiol levels, but not by lipid-peroxidation. Addition of the disulfide reducing agent, dithiothreitol, prevented the artificially created cytotoxicity of 3,5-dimethyl-NAPQI. It is concluded that prevention of paracetamol-induced toxicity by 3,5-dialkyl substitution is primarily due to prevention of irreversible GSH-depletion, presumably caused by the inability of 3,5-dialkyl-NAPQI to conjugate with thiols. As a result, the GSH-dependent cellular defense mechanism against potential oxidative cellular injury by 3,5-dialkyl-NAPQI is left unimpaired. Our observations indicate that a compound, not capable of covalent binding to thiol groups of proteins, can induce toxicity solely as a result of protein thiol oxidation without inducing lipid-peroxidation.