Luc Smits

Short interpregnancy intervals and unfavourable pregnancy outcome: role of folate depletion

There is no generally accepted explanation for the excess risk of adverse pregnancy outcome after short interpregnancy intervals. In this paper, we present a hypothesis that is both biologically plausible, empirically testable, and able to explain many observations. Maternal serum and erythrocyte concentrations of folate decrease from the fifth month of pregnancy onwards and remain low for a fairly long time after delivery. Women who become pregnant before folate restoration is complete have a raised risk of folate insufficiency at the time of conception and during pregnancy. As a consequence, their offspring have higher risks of neural tube defects, intrauterine growth retardation, and preterm birth. We make several predictions based on our hypothesis and suggest ways of testing them empirically. The proposed mechanism implies, among other things, that postpartum supplementation with folic acid might prevent excess risk of unfavourable pregnancy outcome in women with short interpregnancy intervals.

Influence of SERTPR and STin2 in the serotonin transporter gene on the effect of selective serotonin reuptake inhibitors in depression: a systematic review.

Large differences in clinical response to selective serotonin reuptake inhibitors (SSRIs) are observed in depressive patients with different genotypes. Quantification of these differences is needed to decide if genetic testing prior to antidepressant treatment is useful. We conducted a systematic review of the literature on the influence of polymorphisms in the serotonin transporter gene (SERTPR (or 5-HTTLPR) and STin2) on SSRI response. Studies were identified by the use of MEDLINE, EmBase and PsycINFO, references of articles, reviews and information from pharmaceutical companies. Nine studies assessing the influence of SERTPR or STin2 on treatment response were included. Outcome was expressed as the percentage of decrease in depression score (HAM-D or MADRS) or as the percentage of responders (≥50% reduction on the depression scale). Both study methodologies and study outcomes showed large heterogeneity. Weighted mean decreases in depression score for patients with the s/s, s/l and l/l genotypes were 35.4, 46.3 and 48.0% at week 4, respectively, and 53.9, 54.6 and 48.3% at week 6. Among Caucasian patients, both mean decrease in depression score and response rate were lowest in the s/s group, while among Asian patients, results were inconsistent. Weighted response rates were 36.1% for the 10/12 genotype of the STin2 polymorphism and 80.7% for the 12/12 genotype (χ2=27.8, P<0.001) (only Asians). The available evidence points to a less favourable response to SSRI treatment among Caucasian patients with the SERTPR s/s genotype and among (Asian) patients with the STin2 10/12 genotype. In view of the scarcity and heterogeneity of the studies, however, current information is insufficiently reliable as a basis for implementing genetic testing in the diagnostic work-up of the depressive patient.

Further evidence that culture media affect perinatal outcome: findings after transfer of fresh and cryopreserved embryos

BACKGROUND We have previously shown that the medium used for culturing IVF embryos affects the birthweight of the resulting newborns. This observation with potentially far-reaching clinical consequences during later life, was made in singletons conceived during the first IVF treatment cycle after the transfer of fresh embryos. In the present study, we hypothesize that in vitro culture of embryos during the first few days of preimplantation development affects perinatal outcome, not only in singletons conceived in all rank order cycles but also in twins and in children born after transfer of frozen embryos. Furthermore, we investigated the effect of culture medium on gestational age (GA) at birth. METHODS Oocytes and embryos from consecutive treatment cycles were alternately assigned to culture in either medium from Vitrolife or from Cook. Data on a cohort of 294 live born singletons conceived after fresh transfer during any of a patients IVF treatment cycles, as well as data of 67 singletons conceived after frozen embryo transfer (FET) and of 88 children of 44 twin pregnancies after fresh transfer were analysed by means of multiple linear regression. RESULTS In vitro culture in medium from Cook resulted in singletons after fresh transfer with a lower mean birthweight (adjusted mean difference, 112 g, P= 0.03), and in more singletons with low birthweight (LBW) <2500 g (P= 0.006) and LBW for GA ≥ 37 weeks (P= 0.015), when compared with singletons born after culture in medium from Vitrolife AB. GA at birth was not related to the medium used (adjusted difference, 0.05 weeks, P = 0.83). Among twins in the Cook group, higher inter-twin mean birthweight disparity and birthweight discordance were found. Z-scores after FET were -0.04 (± 0.14) in the Cook group compared with 0.18 (± 0.21) in the Vitrolife group (P> 0.05). CONCLUSIONS Our findings support our hypothesis that culture medium influences perinatal outcome of IVF singletons and twins. A similar trend is seen in case of singletons born after FET. GA was not affected by culture medium. These results indicate that in vitro culture might be an important factor explaining the poorer perinatal outcome after assisted reproduction technology (ART). Further research is needed to confirm this culture medium-induced effect in humans and to provide more insight into whether it is caused by epigenetic disturbance of imprinted genes in fetal or placental tissues. Moreover, embryo culture media and their effects need to be investigated thoroughly to select the best embryo culture medium in order to minimize or prevent short-term risks and maybe even long-term disease susceptibility.

Association between short birth intervals and schizophrenia in the offspring

Pregnancy burdens maternal folate reserves. Postpartum restoration to normal folate values may take up to 1 year. Maternal folate deficiency during early pregnancy has been hypothesized as a cause of schizophrenia in the offspring. We investigated whether the risk of schizophrenia is increased in persons conceived shortly after another birth. A population-based cohort was established of 1.43 million persons born in Denmark between 1950 and 1983, yielding 17.6 million person-years of follow-up. Schizophrenia in cohort members (5095 cases) and their siblings and parents was identified by linkage with the Danish Psychiatric Case Register. Relative risks of schizophrenia were estimated by use of log-linear Poisson regression. As compared to intervals of 45 months and longer, the schizophrenia risk ratio was 1.14 (95% confidence interval [CI], 0.97 to 1.35) for interbirth intervals of up to 15 months, 1.32 (95% CI, 1.12 to 1.56) for intervals of 15 to 17 months, 1.38 (95% CI, 1.18 to 1.61), for intervals of 18 to 20 months and 1.13 (95% CI, 1.00 to 1.29) for intervals of 21 to 26 months. Relative risks did not essentially change after adjustment for age, sex, calendar year of diagnosis, maternal and paternal age, history of mental illness in a parent or sibling, sibship size, place of birth, and distance to younger sibling. These results show an association between short birth intervals and schizophrenia in the offspring. Although maternal folate depletion may play a role in this association, we cannot rule out other explanations such as maternal stress during pregnancy and childhood infections.

IVF culture medium affects post-natal weight in humans during the first 2 years of life

STUDY QUESTION Is post-natal growth during the first 2 years of life in IVF singletons affected by type of medium used for culturing human embryos during an IVF treatment? SUMMARY ANSWER The in vitro culture of human embryos in medium from Cook resulted in singletons with a lower weight during the first 2 years of life compared with singletons born after embryo culture in medium from Vitrolife. WHAT IS KNOWN ALREADY In a previous study, we reported that type of medium used for culturing human IVF embryos during the first few days after fertilization until fresh embryo transfer significantly affects fetal growth and consequently birthweight of the resulting singletons. STUDY DESIGN, SIZE, DURATION From July 2003 to December 2006, a total of 1432 IVF treatment cycles with fresh embryo transfer were randomly allocated to have all embryos cultured in medium from Vitrolife AB (n = 715) or from Cook (n = 717). Two years after delivery, questionnaires were sent to the parents of all children requesting data about weight, height and head circumference around 1, 2, 3, 4, 6, 7.5, 9, 11, 14, 18 and 24 months of age. These measurements were collected as part of the childrens health programme at municipal infant welfare centres in the Netherlands by health professionals unaware of this study. PARTICIPANTS/MATERIALS, SETTING, METHODS Patients requiring donor oocytes or applying for PGD were excluded from the study. From the 294 live born singletons that fulfilled our inclusion criteria, 29 were lost to follow-up. The remaining 265 singletons (Cook group: 117, Vitrolife group: 148) were included in the analysis. Data analysis included linear regression, to compare cross-sectionally weight standard deviation score (SDS), height SDS and head circumference, and the first order Berkey-Reed model for a longitudinal analysis of the growth data. MAIN RESULTS AND THE ROLE OF CHANCE Singletons in the Vitrolife group were heavier during the first 2 years of life compared with singletons in the Cook group. Cross-sectional analyses showed that adjusted weight SDS differed between groups at 1 (0.35 ± 0.14, P = 0.010), 2 (0.39 ± 0.14, P = 0.006), 3 (0.35 ± 0.14, P = 0.011), 4 (0.30 ± 0.13, P = 0.020), 11 (0.28 ± 0.13, P = 0.036), 14 (0.32 ± 0.13, P = 0.014) and 24 (0.39 ± 0.15, P = 0.011) months of age, while adjusted height SDS was only significantly different at 1 (0.21 ± 0.11, P = 0.048) month of age. Head circumference was similar between the two groups at all ages. Longitudinal analyses showed that both post-natal weight (P = 0.005) and height (P = 0.031) differed between the groups throughout the first 2 years of life, while the growth velocity was not significantly different between the two groups. LIMITATIONS, REASONS FOR CAUTION Factors that might influence post-natal growth were included in the analysis; however, it was not possible to include all such factors, for example childhood diseases or nutrition, as this information was not available. WIDER IMPLICATIONS OF THE FINDINGS The effect of culture medium during the first few days after fertilization on prenatal growth and birthweight persists during the first 2 years of life. This suggests that the human embryo is sensitive to its very early environment, and that the culture medium used in IVF may have lasting consequences. Further monitoring of the long-term growth, development and health of IVF children is therefore warranted. STUDY FUNDING/COMPETING INTEREST(S) W.V. was funded with an unrestricted research grant from the Stichting Fertility Foundation. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER Not applicable.

Peri-partum reference ranges for ROTEM® thromboelastometry

BACKGROUND Post-partum haemorrhage (PPH) causes rapidly developing deficiencies in clotting factors and contributes to substantial maternal morbidity and mortality. Rotational thromboelastometry (ROTEM(®)) is increasingly used as a point of care coagulation monitoring device in patients with massive haemorrhage; however, there are limited data on reference ranges in the peri-partum period. These are required due to the haemostatic changes in pregnancy. METHODS In a Dutch multi-centre trial, 161 subjects were included; blood samples were obtained during labour (T1) and within 1 h of delivery (T2). Reference ranges of ROTEM(®) INTEM, EXTEM, FIBTEM, and APTEM were set and correlation with laboratory results was investigated using the guidelines of the International Federation of Clinical Chemistry. RESULTS Reference ranges were obtained for clotting time (CT), clot formation time (CFT), α-angle, clot firmness at 10 and 20 min (A10, A20), maximum clot firmness (MCF), and maximum lysis (ML). These were comparable from centre to centre, and between T1 and T2. Reference ranges T1: EXTEM: CT 31-63 s, CFT 41-120 s, and MCF 42-78 mm. INTEM CT 109-225 s, CFT 40-103, and MCF 63-78 mm. FIBTEM CT 31-79 s and MCF 13-45 mm. APTEM CT 33-62 s, CFT 42-118, and MCF 61-79 mm. CONCLUSIONS Reference values for ROTEM(®) parameters are reported. The previously published correlation between FIBTEM parameters and plasma fibrinogen levels by the Clauss method is confirmed. Further research is needed to define threshold values for haemostatic therapy in the course of PPH. Clinical trial registration NTR 2515 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2515).

The influence of 5-HTTLPR and STin2 polymorphisms in the serotonin transporter gene on treatment effect of selective serotonin reuptake inhibitors in depressive patients.

Background Serotonin transporter gene (SLC6A4) variations have been proposed as an explanation for interindividual differences in selective serotonin reuptake inhibitors (SSRIs) effects. Quantitative assessment of genetic influences is necessary to evaluate whether genetic testing before antidepressant prescription would lead to earlier treatment effects. This study evaluates the influence of two polymorphisms (5-HTTLPR and STin2) on SSRI treatment outcome in depression. Methods We included 50 SSRI nonresponders (cases) and 164 referents meeting Diagnostic and Statistical Manual Of Mental Disorder-IV criteria for major depression and using an SSRI for at least 6 weeks. Blood samples or buccal swabs were gathered to determine 5-HTTLPR (N=48 for cases and 161 for referents) and STin2 (N=50 for cases and 162 for referents) genotypes. The association between genotype and SSRI response was assessed by use of logistic regression. Results Patients with the 5-HTTLPR s-allele had a nonsignificantly increased risk of SSRI nonresponse; odds ratio (OR) 1.60, 95% confidence interval (CI) 0.66–3.89. 5-HTTLPR effects were strongest in female patients (OR 3.54, 95% CI 1.05–11.92), and for male patients 5-HTTLPR seemed to have no effect (OR 0.29, 95% CI 0.04–2.34). An age-dependent effect of 5-HTTLPR was observed; patients under 44 years of age had an increased nonresponse risk (OR 9.34, 95% CI 1.41–61.98). STin2 genotype had no clear influence on treatment outcome. Conclusion Our findings indicate that women with the 5-HTTLPR s-allele have a less favorable response to SSRI treatment. To our knowledge, this is the first time that a gender-dependent influence of 5-HTTLPR is reported. More research is needed, particularly in subgroups of patients, before implementation of genetic testing can be recommended.

Value of a single early third trimester fetal biometry for the prediction of birth weight deviations in a low risk population.

Abstract Objective: To analyze the value of a single ultrasound biometry examination at the onset of the third trimester of pregnancy for the detection of small-for-gestational-age (SGA) and large-for-gestational-age (LGA) at birth in a low risk population. The aim of this study was to develop a simple and useful method for the detection of growth deviations during pregnancy in primary care (midwife or general practitioner) practices. Setting: A Dutch primary care midwifery practice. Study design: In an earlier study, we developed parity and sex specific fetal growth charts of abdominal circumference (AC) and head circumference (HC) on the basis of ultrasound data of a low-risk midwifery population in the Netherlands. In the present study, we calculated sensitivity, specificity and predictive values at different cut-off points of AC and HC for the prediction of growth deviations at birth. Patients booked for perinatal care between 1 January 1993 and 31 December 2003 (n=3449) were used for the identification of cut-off points (derivation cohort) and those admitted between 1 January 2004 and 31 December 2005 (n=725) were used to evaluate the performance of these cut-offs in an independent population (validation cohort). For the determination of SGA and macrosomia at birth, we used the recently published Dutch birth weight percentiles. Results: Most promising cut-offs were AC ≤25th percentile for the prediction of SGA (birth weight ≤10th percentile) and AC ≥75th percentile for the prediction of macrosomia (birth weight ≥90th percentile). Within the validation cohort these cut-offs performed slightly better than in the derivation cohort. For the prediction of SGA, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 53% (95% CI 49–58%), 81% (95% CI 80–83%), 26% (95% CI 23–29%), and 93% (95% CI 93–94%), respectively. The false positive rate was 74%. For the prediction of macrosomia, the values of these parameters were 64% (95% CI 59–69%), 80% (95% CI 78–81%), 23% (95% CI 20–26%), and 96% (95% CI 95–97%), respectively. Here, false positive rate was 77%. No cut-offs were found that predicted extreme birth weight deviations (≤2.3 percentile; ≥97.7 percentile) sufficiently well. Conclusions: In a low risk population, we could predict future growth deviations with a higher sensitivity and in a significant earlier stage (at the onset of the third trimester of pregnancy) than with the use of conventional screening methods (i.e., palpation of the uterus only and fundus-symphysis measurement). Sonographic measurement of fetal abdominal circumference enables to detect more than half of cases of SGA at birth and more than two-thirds of cases of macrosomia with acceptable false-positive rates. We suggest that fetuses with biometry results below the 25th percentile or above the 75th percentile at the onset of the third trimester of pregnancy should be more intensively investigated in order to distinguish between pathology (e.g., IUGR or macrosomia) and physiology and to decide about the appropriate level of further perinatal care.

Early versus late epidural analgesia and risk of instrumental delivery in nulliparous women: a systematic review.

Please cite this paper as: Wassen M, Zuijlen J, Roumen F, Smits L, Marcus M, Nijhuis J. Early versus late epidural analgesia and risk of instrumental delivery in nulliparous women: a systematic review. BJOG 2011;118:655–661.

A simple formula for the calculation of sample size in pilot studies

One of the goals of a pilot study is to identify unforeseen problems, such as ambiguous inclusion or exclusion criteria or misinterpretations of questionnaire items. Although sample size calculation methods for pilot studies have been proposed, none of them are directed at the goal of problem detection. In this article, we present a simple formula to calculate the sample size needed to be able to identify, with a chosen level of confidence, problems that may arise with a given probability. If a problem exists with 5% probability in a potential study participant, the problem will almost certainly be identified (with 95% confidence) in a pilot study including 59 participants.