Biomedical subjects
Publications and source records attributed to G A Dekker.
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Preeclampsia still ranks as one of obstetrics major problems. Clinicians typically encounter preeclampsia as maternal disease with variable degrees of fetal involvement. More and more the unique immunogenetic maternal-paternal relationship is appreciated, and as such also the specific 'genetic conflict' that is characteristic of haemochorial placentation. From that perspective preeclampsia can also been seen as a disease of an individual couple with primarily maternal and fetal manifestations. Factors that are unique to a specific couple would include the length and type of sexual relationship, the maternal (decidual natural killer cells) acceptation of the invading cytotrophoblast (paternal HLA-C), and seminal levels of transforming growth factor-beta and probably other cytokines. The magnitude of the maternal response would be determined by factors including a maternal set of genes determining her characteristic inflammatory responsiveness, age, quality of her endothelium, obesity/insulin resistance and probably a whole series of susceptibility genes amongst which the thrombophilias received a lot of attention in recent years.
Since cervical incompetence was introduced in the English literature in 1678, our understanding and obstetric management of this clinical entity, have changed tremendously over the years. This review shows the historical perspective of the development of cervical incompetence as a distinct clinical entity and an all or nothing phenomenon to cervical incompetence as part of a spectrum leading to preterm delivery, which can express differently in subsequent pregnancies. These changes in our understanding imply consequences for the obstetric management of cervical incompetence. This review focuses on the obstetric management of women considered to be at high risk of preterm delivery due to cervical incompetence, by transvaginal ultrasonographic follow-up of cervical length and transvaginal cervical cerclage.
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OBJECTIVES: The purpose of this study is to compare the hemodynamic and metabolic changes after ritodrine and nifedipine tocolysis. METHODS: For an open randomized study, patients with preterm labor (N=185) were allocated to groups to receive ritodrine intravenously (N=90) or nifedipine orally (N=95). RESULTS: The mean diastolic blood pressure was significantly lower in the ritodrine group 24 h (65+/-12 vs. 70+/-8, P=0.001) and 48 h (65+/-12 vs. 71+/-8, P=0.004) after starting tocolysis compared with the nifedipine group. Mean maternal heart rate was significantly higher in the ritodrine group 24 h (105+/-17 vs. 86+/-13, P<0.0001) and 48 h (100+/-21 vs. 85+/-12, P<0.0001) after starting tocolysis compared with the nifedipine group. Mean fasting glucose levels were higher (6.68+/-2.53 vs. 4.93+/-1.23, P=0.0016), while mean potassium levels were lower (3.52+/-0.84 vs. 3.81+/-0.45, P=0.04) in the ritodrine group 48 h after starting tocolysis compared with the nifedipine group. CONCLUSIONS: Use of nifedipine for preterm labor is associated with a lower incidence of adverse hemodynamic and metabolic changes compared with ritodrine after 24 and 48 h of tocolysis. In our opinion nifedipine is the preferred drug of choice for the treatment of preterm labor.
BACKGROUND: Preterm birth is a major contributor to perinatal mortality and morbidity and affects approximately six to seven per cent of births in developed countries. Tocolytics are drugs used to suppress uterine contractions. The most widely tested tocolytics are betamimetics. Although they have been shown to delay delivery, betamimetics have not been shown to improve perinatal outcome, and they have a high frequency of unpleasant and even fatal maternal side effects. There is growing interest in calcium channel blockers as a potentially effective and well tolerated form of tocolysis. OBJECTIVES: To assess the effects on maternal, fetal and neonatal outcomes of calcium channel blockers, administered as a tocolytic agent, to women in preterm labour. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's specialised register of controlled trials, the Cochrane Controlled Trials Register (February 2002), MEDLINE, EMBASE, and Current Contents. We also contacted recognised experts and cross referenced relevant material. SELECTION CRITERIA: All published and unpublished randomised trials in which calcium channel blockers were used for tocolysis for women in labour between 20 and 36 weeks gestation. DATA COLLECTION AND ANALYSIS: Standard methods of the Cochrane Collaboration and the Cochrane Pregnancy and Childbirth Group were used. Evaluation of methodological quality and trial data extraction were undertaken independently by three authors. Additional information was sought to enable assessment of methodology and conduct of intention-to-treat analyses. Meta-analysis was conducted assessing the effects of calcium channel blockers compared with any other tocolytic agent. Results are presented using relative risk for categorical data and weighted mean difference for continuous data. MAIN RESULTS: Eleven randomised controlled trials involving 870 women were included. When compared with any other tocolytic agent (mainly betamimetics), calcium channel blockers reduced the number of women giving birth within 48 hours (relative risk (RR) 0.73; 95% confidence interval (CI) 0.54, 0.98) and within seven days (RR 0.76; 95% CI 0.59, 0.99). Calcium channel blockers also reduced the requirement for women to have treatment ceased for adverse drug reaction (RR 0.15; 95% CI 0.06, 0.43), the frequency of neonatal respiratory distress syndrome (RR 0.64; 95% CI 0.45, 0.91) and neonatal jaundice (RR 0.73; 95% CI 0.57, 0.93). REVIEWER'S CONCLUSIONS: When tocolysis is indicated for women in preterm labour, calcium channel blockers are preferable to betamimetic agents. Further research should address the effects of different dosage regimens and formulations of nifedipine on maternal and neonatal outcomes.
For the management of acute thrombotic events in pregnancy therapeutic doses of low molecular weight heparins (LMWH) may be used, unless the shorter half-life of intravenous unfractionated heparin (UH) and predictable reversibility by protamine are important. Treatment should be continued up until delivery and into the puerperium. Pregnant women who have had an acute thrombotic event should be delivered by a specialist team. In the case of recent thrombosis, delivery should be planned and the time during which anticoagulation therapy is ceased around the time of delivery should be minimised. Therapeutic doses of LMWH contraindicate the use of regional anaesthesia, and a switch to intravenous UH before delivery may allow greater flexibility in this regard. Prophylactic doses of LMWH can be used to reduce the risk of recurrent thromboembolic events in pregnancy. The regimen used will depend on the previous history, the family history and the presence of risk factors, including the genetic and acquired causes of thrombophilia. Women with mechanical heart valves are at high risk during pregnancy and require therapeutic anticoagulation throughout pregnancy under the direction of experienced specialists. Low-dose aspirin can reduce the risk of recurrent pre-eclampsia by about 15%, but the role of UH and LMWH in the prevention of recurrent miscarriage or obstetric complications associated with uteroplacental insufficiency is still uncertain.
OBJECTIVE: To study the effect of the loop electrosurgical excision procedure (LEEP) on gestational age at delivery in the subsequent pregnancy. METHOD: Identification of women with LEEP. Chart analysis and inquiry into gestational age at the subsequent delivery. Exclusion of first trimester abortions, multiple gestations, cold knife conizations and women over 40 years during LEEP. For comparison, 40 weeks was used as the mean date of delivery in a normal population. Wilcoxon signed rank test was used and P<0.05 was considered significant. RESULT: Fifty-six women delivered after LEEP. Seven delivered preterm of whom three were induced and one had a history of preterm delivery. Deliveries prior to 32 weeks of gestation did not occur. Mean gestational age at delivery was 39 2/7 weeks (95%CI: 38 5/7-39 6/7) which is significantly earlier (P=0.03) than the hypothetical 40 weeks. CONCLUSION: After LEEP, deliveries prior to 32 weeks did not occur. Gestational age at delivery was only 5 days earlier than expected. LEEP cannot be considered a risk for early preterm delivery.
OBJECTIVE: To investigate potential association or linkage among nine polymorphisms in the genes encoding tumor necrosis factor (TNF) alpha or lymphotoxin (LT) alpha and preeclampsia. METHODS: Four di-allelic polymorphisms and five microsatellite markers in the genes encoding TNF-alpha (TNF) and LTalpha (LTA) and their haplotypes were studied in 150 Dutch families. These families contained sib-pairs of women affected with preeclampsia; eclampsia; the hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome (strict criteria); or pregnancy-induced hypertension (mild criteria). Frequencies were compared with 98 healthy controls. Nonparametric affected sib-pair analyses for allele sharing among siblings were carried out for all nine markers. Each sibship was composed of an affected index woman and one or more affected sisters. RESULTS: Although we found a striking association with the TNF-I haplotype in 30 index women with (pre-)eclampsia or HELLP syndrome compared with controls (odds ratio [OR] 3.8; 95% confidence interval [CI] 1.6, 8.9), this association was not found in their 30 sisters meeting similar disease criteria. Analyses in all 150 families showed a similar TNF-I association in 122 index women meeting the strict criteria compared with controls (OR 1.9; 95% CI 1.1, 3.3), but, again, not in their 91 sisters meeting similar disease criteria. This association was stronger in a subgroup of 75 index women with preeclampsia only (OR 2.3; 95% CI 1.2, 4.2). No excess allele sharing for any marker was seen between the siblings. CONCLUSION: The nine polymorphisms studied in the TNF-LTA region did not show evidence for association or linkage with familial preeclampsia.
Hypertensive disorders constitute the most common medical complications of pregnancy. In normal pregnancy, impressive physiological changes take place in the maternal cardiovascular system. Morphological changes are the result of invasion of migratory trophoblast cells into the walls of the spiral arteries. After destruction of elastic, muscular and neural tissue in the media, the trophoblast cells get incorporated into the vessel wall and the endothelial lining of the spiral arteries is restored. The physiological changes create a low-resistance, low-pressure, high-flow system with the absence of maternal vasomotor control. Biochemical adaptations in maternal vasculature include changes in the prostaglandin system, the renin-angiotensin-aldosteron system and the kallikrein-kinin system. In preeclampsia, physiological changes in the spiral arteries are confined to the decidual portion of the arteries. Myometrial segments remain anatomically intact and fail to dilate. In addition, the adrenergic nerve supply is left intact. The cause of this impaired endovascular trophoblast invasion is not yet elucidated. But in combination with the imbalance between vasodilator and vasoconstrictor eicosanoids, it gives rise to reduced perfusion of the intervillous space. In the absence of an adequate production of antiaggregatory prostacyclin (PGI(2)), nitric oxide, or both, surface-mediated platelet activation is supposed to occur on the surface of the spiral arteries. Because platelets are the principal source of circulating serotonin, the increased platelet aggregation in preeclampsia causes an increase in serotonin levels. Interaction of serotonin with serotonin(1)- or serotonin(2)-receptors depends on the state of the endovascular trophoblast or endothelium in the spiral arteries and has opposite effects with regard to vasodilating and vasoconstrictive influences.
Hypertensive disorders of pregnancy are the leading cause of maternal and perinatal mortality and morbidity in developing and developed countries. The etiology of preeclampsia is still unknown. Delivering the baby is the only definite treatment. The benefits of acute pharmacological control of severe hypertension prior to and/or post-delivery are generally accepted. Most drugs commonly used in the management of severe hypertension in pregnancy have significant maternal and/or neonatal adverse side effects. Furthermore, some are not effective to acutely lower the blood pressure in patients with a hypertensive crisis. Until recently not one of the commonly used antihypertensive drugs has been tailored to the pathophysiology of severe preeclampsia, being a clinical syndrome characterized by endothelial cell dysfunction, vasospasm and platelet aggregation. Ketanserin, a serotonin(2)-receptor blocker, is a drug that appears to be tailored for treating this pregnancy-associated enthothelial cell dysfunction. The results of several prospective trials show that there is a definite place for serotonin(2)-receptor blockers in the treatment of pregnancy-induced hypertensive disorders. This review provides a summary on the more established drugs as well as on some of the newer antihypertensive drugs used in pregnancy with emphasis on the existing experience with ketanserin.
Preeclampsia is associated with increased maternal and perinatal morbidity and mortality. Preeclampsia is more than pregnancy-induced hypertension. The hypertension is only one manifestation of an underlying multifactorial, multisystem disorder, initiated early in pregnancy. In established severe disease there is volume contraction, reduced cardiac output, enhanced vascular reactivity, increased vascular permeability and platelet consumption. Medical treatment of severe hypertension in pregnancy is required. The more controversial issues are the role of pharmacological treatment in conservative management of severe preeclampsia aiming at prolongation of pregnancy, the ability of such therapy to modify the course of the underlying systemic disorder and the effects on fetal and maternal outcome. This paper presents an overview concerning the current developments in management and monitoring of severe preeclampsia. Controversial topics such as the role of plasma volume expansion in preeclampsia, expectant versus aggressive management of severe preeclampsia remote from term, and pharmacological interventions in the management of eclampsia and the HELLP syndrome are addressed.
Calcium channel blockers (CCBs) have the ability to inhibit contractility in smooth muscle cells. CCBs have an already established role in the treatment of non-pregnant hypertension and angina pectoris. Some epidemiological studies found an association between the use of CCBs and an increase in cardiovascular mortality, malignancy, and gastrointestinal bleeding. More recent studies with many more patients and a longer follow-up did not find these associations. In obstetrics CCBs have become increasingly popular for the management of preterm labor and pregnancy-induced hypertensive disorders. Meta-analysis shows that use of nifedipine in comparison with betamimetics is associated with a more frequent successful prolongation of pregnancy in case of preterm labor, resulting in significantly fewer admissions of newborns to the neonatal intensive care unit (NICU), and is associated with a lower incidence of respiratory distress syndrome. No adverse fetal side effects in humans have been reported with the use of nifedipine for obstetric indications. Nifedipine is an effective and safe drug to use when tocolytic therapy is indicated for preterm labor. In preeclampsia nifedipine effectively lowers blood pressure and can be a good alternative for (di) hydralazine.
Preeclampsia, hallmarked by de novo hypertension and proteinuria in pregnancy, has a familial tendency. Recently, a large Icelandic genome-wide scan provided evidence for a maternal susceptibility locus for preeclampsia on chromosome 2p13 which was confirmed by a genome scan from Australia and New Zealand (NZ). The current study reports on a genome-wide scan of Dutch affected sib-pair families. In total 67 Dutch affected sib-pair families, comprising at least two siblings with proteinuric preeclampsia, eclampsia or HELLP-syndrome, were typed for 293 polymorphic markers throughout the genome and linkage analysis was performed. The highest allele sharing lod score of 1.99 was seen on chromosome 12q at 109.5 cM. Two peaks overlapped in the same regions between the Dutch and Icelandic genome-wide scan at chromosome 3p and chromosome 15q. No overlap was seen on 2p. Re-analysis in 38 families without HELLP-syndrome (preeclampsia families) and 34 families with at least one sibling with HELLP syndrome (HELLP families), revealed two peaks with suggestive evidence for linkage in the non-HELLP families on chromosome 10q (lod score 2.38, D10S1432, 93.9 cM) and 22q (lod score 2.41, D22S685, 32.4 cM). The peak on 12q appeared to be associated with HELLP syndrome; it increased to a lod score of 2.1 in the HELLP families and almost disappeared in the preeclampsia families. A nominal peak on chromosome 11 in the preeclampsia families showed overlap with the second highest peak in the Australian/NZ study. Results from our Dutch genome-wide scan indicate that HELLP syndrome might have a different genetic background than preeclampsia.
OBJECTIVE: This study was undertaken to assess frequencies of the methylenetetrahydrofolate reductase gene mutations cytosine-to-thymine substitution at base 677 (C677T) and adenine-to-cytosine substitution at base 1298 (A1298C) and their interactions with homocysteine and vitamin levels among Dutch women with preeclampsia. STUDY DESIGN: Mutations were studied in the following 5 groups: 47 consecutive women with preeclampsia, 49 women with preeclampsia and with hyperhomocysteinemia, 36 women with preeclampsia but without hyperhomocysteinemia, 127 women with familial preeclampsia (typed for C677T mutations only), and 120 control subjects. Plasma levels of homocysteine, folate, and vitamin B12 were measured. RESULTS: Although 10.6% of the consecutive women with preeclampsia had strictly defined hyperhomocysteinemia (values >97.5th percentile), neither mutation was found in excess relative to the control group. Women with preeclampsia who had mild hyperhomocysteinemia (values >75th percentile) had a significant excess of the TT genotype (homozygosity for C677T mutation) relative to the women with preeclampsia who did not have hyperhomocysteinemia (odds ratio, 8.2; 95% confidence interval, 1.8-39). They also had significantly lower vitamin levels. CONCLUSION: Hyperhomocysteinemia in women with preeclampsia was associated with mutations in the gene for methylenetetrahydrofolate reductase, but the high frequency of hyperhomocysteinemia itself cannot be explained by these mutations alone.
OBJECTIVE: To compare preterm delivery rates (before 34 weeks of gestation) and neonatal morbidity and mortality in patients with risk factors or symptoms of cervical incompetence managed with therapeutic McDonald cerclage and bed rest versus bed rest alone. STUDY DESIGN: Cervical length was measured in patients with risk factors or symptoms of cervical incompetence. Risk factors for cervical incompetence included previous preterm delivery before 34 weeks of gestation that met clinical criteria for the diagnosis of cervical incompetence, previous preterm premature rupture of membranes before 32 weeks of gestation, history of cold knife conization, diethylstilbestrol exposure, and uterine anomaly. When a cervical length of <25 mm was measured before a gestational age of 27 weeks, a randomization for therapeutic cerclage and bed rest (cerclage group) or bed rest alone (bed rest group) was performed. The analysis is based on intention to treat. RESULTS: Of the 35 women who met the inclusion criteria, 19 were allocated randomly to the cerclage group and 16 to the bed rest group. Both groups were comparable for mean cervical length and mean gestational age at time of randomization, mean overall 20 mm and 21 weeks. Preterm delivery before 34 weeks was significantly more frequent in the bed rest group than in the cerclage group (7 of 16 vs none, respectively; P =.002). There was no statistically significant difference in neonatal survival between the groups (13 neonates survived in the bed rest group vs all in the cerclage group). The compound neonatal morbidity, defined as admission to the neonatal intensive care unit or neonatal death, was significantly higher in the bed rest group than in the cerclage group (8 of 16 vs 1 of 19, respectively; P =.005; RR = 9.5, 95% CI, 1.3-68.1). CONCLUSIONS: Therapeutic cerclage with bed rest reduces preterm delivery before 34 weeks of gestation and compound neonatal morbidity in women with risk factors and/or symptoms of cervical incompetence and a cervical length of <25 mm before 27 weeks of gestation.
OBJECTIVE: To compare maternal and perinatal outcome with the use of either intravenous ketanserin or dihydralazine in treatment of women with preeclampsia. METHODS: The records from January 1989 to January 1997 of all patients receiving intravenous ketanserin or dihydralazine as first line antihypertensive therapy were reviewed and standardized data forms were completed. 315 charts of patients were identified and evaluated for effects on blood pressure, laboratory parameters, maternal and perinatal outcome. RESULTS: During the study interval 169 patients received ketanserin and 146 dihydralazine. Significantly fewer antepartum (27% versus 38%, p = 0.04) and postpartum (25% versus 39%, p = 0.01) maternal complications were noted in patients receiving ketanserin. Occurrence of HELLP syndrome was significantly lower among patients who received ketanserin (20%) than among those who received dihydralazine (40%, p = 0.0001). Side-effects were reported with significantly higher frequency in patients receiving dihydralazine (60%) as compared to those receiving ketanserin (17%, p < 0.0001). Perinatal outcome was comparable, however, umbilical cord arterial pH values (mean +/- SD) were higher with ketanserin compared to dihydralazine (7.25 +/- 0.07 vs 7.23 +/- 0.09, p = 0.038). The incidence of placental abruption was higher in patients receiving dihydralazine (5.5%) versus those receiving ketanserin (0.6%, p = 0.014). CONCLUSION: Ketanserin appears to be a better option than dihydralazine for treatment of severe preeclampsia since fewer maternal complications and side-effects were observed in patients receiving ketanserin.