Identification of cases with adverse neonatal outcome monitored by cardiotocography versus ST analysis: secondary analysis of a randomized trial.

OBJECTIVE: To evaluate whether correct adherence to clinical guidelines might have led to prevention of cases with adverse neonatal outcome. DESIGN: Secondary analysis of cases with adverse outcome in a multicenter randomized clinical trial. SETTING: Nine Dutch hospitals. POPULATION: Pregnant women with a term singleton fetus in cephalic position. METHODS: Data were obtained from a randomized trial that compared monitoring by STAN® (index group) with cardiotocography (control group). In both trial arms, three observers independently assessed the fetal surveillance results in all cases with adverse neonatal outcome, to determine whether an indication for intervention was present, based on current clinical guidelines. MAIN OUTCOME MEASURES: Adverse neonatal outcome cases fulfilled one or more of the following criteria: (i) metabolic acidosis in umbilical cord artery (pH < 7.05 and base deficit in extracellular fluid >12 mmol/L); (ii) umbilical cord artery pH < 7.00; (iii) perinatal death; and/or (iv) signs of moderate or severe hypoxic ischemic encephalopathy. RESULTS: We studied 5681 women, of whom 61 (1.1%) had an adverse outcome (26 index; 35 control). In these women, the number of performed operative deliveries for fetal distress was 18 (69.2%) and 16 (45.7%), respectively. Reassessment of all 61 cases showed that there was a fetal indication to intervene in 23 (88.5%) and 19 (57.6%) cases, respectively. In 13 (50.0%) vs. 11 (33.3%) cases, respectively, this indication occurred more than 20 min before the time of delivery, meaning that these adverse outcomes could possibly have been prevented. CONCLUSIONS: In our trial, more strict adherence to clinical guidelines could have led to additional identification and prevention of adverse outcome.

Prediction of neonatal metabolic acidosis in women with a singleton term pregnancy in cephalic presentation.

We sought to predict neonatal metabolic acidosis at birth using antepartum obstetric characteristics (model 1) and additional characteristics available during labor (model 2). In 5667 laboring women from a multicenter randomized trial that had a high-risk singleton pregnancy in cephalic presentation beyond 36 weeks of gestation, we predicted neonatal metabolic acidosis. Based on literature and clinical reasoning, we selected both antepartum characteristics and characteristics that became available during labor. After univariable analyses, the predictors of the multivariable models were identified by backward stepwise selection in a logistic regression analysis. Model performance was assessed by discrimination and calibration. To correct for potential overfitting, we (internally) validated the models with bootstrapping techniques. Of 5667 neonates born alive, 107 (1.9%) had metabolic acidosis. Antepartum predictors of metabolic acidosis were gestational age, nulliparity, previous cesarean delivery, and maternal diabetes. Additional intrapartum predictors were spontaneous onset of labor and meconium-stained amniotic fluid. Calibration and discrimination were acceptable for both models (c-statistic 0.64 and 0.66, respectively). In women with a high-risk singleton term pregnancy in cephalic presentation, we identified antepartum and intrapartum factors that predict neonatal metabolic acidosis at birth.

Neonatal morbidity in term neonates is related to gestational age at birth and level of care.

AIMS: The objective of this study was to assess whether the incidence of neonatal morbidity of neonates born at term and admitted to a neonatal intensive care unit (NICU) differs by gestational age and level of care. METHODS: This is a 5-year retrospective cohort study of singleton term births admitted to the NICU of the VU University Medical Center with a gestational age ≥37+0 weeks. RESULTS: In total, 497 neonates were included in the study. The incidence of neonates born with an arterial cord blood pH<7.10, neonatal asphyxia, and meconium aspiration syndrome increased with advancing gestational age. The incidence of secondary cesarean section and operative vaginal delivery also increased with advancing gestational age. Neonatal death occurred in 29 (5.84%) of the 497 cases; 27 (93%) of 29 were due to asphyxia. Seventeen (34%) of the 50 neonates born in primary care were admitted for asphyxia. Eight (47%) of these 17 neonates died. CONCLUSIONS: Neonatal morbidity in term neonates is related to gestational age at birth. Since asphyxia is an important cause of both morbidity and mortality in term neonates, it is important to clearly define and include asphyxia in future perinatal audits.

Cost-effectiveness of cardiotocography plus ST analysis of the fetal electrocardiogram compared with cardiotocography only.

OBJECTIVE: To assess the cost-effectiveness of addition of ST analysis of the fetal electrocardiogram (ECG; STAN) to cardiotocography (CTG) for fetal surveillance during labor compared with CTG only. DESIGN: Cost-effectiveness analysis based on a randomized clinical trial on ST analysis of the fetal ECG. SETTING: Obstetric departments of three academic and six general hospitals in The Netherlands. Population. Laboring women with a singleton high-risk pregnancy, a fetus in cephalic presentation, a gestational age >36 weeks and an indication for internal electronic fetal monitoring. METHODS: A trial-based cost-effectiveness analysis was performed from a health-care provider perspective. MAIN OUTCOME MEASURES: Primary health outcome was the incidence of metabolic acidosis measured in the umbilical artery. Direct medical costs were estimated from start of labor to childbirth. Cost-effectiveness was expressed as costs to prevent one case of metabolic acidosis. RESULTS: The incidence of metabolic acidosis was 0.7% in the ST-analysis group and 1.0% in the CTG-only group (relative risk 0.70; 95% confidence interval 0.38-1.28). Per delivery, the mean costs per patient of CTG plus ST analysis (n= 2 827) were €1,345 vs. €1,316 for CTG only (n= 2 840), with a mean difference of €29 (95% confidence interval -€9 to €77) until childbirth. The incremental costs of ST analysis to prevent one case of metabolic acidosis were €9 667. CONCLUSIONS: The additional costs of monitoring by ST analysis of the fetal ECG are very limited when compared with monitoring by CTG only and very low compared with the total costs of delivery.

Cardiotocography plus ST analysis of fetal electrocardiogram compared with cardiotocography only for intrapartum monitoring: a randomized controlled trial.

OBJECTIVE: To estimate the effectiveness of intrapartum fetal monitoring by cardiotocography plus ST analysis using a strict protocol for performance of fetal blood sampling. METHODS: We performed a multicenter randomized trial among laboring women with a high-risk singleton pregnancy in cephalic presentation beyond 36 weeks of gestation. Participants were assigned to monitoring by cardiotocography with ST analysis (index) or cardiotocography only (control). Primary outcome was metabolic acidosis, defined as an umbilical cord artery pH below 7.05 combined with a base deficit calculated in the extracellular fluid compartment above 12 mmol/L. Secondary outcomes were metabolic acidosis in blood, operative deliveries, Apgar scores, neonatal admissions, and hypoxic-ischemic encephalopathy. RESULTS: We randomly assigned 5,681 women to the two groups (2,832 index, 2,849 control). The fetal blood sampling rate was 10.6% in the index compared with 20.4% in the control group (relative risk 0.52; 95% [CI] 0.46-0.59). The primary outcome occurred 0.7% in the index compared with 1.1% in the control group (relative risk 0.70; 95% CI 0.38-1.28; number needed to treat 252). Using metabolic acidosis calculated in blood, these rates were 1.6% and 2.6%, respectively (relative risk 0.63; 95% CI 0.42-0.94; number needed to treat 100). The number of operative deliveries, low Apgar scores, neonatal admissions, and newborns with hypoxic-ischemic encephalopathy was comparable in both groups. CONCLUSION: Intrapartum monitoring by cardiotocography combined with ST analysis does not significantly reduce the incidence of metabolic acidosis calculated in the extracellular fluid compartment. It does reduce the incidence of metabolic acidosis calculated in blood and the need for fetal blood sampling without affecting the Apgar score, neonatal admissions, hypoxic-ischemic encephalopathy, or operative deliveries. LEVEL OF EVIDENCE: I.

Recurrent incarceration of the gravid uterus.

Incarceration of the gravid uterus is a rare phenomenon, associated with maternal and fetal morbidity and mortality. A 37-year-old gravida 2 para 1 develops a recurrent incarceration in her second pregnancy. Therefore, examination and follow-up early in the next pregnancy is advised.

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 beta 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 beta 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.

Misidentification of maternal for fetal heart rate patterns after delivery of the first twin.

BACKGROUND: The 2nd born in twin delivery is at higher risk of fetal asphyxia. We tested the hypothesis that inadequate, fetal heart rate (FHR) monitoring has contributed to an inadvertent outcome. STUDY DESIGN: A database was reviewed consisting of 41 twin deliveries with a pH in the umbilical artery of the 2nd twin below 7.05. Cardiotocograms were examined for possible signs of a maternal instead of a fetal origin of the heart rate pattern. RESULTS: In four of the reviewed cases, a good outcome had been anticipated by the attending physician based on the cardiotocogram, whereas the 2nd twin was born with low Apgar scores and a low pH of the umbilical artery. In retrospect it was concluded that the recorded heart rate pattern was of maternal origin. In all four cases the heart rate tracings had characteristics typical for a maternal origin. CONCLUSION: Misidentifying the maternal for the fetal heart rate increases the risk that a compromised fetal condition is missed. This occurrence may contribute to the increased incidence of fetal asphyxia in 2nd twins.

Metastatic renal cell cancer in a 20-year-old pregnant woman.

We report unusual magnetic resonance imaging findings of a 20-year-old pregnant woman at 18 weeks of gestation who was diagnosed with metastatic renal cell cancer (RCC) with a large liver metastasis.

The quality of intrapartum uterine activity monitoring.

AIMS: To determine the quality of intrapartum uterine activity (UA) monitoring in daily practice during the first and second stage of labor. The total duration of inadequate UA monitoring is quantified in relation to the technique applied: external or internal. METHODS: One hundred and ninety-two UA recordings, collected from 1 April 2006 untill 1 October 2006 from consecutive deliveries at the Vrije Universiteit Medical Center in Amsterdam, were analyzed. Included recordings were from singleton, spontaneous, vaginal deliveries. The last two hours of the first stage and the complete second stage had to be monitored. Internal and external UA recordings were judged by their quality: adequate, a recognizable and reliable UA pattern during the complete registration, or inadequate. Recordings labeled as inadequate were divided into two groups: absence of UA recording (non recognizable) or inadequate calibration (unreliable). Statistical analyses were performed with the Mann-Whitney U-test and the Wilcoxon signed ranks test. RESULTS: The percentages of adequate UA recordings in the first stage of labor were much higher for the internal than the external mode. Only 2% of the external recordings were of good quality vs. 40% of the internal recordings. In the second stage, percentages of adequate UA recordings were nearly equal, approximately 30%. Inadequate external registrations were characterized by almost 30% of the time absent UA monitoring, whereas with inadequate internal registrations the primary problem was correct calibration. CONCLUSION: Intrapartum UA monitoring in daily practice via the direct mode provides a more recognizable UA trace.

Uterine activity: implications for the condition of the fetus.

AIM: The aim of this review is to provide more insight in the fetal mechanisms as a response to uterine contractions and to emphasize the importance of correct assessment of uterine activity (UA) patterns during labor. STUDY RESULTS: UA causes a decreased flow through the uterine artery. In the healthy uncompromised fetus, this will not cause fetal acidemia. The fetus has developed certain protection mechanisms to survive labor; (1) During a contraction, fetal preload increases and enables the fetus to maintain a constant blood flow through the umbilical artery and (2) UA increases the blood flow in the fetal middle cerebral artery, i.e., a brain sparing effect. The shortcoming of those protection mechanisms in the compromised fetus and in case of excessive UA increases the risk of adverse fetal outcome. The brain sparing effect will become more pronounced to compensate for the decreased umbilical artery blood flow and fetal oxygen saturation. Maintenance of normal UA, especially a sufficiently long relaxation time, is essential so that the supply of well oxygenated maternal blood to the intervillous space will be restored and the fetal cerebral oxygen saturation can remain stable. CONCLUSION: Adequate UA monitoring is a prerequisite for proper reading and interpretation of cardiotocograms. It alarms in cases of excessive UA and can help to prevent fetal acidemia. Uterine contraction monitoring deserves full attention in daily obstetric practice.

Fetal brain sonography and fetal heart rate patterns in the preterm fetus.

OBJECTIVE: The objective of the study was to study whether peri- and intraventricular echodensities in the brain of fetuses at risk for preterm birth are associated with changes in fetal heart rate (FHR) parameters. STUDY DESIGN: Twenty preterm fetuses with peri- and intraventricular echodensities detected by transvaginal ultrasonography were matched with 20 fetuses without echodensities for gestational age, growth parameters, clinical disease, and maternal medication. Baseline FHR, long- and short-term variability, and the presence of accelerations and decelerations were analyzed with a computerized system and compared with the Wilcoxon matched-pairs signed-rank test. Both cases and controls were compared with a normal population. RESULTS: No statistical differences in FHR parameters were found between cases with and controls without peri- and intraventricular echodensities. Both cases and controls had lower long- and short-term variabilities than the normal population. CONCLUSION: No association between the presence of peri- and intraventricular echodensities and specific FHR changes was demonstrated.

Use of recombinant activated factor VII in massive postpartum haemorrhage.

OBJECTIVE: Postpartum haemorrhage (PPH) remains an important cause of maternal morbidity and mortality. With regard to morbidity, preservation of the uterus is of paramount importance in fertile women. The objective of the study was to describe the cumulative experience of a cohort of women that were treated with recombinant factor VIIa. STUDY DESIGN: In this retrospective, descriptive study we approached all departments of obstetrics and gynaecology in the Netherlands to find out if they had used rFVIIa for this indication. Twenty-seven cases were reported to us. To evaluate each case, we used a standardized case record form. RESULTS: The main cause of PPH was uterine atony (82%). In 21 cases rFVIIa was explicitly given to prevent a hysterectomy. This was successful in 16 cases (76%). Relevant reduction or complete cessation of bleeding after rFVIIa was noted in 24/27 cases (89%). There was a reduction in blood product requirements following rFVIIa administration. The dose of rFVIIa was variable and ranged from 16 to 128mug/kg. CONCLUSION: There appears to be a role for the use of rFVIIa in PPH unresponsive to conventional therapy. Recombinant FVIIa can be helpful and avoid an emergency hysterectomy.

Uterine activity monitoring during labor.

AIM: To summarize the currently available knowledge on (1) the methods to monitor uterine activity (UA); (2) the units to quantify UA; and (3) to assess the importance of abnormal contraction patterns on the condition of the fetus. The need for correct assessment and interpretation of the uterine contraction curve to improve fetal outcome will be emphasized. STUDY RESULTS: Correct assessment of the uterine contraction curve is an essential part of the cardiotocogram and should be obtained by the best method available; i.e., internal tocography (IT). IT provides objective information on quantization of UA and has the ability to obtain a good quality trace in an obese, restless patient. Accurate information on UA is essential because elevated UA during the first and second stage of labor can increase the risk of adverse fetal outcome. The relaxation time appears to be an important contraction parameter to maintain fetal well-being during labor. Almost all abnormal contraction patterns are characterized by shortening of the relaxation time and can lead to severe asphyxia. Duration, amplitude and frequency of contractions are of importance as well. The mean active pressure unit is the means to quantify UA since it incorporates these three contraction parameters. CONCLUSION: Proper application of UA monitoring by means of the internal method and adequate reading and interpretation of the uterine contraction curve is a prerequisite for high quality electronic fetal heart rate monitoring.

Nifedipine pharmacokinetics and plasma levels in the management of preterm labor.

The aim of this study was to determine if the dose regimen of nifedipine used for tocolysis was effective to achieve uterine quietness, and at which plasma concentration levels this tocolysis was achieved to optimize our dose regimen of nifedipine. In women with preterm labor, nifedipine was administered orally to achieve uterine quietness to prevent preterm birth. Patients (n = 5) were administered 10 mg nifedipine capsules (Adalat capsules, Bayer AG) orally every 15 minutes up to 40 mg in the first hour, and were subsequently given 1 tablet of 20 mg nifedipine slow release (Adalat retard, Bayer AG) t = 90 min. Plasma levels of nifedipine were measured at regular intervals during the first 4 hours after starting tocolysis. In all 5 patients tocolysis was achieved with nifedipine. Peak plasma concentration of nifedipine was 127.2 +/- 44 ng/mL at 1.2 +/- 0.1 hours. Mean plasma concentrations of nifedipine was 67.4 +/- 28.4 ng/mL. In all patients, tocolysis was achieved during the 4 hours of blood sampling. There were no adverse hemodynamic side effects seen before and after starting tocolysis with nifedipine. Initial dose regimen of 4 times 10 mg nifedipine capsule orally in the first hour, followed by 20 mg slow release nifedipine at t = 90 min is effective in achieving tocolysis in women with preterm labor. In steady state, the mean nifedipine plasma concentration to achieve tocolysis is about the half of that measured after initial tocolysis. Use of nifedipine for preterm labor was not associated with any adverse hemodynamic side effects.

A randomised clinical trial on cardiotocography plus fetal blood sampling versus cardiotocography plus ST-analysis of the fetal electrocardiogram (STAN) for intrapartum monitoring.

BACKGROUND: Cardiotocography (CTG) is worldwide the method for fetal surveillance during labour. However, CTG alone shows many false positive test results and without fetal blood sampling (FBS), it results in an increase in operative deliveries without improvement of fetal outcome. FBS requires additional expertise, is invasive and has often to be repeated during labour. Two clinical trials have shown that a combination of CTG and ST-analysis of the fetal electrocardiogram (ECG) reduces the rates of metabolic acidosis and instrumental delivery. However, in both trials FBS was still performed in the ST-analysis arm, and it is therefore still unknown if the observed results were indeed due to the ST-analysis or to the use of FBS in combination with ST-analysis. METHODS/DESIGN: We aim to evaluate the effectiveness of non-invasive monitoring (CTG + ST-analysis) as compared to normal care (CTG + FBS), in a multicentre randomised clinical trial setting. Secondary aims are: 1) to judge whether ST-analysis of fetal electrocardiogram can significantly decrease frequency of performance of FBS or even replace it; 2) perform a cost analysis to establish the economic impact of the two treatment options. Women in labour with a gestational age > or = 36 weeks and an indication for CTG-monitoring can be included in the trial. Eligible women will be randomised for fetal surveillance with CTG and, if necessary, FBS or CTG combined with ST-analysis of the fetal ECG. The primary outcome of the study is the incidence of serious metabolic acidosis (defined as pH < 7.05 and Bdecf > 12 mmol/L in the umbilical cord artery). Secondary outcome measures are: instrumental delivery, neonatal outcome (Apgar score, admission to a neonatal ward), incidence of performance of FBS in both arms and cost-effectiveness of both monitoring strategies across hospitals. The analysis will follow the intention to treat principle. The incidence of metabolic acidosis will be compared across both groups. Assuming a reduction of metabolic acidosis from 3.5% to 2.1 %, using a two-sided test with an alpha of 0.05 and a power of 0.80, in favour of CTG plus ST-analysis, about 5100 women have to be randomised. Furthermore, the cost-effectiveness of CTG and ST-analysis as compared to CTG and FBS will be studied. DISCUSSION: This study will provide data about the use of intrapartum ST-analysis with a strict protocol for performance of FBS to limit its incidence. We aim to clarify to what extent intrapartum ST-analysis can be used without the performance of FBS and in which cases FBS is still needed. TRIAL REGISTRATION NUMBER: ISRCTN95732366.

The quality of nifedipine studies used to assess tocolytic efficacy: a systematic review.

OBJECTIVE: To assess the quality of studies of nifedipine used to treat spontaneous preterm labor. DESIGN: A systematic review of study quality using a novel validity assessment tool, examining method-specific and topic-specific items in the domains of selection, performance and measurement biases. DATA SOURCES: Medline (1996-2003), EMBASE (1996-2003), BIOSIS (1993-2003), Current Contents (1995-2003), DERWENT DRUGFILE (1983-2003), Cochrane Database of Systematic Reviews. Bibliographies of existing meta-analyses and systematic reviews of nifedipine as a tocolytic. METHODS OF STUDY SELECTION: Forty-five studies evaluating the effectiveness of nifedipine were identified. DATA EXTRACTION: Each study was assessed for 40 method-specific and topic-specific items of quality in duplicate using piloted data extraction forms. Disagreements between assessors were settled by consensus/arbitration. DATA SYNTHESIS: Very few of the studies complied with adequacy criteria of quality for either method-specific or topic-specific items. There was no improvement in quality over time. The quality of method-specific items was significantly poorer when compared with topic-specific items of quality overall (P<0.0001) and in the domains of selection bias (P<0.0001) and performance bias (P<0.0001). CONCLUSION: Studies of the effectiveness of nifedipine as a tocolytic are of poorer quality with respect to method-specific items than topic-specific items. These deficiencies should be highlighted in meta-analyses or systematic reviews which measure efficacy and should influence the generation of guideline statements or recommendations for the use of nifedipine as a tocolytic. A large randomized trial fulfilling the quality items is necessary to assess the real efficacy of nifedipine in preterm labor.

Does intra-uterine environment influence fetal head-position preference? A comparison between breech and cephalic presentation.

BACKGROUND: Cephalic fetuses have increasing lateralised head-position near term. AIM: Is this development affected by breech presentation? SUBJECTS AND METHODS: Fetal head-position was studied longitudinally in 13 healthy fetuses in breech presentation and 10 healthy fetuses in cephalic presentation by means of real-time ultrasound. Recordings were obtained weekly from 33 weeks gestational age until birth. RESULTS: As in previous research, a significant (p = 0.045) decrease in midline head-position was found for the cephalic fetuses with advancing gestational age. The development of a lateralised head-position preference was clearly less outspoken in the breech fetuses when compared to the cephalic ones, especially after 36 weeks gestational age. Furthermore, as cephalic fetuses showed a preference for a right-sided head-position, breech fetuses that did show a lateralised head-position did not have a clear preference for left or right. Our data show an association between the orientation of the fetal vertebral column and head-position predominance in the group of cephalic fetuses, which complies with Previc's left-otolithic dominance theory. No association could be detected between fetal head shape and head-position preference. CONCLUSIONS: This study shows evidence that development in head laterality is influenced by the breech presentation. The discussion addresses possible explanations for the differences we found between the breech and cephalic fetuses.

Strategies for prevention--cervical cerclage.

Transvaginal cervical cerclage was introduced as a treatment for cervical incompetence in 1951. Over the years, our understanding of this clinical entity has changed tremendously, which has implications for obstetric management. This review focuses on the obstetric management of women considered to be at high risk of preterm delivery due to cervical incompetence at different stages of pregnancy.

Nifedipine trials: effectiveness and safety aspects.

Nifedipine (Adalat) is marketed as an anti-hypertensive agent. Nifedipine inhibits voltage-dependent L-type calcium channels, which leads to vascular (and other) smooth muscle relaxation and negative inotropic and chronotropic effects on the heart. Vasodilation, followed by a baroreceptor-mediated increase in sympathetic tone then results in indirect cardiostimulation. Nifedipine was introduced as a tocolytic agent at a time when beta-agonists and magnesium sulphate dominated the arena for the prevention of preterm birth. The oral administration route, the availability of immediate and slow-release preparations, the low incidence of (mild) side effects, and its limited costs explain the attraction to this medication from the obstetric field and its rapid and widespread distribution. Currently, over 40 studies have been published on nifedipine's tocolytic effectiveness, including seven meta-analyses. The quality of the studies suffers particularly from performance bias because the majority of them failed to ensure adequate blinding to treatment both for providers and patients. Concerns about other methodological flaws include measurements, outcome assessment and attrition bias. In particular, the safety aspects of nifedipine for tocolysis have been under-assessed. Conclusions from the meta-analyses, favouring the use of nifedipine as a tocolytic agent, are not supported by close examination of the data. The tocolytic effectiveness and "safety" of nifedipine has been studied primarily in normal pregnancies. Based on its pharmacological properties, one should be cautious to administer nifedipine when the maternal cardiovascular condition is compromised, such as with intrauterine infection, twin pregnancy, maternal hypertension, cardiac disease, etc. Life-threatening pulmonary oedema and/or cardiac failure are definite risks and have been reported. Under such circumstances, the baroreceptor-mediated increase in sympathetic tone may not balance the cardiac-depressant activity of nifedipine.