Johannes J. Duvekot

Early pregnancy changes in hemodynamics and volume homeostasis are consecutive adjustments triggered by a primary fall in systemic vascular tone.

OBJECTIVE The purpose of this study was to test the hypothesis that early pregnancy changes in volume homeostasis develop as a consequence of preceding changes in maternal hemodynamics. STUDY DESIGN Maternal cardiovascular function of 10 pregnant women was followed up by Doppler echocardiography. Vascular filling state and volume homeostasis were evaluated by echocardiographic index values, glomerular filtration rate, serum osmolality, and volume-regulating hormones. Studies were performed weekly in early pregnancy, in the second and third trimesters, and post partum. Changes relative to the fifth week and the consistency of changes between weeks 5 and 8 were evaluated by nonparametric statistics. RESULTS In early pregnancy cardiac output increased and afterload decreased. Concomitant increases in ultrasonic preload index values and glomerular filtration rate were accompanied by decreases in serum renin, Na+, and osmolality. CONCLUSION These data support the concept that maternal hemodynamic adaptation to pregnancy is most likely triggered by a primary fall in systemic vascular tone. The resulting rapid fall in preload and afterload leads to a compensatory increase in heart rate and activation of the volume-restoring mechanisms. Subsequently cardiac output increases because of a rise in stroke volume, which develops because the vascular filling state normalizes, whereas the reduced afterload reduction is maintained.

Maternal cardiovascular hemodynamic adaptation to pregnancy.

Maternal cardiovascular adaptation to pregnancy involves enormous changes. Cardiac output increases in early pregnancy, initially as a result of an increased heart rate, soon followed by an increased stroke volume. Cardiac output continues to increase until midpregnancy, and remains stable afterward, with a possible small decline in the last weeks of pregnancy. Blood pressure decreases in early pregnancy, reaching a minimum in midpregnancy, then returning to baseline levels at term. Consequently, peripheral vascular resistance is reduced throughout pregnancy. Myocardial contractility seems to be increased during all trimesters of pregnancy, thus gradually provoking the development of a mild ventricular hypertrophy. The increase in preload, which develops in concert with the increment in blood volume, leads to an increase in left atrial diameter, which also begins during early pregnancy. During labor, both cardiac output and blood pressure increase. After delivery, cardiac output initially increases, but begins to decrease within the first hour to reach baseline levels 2 weeks postpartum. Most cardiovascular parameters show their greatest changes within 2 weeks postpartum. Five months postnatally, only a mild residual ventricular hypertrophy persists.

Induction versus expectant monitoring for intrauterine growth restriction at term: randomised equivalence trial (DIGITAT)

Objective To compare the effect of induction of labour with a policy of expectant monitoring for intrauterine growth restriction near term. Design Multicentre randomised equivalence trial (the Disproportionate Intrauterine Growth Intervention Trial At Term (DIGITAT)). Setting Eight academic and 44 non-academic hospitals in the Netherlands between November 2004 and November 2008. Participants Pregnant women who had a singleton pregnancy beyond 36+0 weeks’ gestation with suspected intrauterine growth restriction. Interventions Induction of labour or expectant monitoring. Main outcome measures The primary outcome was a composite measure of adverse neonatal outcome, defined as death before hospital discharge, five minute Apgar score of less than 7, umbilical artery pH of less than 7.05, or admission to the intensive care unit. Operative delivery (vaginal instrumental delivery or caesarean section) was a secondary outcome. Analysis was by intention to treat, with confidence intervals calculated for the differences in percentages or means. Results 321 pregnant women were randomly allocated to induction and 329 to expectant monitoring. Induction group infants were delivered 10 days earlier (mean difference −9.9 days, 95% CI −11.3 to −8.6) and weighed 130 g less (mean difference −130 g, 95% CI −188 g to −71 g) than babies in the expectant monitoring group. A total of 17 (5.3%) infants in the induction group experienced the composite adverse neonatal outcome, compared with 20 (6.1%) in the expectant monitoring group (difference −0.8%, 95% CI −4.3% to 3.2%). Caesarean sections were performed on 45 (14.0%) mothers in the induction group and 45 (13.7%) in the expectant monitoring group (difference 0.3%, 95% CI −5.0% to 5.6%). Conclusions In women with suspected intrauterine growth restriction at term, we found no important differences in adverse outcomes between induction of labour and expectant monitoring. Patients who are keen on non-intervention can safely choose expectant management with intensive maternal and fetal monitoring; however, it is rational to choose induction to prevent possible neonatal morbidity and stillbirth. Trial registration International Standard Randomised Controlled Trial number ISRCTN10363217.

Adverse drug reactions to tocolytic treatment for preterm labour: prospective cohort study

Objective To evaluate the incidence of serious maternal complications after the use of various tocolytic drugs for the treatment of preterm labour in routine clinical situations. Design Prospective cohort study. Setting 28 hospitals in the Netherlands and Belgium. Participants 1920 consecutive women treated with tocolytics for threatened preterm labour. Main outcome measures Maternal adverse events (those suspected of being causally related to treatment were considered adverse drug reactions) leading to cessation of treatment. Results An independent panel evaluated the recorded adverse events, without knowledge of the type of tocolytic used. Of the 1920 women treated with tocolytics, 1327 received a single course of treatment (69.1%), 282 sequential courses (14.7%), and 311 combined courses (16.2%). Adverse drug reactions were categorised as serious or mild in 14 cases each. The overall incidence of serious adverse drug reaction was 0.7%. Compared with atosiban, the relative risk of an adverse drug reaction for single treatment with a β adrenoceptor agonist was 22.0 (95% confidence interval 3.6 to 138.0) and for single treatment with a calcium antagonist was 12 (1.9 to 69). Multiple drug tocolysis led to five serious adverse drug reactions (1.6%). Multiple gestation, preterm rupture of membranes, and comorbidity were not independent risk factors for adverse drug reactions. Conclusions The use of β adrenoceptor agonists or multiple tocolytics for preventing preterm birth is associated with a high incidence of serious adverse drug reactions. Indometacin and atosiban were the only drugs not associated with serious adverse drug reactions. A direct comparison of the effectiveness of nifedipine and atosiban in postponing preterm delivery is needed.

Conservative Management of Abnormally Invasive Placentation

Due to the growing number of cesarean deliveries, the frequency of abnormally invasive placentation is increasing. The optimal management of this condition remains unclear. This article reviews the efficacy and safety of conservative management of abnormally invasive placentation. We performed a MEDLINE and Embase search and reviewed all articles on conservative management of abnormally invasive placentation published from 1985 through 2006. Over the past 20 years, 48 reports have described outcomes of 60 women who were treated conservatively for abnormally invasive placentation. Twenty-six women were managed without any additional interventions. In most of these patients (19/26), the placenta had been partially removed. In 4 of these 26, conservative therapy failed. Twenty-two women received adjuvant methotrexate. In most of these women (19/22), the entire placenta was left in situ. In 5, therapy failed. Twelve women were managed with arterial embolization. In most of these (9/12), the diagnosis was made antepartum and the placenta was completely left in situ. In 3, therapy failed. Overall, 11 women experienced infection (11/60), 21 women experienced vaginal bleeding (21/60), and 4 suffered disseminated intravascular coagulopathy (4/60). Spontaneous loss of placental tissue was noted in 16 women. Subsequent pregnancies were reported in 8 women. Conservative management of abnormally invasive placentation can be effective and fertility can be preserved. It should only be considered in highly selected cases when blood loss is minimal and there is desire for fertility preservation. Whether adjuvant methotrexate or selective arterial embolization is beneficial is uncertain. Undetectable hCG values do not seem to guarantee complete resorption of retained placental tissue. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to explain that there are methods to successfully treat abnormal placentation with conservative means, but these methods must be applied only in highly selected cases and recall that no one method is superior to the other.

Perinatal morbidity and mortality in early‐onset fetal growth restriction: cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE)

Few data exist for counseling and perinatal management of women after an antenatal diagnosis of early‐onset fetal growth restriction. Yet, the consequences of preterm delivery and its attendant morbidity for both mother and baby are far reaching. The objective of this study was to describe perinatal morbidity and mortality following early‐onset fetal growth restriction based on time of antenatal diagnosis and delivery.

2 year neurodevelopmental and intermediate perinatal outcomes in infants with very preterm fetal growth restriction (TRUFFLE): A randomised trial

BACKGROUND No consensus exists for the best way to monitor and when to trigger delivery in mothers of babies with fetal growth restriction. We aimed to assess whether changes in the fetal ductus venosus Doppler waveform (DV) could be used as indications for delivery instead of cardiotocography short-term variation (STV). METHODS In this prospective, European multicentre, unblinded, randomised study, we included women with singleton fetuses at 26-32 weeks of gestation who had very preterm fetal growth restriction (ie, low abdominal circumference [<10th percentile] and a high umbilical artery Doppler pulsatility index [>95th percentile]). We randomly allocated women 1:1:1, with randomly sized blocks and stratified by participating centre and gestational age (<29 weeks vs ≥29 weeks), to three timing of delivery plans, which differed according to antenatal monitoring strategies: reduced cardiotocograph fetal heart rate STV (CTG STV), early DV changes (pulsatility index >95th percentile; DV p95), or late DV changes (A wave [the deflection within the venous waveform signifying atrial contraction] at or below baseline; DV no A). The primary outcome was survival without cerebral palsy or neurosensory impairment, or a Bayley III developmental score of less than 85, at 2 years of age. We assessed outcomes in surviving infants with known outcomes at 2 years. We did an intention to treat study for all participants for whom we had data. Safety outcomes were deaths in utero and neonatal deaths and were assessed in all randomly allocated women. This study is registered with ISRCTN, number 56204499. FINDINGS Between Jan 1, 2005 and Oct 1, 2010, 503 of 542 eligible women were randomly allocated to monitoring groups (166 to CTG STV, 167 to DV p95, and 170 to DV no A). The median gestational age at delivery was 30·7 weeks (IQR 29·1-32·1) and mean birthweight was 1019 g (SD 322). The proportion of infants surviving without neuroimpairment did not differ between the CTG STV (111 [77%] of 144 infants with known outcome), DV p95 (119 [84%] of 142), and DV no A (133 [85%] of 157) groups (ptrend=0·09). 12 fetuses (2%) died in utero and 27 (6%) neonatal deaths occurred. Of survivors, more infants where women were randomly assigned to delivery according to late ductus changes (133 [95%] of 140, 95%, 95% CI 90-98) were free of neuroimpairment when compared with those randomly assigned to CTG (111 [85%] of 131, 95% CI 78-90; p=0.005), but this was accompanied by a non-significant increase in perinatal and infant mortality. INTERPRETATION Although the difference in the proportion of infants surviving without neuroimpairment was non-significant at the primary endpoint, timing of delivery based on the study protocol using late changes in the DV waveform might produce an improvement in developmental outcomes at 2 years of age. FUNDING ZonMw, The Netherlands and Dr Hans Ludwig Geisenhofer Foundation, Germany.

Severely impaired fetal growth is preceded by maternal hemodynamic maladaptation in very early pregnancy

Objective. To test the hypothesis that in pregnancies complicated by intrauterine growth retardation (IUGR) maternal cardiovascular adaptation is already abnormal in the first weeks of pregnancy.

Maternal Volume Homeostasis in Early Pregnancy in Relation to Fetal Growth Restriction

Objective To test the hypothesis that volume adaptation in pregnancies complicated by fetal growth restriction (FGR) is already abnormal very early in pregnancy. Methods In six pregnancies later complicated by FGR, volume homeostasis in the first 8 weeks was compared to that in ten normal pregnancies. Creatinine clearance, volume-dependent hormones, hemodilution-related variables, and ultrasonic cardiovascular dimensions were measured weekly between weeks 5 and 10, in the second and third trimesters, and postpartum. Differences between the two groups were analyzed by nonparametric tests. Results Very early in pregnancy, pregnancies complicated by FGR differed from normal pregnancies in the following ways: smaller left atrial diameter, smaller collapsible part of the inferior vena cava, lower serum sodium concentration, and smaller fall in serum creatinine and urea. Conclusion Fetal growth restriction is preceded by defective volume adaptation very early in pregnancy. It appears that the maternal compensation mechanisms are unable to resolve the transient state of vascular underfill seen in this period in normal gestation.

Renal hemodynamics and volume homeostasis in pregnancy.

Maternal hemodynamic adaptation to pregnancy consists of profound changes in various interdependent systems. Of crucial importance in the early adaptation of the volume homeostatic mechanisms to pregnancy is the resetting of the volume and osmoreceptors. This resetting may be induced by a reduction in vascular tone and leads to early changes in plasma osmolality and glomerular filtration rate. After this initial adaptation other volume-regulating mechanisms such as the renin-angiotensin-aldosterone system, pregnancy hormones, and alpha-ANP adapt to the rising blood volume. The initial adaptation results in a state of relative vascular underfill, inducing secondary compensations in the volume homeostasis. The initially increased vascular capacitance in pregnancy is compatible with the signals of vascular overfill. Contrarily, the protracted filling of this enlarged vascular bed triggers signals compatible with vascular underfill.