Knowledge and attitudes of pregnant women on maternal immunization against COVID-19 in Croatia.

OBJECTIVES: The aim of this study was to assess pregnant women's knowledge and attitudes regarding maternal COVID-19 immunization during pregnancy. METHODS: A cross-sectional study was performed in two teaching hospitals between May and October 2021 in Zagreb, Croatia. During antenatal clinic visit pregnant women were approached and asked to fill out a predesigned questionnaire about their knowledge and attitudes towards COVID-19 vaccination. Collected data was later analyzed. RESULTS: A total of 430 women participated in the study. Only 16% of women expressed their willingness to be vaccinated against COVID-19 if offered, despite that 71% of them believe that COVID-19 might be a serious illness in pregnant women. The most important obstacle in having better acceptance of the vaccines is in the assumption that the vaccines are not safe for pregnant women (73%) or the fetus (75%), or that the vaccines are not effective (41%). The relationship exists between acceptance of vaccination in general and willingness to get other vaccines in pregnancy and readiness to be vaccinated against COVID-19 in pregnancy. Only one out of 55 women who were not adherent to the current vaccination recommendations in Croatia would accept the COVID-19 vaccine during pregnancy if offered. 21 (5%) women stated that vaccination against influenza and pertussis during pregnancy is necessary and 13 (62%) of them would get vaccinated against COVID-19 if offered. CONCLUSIONS: This study showed that the crucial reasons for refusing vaccination against COVID-19 among pregnant women in Croatia are the concerns about the vaccines' effectiveness and safety. All healthcare providers should put more effort into education of pregnant women on risks of COVID-19, as well as on the benefits and safety of the vaccines.

Comparison of transvaginal sonographic cervical length measurement and Bishop score for predicting labour induction outcomes.

OBJECTIVES: Induction of labour (IOL) is of increasing prevalence worldwide and reliable prediction of its successful outcome is important. Traditional clinical methods for predicting successful IOL outcomes have been supplemented with newer technologies. The aim of this study was to compare transvaginal sonographic (TVS) cervical length measurement with Bishop score in predicting labour induction outcomes. METHODS: This study included pregnant women with term pregnancy, indication for IOL and unfavourable cervix (Bishop score >6) who had TVS performed prior to IOL. Exclusion critetia were regular contractions, ruptured membranes, non-cephalic presentation, uterine scar and pregnancy complications potentially influencing study outcomes. Outcomes measured were successful IOL defined as achievement of active phase of labour and vaginal delivery. Receiver operating characteristic (ROC) curves were used to determine diagnostic accuracy and sensitivity, specificity, positive and negative predictive values. Statistical significance was defined as p<0.05. RESULTS: Among 112 studied participants, IOL was successful in 101 (90.2%) pregnant women. AUC for Bishop score >2 was 0.831 (95% CI, 0.744-0.917, p<0.001) and for cervical length <30 mm 0.679 (95% CI 0.514-0.844, p<0.052). A total of 81 (72.3%) pregnant women delivered vaginally; AUC for Bishop score >2 was 0.754 (95% CI 0.648-0.861, p<0.001) and for cervical length <30 mm 0.602 (95% CI 0.484-0.720, p=0.092) which was the only insignificant predictor. CONCLUSIONS: Bishop score >2 is a better predictor for both successful IOL and vaginal delivery among induced women with term pregnancy and unfavourable cervix compared to cervical length <30 mm.

Comparison of intracervical and intravaginal prostaglandin E2 for induction of labor in term pregnancies with unfavorable cervix: Randomized controlled trial.

OBJECTIVE: The aim of this study was to compare intracervical (IC) and intravaginal (IV) application of prostaglandin E2 (PGE2) for labor induction in term pregnancies with unfavorable cervix. STUDY DESIGN: This prospective randomized trial included 212 pregnant women with term pregnancy and unfavorable cervix randomly assigned for labor induction with either IC (0.5 mg) or IV (2 mg) PGE2 formulation. Main outcome measured was time interval from labor induction to delivery. Difference in mode of delivery and adverse perinatal outcomes between two studied groups was also investigated. Significance was set at p < 0.05. RESULTS: Studied groups did not significantly differ regarding main characteristics such as age, parity, body mass index or Bishop score. Women in IV group compared to those in IC group had shorter induction to delivery time interval (p < 0.001) and induction to active phase time interval (p = 0.001), higher prevalence of vaginal delivery within 24 h of labor induction (63,3% vs 40,6%, p = 0.002) and higher prevalence of successful induction of labor (95,9% vs. 86,5%, p = 0.020). The analysis did not reveal significant difference in mode of delivery between groups (p = 0.453) or other adverse perinatal outcomes. CONCLUSION: IV application of PGE2 compared to IC application is more efficacious and comparably safe for labor induction in term pregnancies with unfavorable cervix and should be the method of choice for labor induction.

Expert advice about therapeutic exercise in the management of sacroiliac dysfunction in pregnancy: Secondary analysis of a randomized trial.

OBJECTIVE: To assess primiparous and multiparous women, and singleton and multiple pregnancies in a recently published randomized trial. STUDY DESIGN: Secondary analysis of a randomized clinical trial was performed. In total, 500 women with sacroiliac dysfunction diagnosed in pregnancy were randomized into a study group (who received expert advice about therapeutic exercise) and a control group (who continued with their normal lifestyle habits). The outcome measures assessed were: pain intensity [visual analogue scale (VAS)] and degree of functional disability (Quebec scale) at enrolment and after 3 and 6 weeks. Primiparous and multiparous women, and singleton and multiple pregnancies in the study and control groups were analysed separately. RESULTS: Sacroiliac dysfunction was more common in primiparous women compared with multiparous women (84.70% vs 77.16%), and in multiple pregnancies compared with singleton pregnancies (86.53% vs 80.07%). For all four subgroups analysed in this secondary analysis, the reduction in pain intensity (p = 0.001) and the degree of functional disability (p = 0.001) were better in the study group compared with the control group. Better results for the two outcome measures were found when comparing primiparous and multiparous women in the study group at follow-up, but the difference in functional disability disappeared 6 weeks after enrolment (p = 0.383). There was no difference in the two outcome measures between singleton and multiple pregnancies 3 and 6 weeks after enrolment (p = 0.061, p = 0.489 and p = 0.741, p = 0.353, respectively). CONCLUSION: Expert advice about therapeutic exercise is effective for the reduction of symptoms of sacroiliac dysfunction in all four subgroups (primiparous and multiparous women, singleton and multiple pregnancies). Earlier reduction of pain intensity and degree of functional disability were obtained in primiparous women compared with multiparous women in the study group.

Prevalence and impact of pre-pregnancy body mass index on pregnancy outcome: a cross-sectional study in Croatia.

The aim of this study was to determine the association of maternal pre-pregnancy body mass index (BMI) and pregnancy outcome among pregnant women in Croatia. Women who gave birth in Croatia in 2017 were categorised into four groups according to pre-pregnancy BMI and analysed regarding maternal characteristics and perinatal outcomes. Among 32,051 pregnant women, 5.3% were underweight, 65.5% had normal BMI, 20.4% were overweight and 8.8% were obese. Overweight and obese women had a higher prevalence of induction of labour and delivery by caesarean section compared to normal-BMI women (p < .001), while underweight and obese women had a higher prevalence of preterm birth (p < .001). Gestational diabetes (GD), gestational hypertension and preeclampsia were higher in overweight and obese group. Multivariate logistic regression model showed that older maternal age, higher BMI, GD, gestational hypertension and preeclampsia were significant predictors of having non-spontaneous onset of labour and of not delivering vaginally.Impact statementWhat is already known on this subject? Women with abnormal body mass index (BMI) compared to women with normal BMI have an increased risk of various complications during pregnancy and labour such as preterm birth and low birth weight for underweight women, and foetal macrosomia, labour induction and delivery by caesarean section for obese women.What do the results of this study add? This study was performed on a large national cohort of pregnant women and its results show that the majority of adverse perinatal outcomes present in obese women are also present among overweight women. Additional attention should be paid to women with a modest increase in BMI who present the majority of women with abnormal BMI.What are the implications of these findings for clinical practice and/or further research? Risks identified in this study must be acknowledged and taken into account when counselling and managing women before and during pregnancy and labour. Women must be encouraged throughout pregnancy to either gain weight or limit weight gain if they are in adverse BMI group.

What is known and what remains unresolved regarding gestational diabetes mellitus (GDM).

Gestational diabetes mellitus (GDM) has become a major public health issue and one of the most discussed topics in contemporary obstetrics. Due to rising prevalence of GDM worldwide impact and importance of this medical condition in good quality antenatal care is growing. GDM is associated with serious adverse perinatal outcomes and unfavorable long-term health consequences for both, mother and her child. Despite a great amount of knowledge accumulated regarding GDM, medical community remains indecisive and still debates the most appropriate diagnostic strategy, screening policy, and treatment options for pregnancies complicated with GDM. These unresolved issues generate controversies, motivate further research and contribute to the growing interest surrounding GDM. In this review we will discuss and try to explain some of them.

Expert advice about therapeutic exercise during pregnancy reduces the symptoms of sacroiliac dysfunction.

Objectives There are growing evidence that exercise improves sacroiliac dysfunction symptoms in pregnant women; but no data about the effect of expert advice regarding this matter. The aim of this study was to assess the effectiveness of expert advice about therapeutic exercise on sacroiliac dysfunction in pregnancy. Methods A total of 500 women with sacroiliac dysfunction diagnosed in pregnancy were randomized in study and control group. Study group has conducted expert advice on therapeutic exercise; while control group continued with their normal lifestyle. Pain intensity by Visual Analog Scale (VAS) and degree of functional disability by Quebec scale were assessed at enrolment and after 3 and 6 weeks. Results Significantly better reduction in pain intensity assessed by VAS (p=0.001) and degree of functional disability assessed by Quebec scale (p=0.001) was noted in study compared to control group. Better results for both outcome measures were obtained if intervention was implemented earlier i.e., in second (p=0.001; p=0.001) compared to third (p=0.005; p=0.001) trimester. Strong positive correlation was found between pain intensity and degree of functional disability in both groups. Conclusions Expert advice on therapeutic exercise is effective in reduction of sacroiliac dysfunction symptoms during pregnancy. Trial registration ACTRN12617000556347.

Incidence, pain, and mobility assessment of pregnant women with sacroiliac dysfunction.

OBJECTIVES: To determine the incidence of sacroiliac dysfunction in pregnancy and assess its progress during the course of the pregnancy. METHODS: The present prospective cohort study, performed between April 1, 2013, and May 31, 2016, enrolled primigravidae aged 25-35 years before 13 weeks of pregnancies who were experiencing back pain and did not have prior symptoms of sacroiliac dysfunction. Participants attended regular follow-up over 6 months and clinical functional tests were used to diagnose sacroiliac dysfunction. Women with sacroiliac dysfunction were assessed at 3-week intervals with a numeric pain rating scale (NPRS) and the pregnancy mobility index (PMI). RESULTS: Among 1500 women who fulfilled the inclusion criteria, 1181 (78.7%) were diagnosed with sacroiliac dysfunction and 1143 completed all follow-up. Pain assessed by the NPRS gradually worsened from the first toward the third trimester (P<0.001). The level of disability assessed by the PMI also increased from the beginning to the end of pregnancy (P<0.001). CONCLUSION: Sacroiliac dysfunction represents an important problem during pregnancy; pain severity and mobility problems increased during the course of pregnancy in the present study. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12613000246785.

Prevalence of diabetes five years after having gestational diabetes during pregnancy - Croatian national study.

AIMS: The aim of this study was to determine the prevalence of diabetes among women 5 years after having gestational diabetes during pregnancy. Also, we sought to determine whether women who develop diabetes after GD during pregnancy differ from women who do not develop diabetes after GD during pregnancy. METHODS: This longitudinal study was performed using data from medical birth certificates and CroDiab diabetes registry. Women burdened with gestational diabetes in Croatia in 2011 were followed up until year 2016. Those registered in CroDiab registry were recognised as new patients with diabetes. RESULTS: Among 40,641 deliveries in 2011, gestational diabetes was reported in 1181 (2.9%) women. Among them 853 (72.23%) were followed up in CroDiab diabetes registry and 32 (3.75%) were identified as new patients with diabetes. Median time from childbirth to onset of diabetes was 29.12 months. The diabetes group did not significantly differ to the group without diabetes according to age (p=0.587), level of education (p=0.549) or marital status (p=0.849) except that the diabetes group was significantly more obese than the group without diabetes (p=0.002). CONCLUSIONS: Based on CroDiab diabetes registry data prevalence of diabetes 5 years after pregnancy complicated with gestational diabetes is 3.75% in Croatia. Women with gestational diabetes during pregnancy, and especially those with higher BMIs, are an important risk group for developing diabetes later in life so screening and preventive measures should be oriented toward them in primary care settings.

Pentalogy of Cantrell with Unilateral Kidney Evisceration: A Case Report and Review of Literature.

Pentalogy of Cantrell (PC) is a congenital malformation syndrome characterized by midline thoracoabdominal wall defect resulting from defective development in the septum transversum. Major hallmarks of this rare anomaly are omphalocele and ectopic heart. In most cases, the diagnosis is made by two-dimensional ultrasound in second trimester. The prognosis of PC relies on the presence and severity of cardiac anomalies but in most cases outcome is fatal. To the best of our knowledge, the presence of kidneys into the omphalocele in Cantrells' pentalogy has not been reported yet. In this article, we report a case of PC associated with unilateral kidney evisceration.

Impact of the Implementation of New WHO Diagnostic Criteria for Gestational Diabetes Mellitus on Prevalence and Perinatal Outcomes: A Population-Based Study.

Objectives. To determine the impact of the implementation of new WHO diagnostic criteria for gestational diabetes mellitus (GDM) on prevalence, predictors, and perinatal outcomes in Croatian population. Methods. A cross-sectional study was performed using data from medical birth certificates collected in 2010 and 2014. Data collected include age, height, and weight before and at the end of pregnancy, while perinatal outcome was assessed by onset of labor, mode of delivery, and Apgar score. Results. A total of 81.748 deliveries and 83.198 newborns were analysed. Prevalence of GDM increased from 2.2% in 2010 to 4.7% in 2014. GDM was a significant predictor of low Apgar score (OR 1.656), labor induction (OR 2.068), and caesarean section (OR 1.567) in 2010, while in 2014 GD was predictive for labor induction (OR 1.715) and caesarean section (OR 1.458) only. Age was predictive for labor induction only in 2014 and for caesarean section in both years, while BMI before pregnancy was predictive for all observed perinatal outcomes in both years. Conclusions. Despite implementation of new guidelines, GDM remains burdened with increased risk of labor induction and caesarean section, but no longer with low Apgar score, while BMI remains an important predictor for all three perinatal outcomes.

Vaginal delivery through annular placenta -- case report.

Annular placenta is an extremely rare morphological type of human placenta. It is commonly related to placental vessel abnormalities frequently causing antenatal and postnatal hemorrhage and operative delivery. Gravida 4 para 1 had an uneventful course of pregnancy and normal vaginal delivery followed by moderate postpartum hemorrhage. Hemorrhage was found to be local in origin but the placenta was annular in shape and the newborn was delivered through one of the openings. Annular placenta was not recognized before delivery. Its implantation site was in the lower uterine segment but high enough to allow the passage of the fetus through its annular defect and vaginal birth. To our knowledge, this is a first report of annular placenta ending in normal vaginal delivery.

Raised electrical uterine activity and shortened cervical length could predict preterm delivery in a low-risk population.

PURPOSE: To compare diagnostic accuracy of sonographic cervical length (CL) measurement and uterine electric activity assessed by electromyography (EMG) in second trimester regarding prediction of preterm delivery (PTD). METHODS: Prospective study of 308 low-risk women. Shortened CL was defined as ≤25 mm (≤5th centile), while raised EMG activity was defined as the presence of ≥20 action potentials in 20 min of assessment (≥95th centile). Outcome measures were diagnostic accuracy of both tests alone or in combination for prediction of PTD and early PTD (≤34 weeks). RESULTS: The incidence of PTD was 23/308 (7.4%) while the incidence of early PTD was 9/308 (2.9%). Shortened CL and raised EMG activity were significantly related to PTD [prevalence-weighted likelihood ratio (pw-LR) 1.9, 95% CI 1.0-3.5 vs. 9.5, 95% CI 2.5-35.7], but not to early PTD (pw-LR 0.4, 95% CI 0.2-0.8 vs. 0.6, 95% CI 0.3-1.7). Significant predictive value for early PTD was found only if both tests were combined (pw-LR 4, 95% CI 1.3-14.3). CONCLUSION: Shortened CL and raised EMG activity in second trimester have significant diagnostic accuracy regarding prediction of PTD in a low-risk population. However, in order to be useful as a predictor for early PTD both tests must be positive.

[The importance of antenatal immunoprophylaxis for prevention of hemolytic disease of the fetus and newborn]. / Vaznost antenatalne imunoprofilakse u prevenciji hemoliticke bolesti fetusa i novorodenieta.

Hemolytic disease of the fetus and newborn (HDFN) is a consequence of maternal alloimmunization against fetal red blood cell antigens. Alloimmunization against D antigen from Rhesus (Rh) blood group system is particularly important because of its strong immunogenicity. During the last few decades, the introduction of RhD prophylaxis by postpartum administration of anti-D immunoglobulin to RhD negative women, now improved with antenatal prophylaxis, has led to a dramatic decrease in perinatal mortality and morbidity from HDFN. However, severe cases have not disappeared, mostly due to prophylaxis failure. In our case, inappropriate prenatal care during the first pregnancy in an RhD negative mother resulted in primary immunization. In the next pregnancy with an RhD positive child, the mother's secondary immune response was extremely strong and led to early development of severe fetal anemia. The fetus survived thanks to the treatment with intrauterine transfusions (IUT), but they caused suppression of erythropoiesis, which lasted for months after birth. The long lasting, late anemia was treated with repeated postnatal red cell transfusions and recombinant human erythropoietin (rHuEPO). Despite the severity of HDFN in our case, the short-term outcome is good. The boy has normal growth until now, but due to the possibility of an adverse long-term neurodevelopmental outcome, this case requires continuous follow up. It also reminds of the fact that RhD alloimmunization remains an actual problem in daily routine. Antenatal prophylaxis is a crucial step in quality care of those who are at a risk of HDFN.

Vaginal pH versus cervical length in the mid-trimester as screening predictors of preterm labor in a low-risk population.

OBJECTIVE: To assess the accuracy of a sign of bacterial vaginosis and a sign of cervical insufficiency in predicting preterm labor (PTL, occurring in the 37th week or earlier) and early PTL (occurring in the 34th week or earlier) in a low-risk cohort of 316 pregnant women. METHOD: Vaginal pH was assessed using test gloves and cervical length (CL) was measured by transvaginal ultrasound. A pH value less than 5.0 (the 95th-percentile threshold) and a CL greater than 26 mm (the 5th-percentile threshold) were considered normal. RESULTS: There were 14 participants (4.4%) with an elevated vaginal pH and 15 (4.7%) with a shortened CL. The incidence of PTL (<37 weeks) was 7.2%, while incidence of early PTL (≤34 weeks) was 2.5%. A shortened CL was significantly correlated with PTL (likelihood ratio [LR] weighted by prevalence; 2.7; 95% CI, 1.1-6.7) but not with early PTL (LR, 0.8; 95% CI, 0.4-1.8). An elevated vaginal pH was a better predictor of PTL (LR, 3.7; 95% CI, 1.3-10.4) and early PTL (LR, 1.7; 95% CI, 1.1-3.1). CONCLUSION: An elevated vaginal pH was a better predictor of early PTL than a shortened CL in this cohort of pregnant women at low risk.

Diagnostic accuracy of sonographic and clinical parameters in the prediction of retained products of conception.

OBJECTIVE: The purpose of this study was to assess the diagnostic accuracy of different parameters (clinical and sonographic) in the prediction and management of retained products of conception (RPOC) in the late postpartum period. METHODS: This was a prospective cohort 3-year audit. Predefined data were collected and compared with histopathologic (HP) reports after uterine evacuation. The primary outcome measure was the diagnostic accuracy of different clinical and sonographic parameters, including color Doppler imaging in diagnosis of RPOC confirmed on HP reports. Secondary outcome measures were complication rates influencing maternal morbidity. RESULTS: In total, 93 patients (0.92% of all deliveries) were selected. The presence of gestational tissue was confirmed on HP reports in 58% of cases. The likelihood ratio of sonography alone was 1.47 (95% confidence interval, 1.25-1.84), whereas that of sonography combined with color Doppler imaging was 2.16 (1.3-3.59), providing statistically significant accuracy regarding the prediction of RPOC. CONCLUSIONS: Sonography alone or combined with color Doppler imaging has better diagnostic accuracy than the usual clinical parameters used for the prediction of RPOC.

Uterine electrical activity and cervical shortening in the midtrimester of pregnancy.

OBJECTIVE: To determine whether a correlation exists between increased uterine electrical activity and cervical length (CL) in the midtrimester of pregnancy. METHOD: In this case-control study, 312 asymptomatic nulliparous women underwent both uterine electromyographic assessment and ultrasound CL measurement between the 16th and 23rd weeks of a singleton pregnancy. The outcome measure was the difference in ultrasound CL measurement between the women found to have uterine action potentials on electromyography and those who did not. RESULTS: Action potentials were detected in 66 (21.1%) of the 312 women; and compared with the remainder of the study population, cervical length was significantly shorter in these women (35.7+/-8.9 mm vs 38.8+/-7.9 mm; P<0.01 by the Mann-Whitney test). CONCLUSION: Ultrasound CL measurement in the midtrimester was significantly shorter in women with increased uterine electrical activity.

[Dillema about the method of delivery for the fetus in breech presentation]. / Dvojbe o nacinu porodaja ploda u stavu zatkom.

The management of preterm and term delivery of fetus in breech presentation is one of the most disputable issues in modern obstetric practice. Several years ago, one of the biggest randomized controlled studies in obstetrics, Term Breech Trial (TBT), tried to set up guidelines and resolve the question of the best method to deliver the fetus at term in breech presentation. The results of this study have shown that the policy of planned cesarean section reduces the risk of short-term adverse perinatal outcome, compared with the policy of planned vaginal birth. Many perinatal centers have accepted the recommendations from this study and different obstetric associations have implemented these results in their guidelines. On the other hand, TBT had some limitations, especially those connected with the impossibility of regular and objective comparison of these two methods of delivery. In addition, the same group of authors did not find differences in long-term outcomes between the planned cesarean section and vaginal delivery. Although the rate of planned cesarean section has increased following the publication of TBT, selective vaginal breech delivery is still very successfully used in the centers where doctors have the possibility to obtain experience in vaginal breech deliveries. The most common method of reduce the noncephalic presentation is external cephalic version at term. It reduces the incidence of noncephalic presentations at labor, thus reducing the number of cesarean sections as well. At this moment, there is not enough evidence to support cesarean section as the method of choice for delivery of preterm and term breech, having in mind obstetric indications and criteria. The decision whether to deliver vaginally or by cesarean section should be individual for each pregnant woman.

Is sonographic assessment of cervical length better than digital examination in screening for preterm delivery in a low-risk population?

BACKGROUND: This randomized controlled trial compared the diagnostic accuracy of the sonographic assessment of cervical length and clinical digital examination of the cervix in the second trimester regarding the prediction of preterm delivery in a low-risk population. METHODS: In total, 282 unselected, asymptomatic women with singleton pregnancy randomly underwent sonographic cervical length measurement (study group, n=138) or clinical digital examination (control group, n=144) in the second trimester. In the study group cervical length or=95th percentile (>or=4) for our population was defined as high. The primary outcome measure was the diagnostic accuracy of both tests regarding the prediction of preterm delivery (<37 weeks). RESULTS: Shortened cervical length was found in 6/138 (4.3%) women whereas the high Bishop score was found in 17/144 (11.8%) (p=0.038, Fisher's exact test). The incidence of preterm delivery was 5.7% (16/282). Regarding the prediction of preterm delivery, shortened cervical length and high Bishop score had sensitivity 57.1% versus 33.3% and positive predictive value 66.7% versus 17.6%. Shortened cervical length in comparison with high Bishop score had 12-fold higher positive likelihood ratio for preterm delivery in a low-risk population (37.4; 95%CI [8.2-170.7] versus 3.2; 95%CI [1.1-9.2]). CONCLUSION: Sonographic assessment of cervical length has better diagnostic accuracy in the prediction of preterm delivery compared to digital examination in a low-risk population.

Placental ischaemia is a consequence rather than a cause of pre-eclampsia.

The aetiology or pre-eclampsia remains unknown, but it is widely accepted that the disorder is placental in origin. Failed trophoblast invasion of the maternal spiral arteries is accepted to be a central pathogenetic mechanism. However, the concept of failed trophoblast invasion is based on an assumption rather than direct scientific observation and there are other likely explanations for this phenomenon. The criteria for disease causation, such as the Bradford-Hill criteria are central to the ascertainment of causal relationships in modern medicine and these criteria are used here to assess the relationship between the placenta and pre-eclampsia. There is a strong association between pre-eclampsia and small (rather than large) placentas and an appropriate dose-response relationship does not exist. Failed trophoblast invasion of the spiral arteries is not specific to pre-eclampsia and occurs in other pregnancy complications and in up to 40% of biopsies from normal pregnancies and the relationship between placental ischaemia and pre-eclampsia is very inconsistent. A placental cause for pre-eclampsia is not consistent with the pathogenesis of other pregnancy complications like gestational diabetes mellitus. If pre-eclampsia was a disease of trophoblast origin, the risk of the disease should be determined by trophoblast rather than maternal factors. However, evidence from assisted reproduction shows that the risk of a woman developing pre-eclampsia is almost entirely dependent on maternal factors and independent of the embryo from which the placenta develops. There is currently no plausible proven mechanism by which the placenta causes pre-eclampsia. The syndrome typically gets worse, and can arise de-novo after the placenta has been removed, calling into question the role of the placenta in its causation. Uterine artery ligation in humans, unlike in animal experiments, is not associated with an increased incidence of pre-eclampsia, calling into question the role of poor utero-placental perfusion in the cause of the disease in humans. The signals that initiate maternal adaptive responses during pregnancy come from or through the placenta into the maternal milieu but as is the case with gestational diabetes mellitus, are not necessarily the cause of maternal disease. Pre-eclampsia causes renal, hepatic, myocardial, cerebral and adrenal ischaemia--that is ischaemia in all highly vascular organs. Placental ischaemia, like ischaemia in all other organs, is a consequence rather than a causal factor in the development of the syndrome and this has profound consequences for research strategies.