Postpartum ovarian vein thrombosis with left renal venous infarction after vaginal delivery.

A primipara in her late 20s presented with abdominal pain and pain in the left flank 14 days after a ventouse delivery. She was treated with antibiotics, antiemetics and analgesics with the initial differential diagnosis of cystitis, pyelonephritis or nephrolithiasis. Despite the treatment, the patient experienced increased colic pain and nausea. An ultrasound showed an enlarged left kidney, suggesting pyelonephritis, and thereby, the antibiotic treatment was adjusted accordingly. Despite additional pain medication, pain relief could not be achieved. The diagnosis of ovarian venous thrombosis was considered, and an abdominal CT scan confirmed the diagnosis. The patient was treated with anticoagulant therapy. Hypercoagulability work-up revealed a heterozygous mutation of the Factor V Leiden. Our patient awaits a haematologic follow-up.

Implementation of integrated maternity care in the southwestern region of the Netherlands: evaluation of its effect on preterm birth, low birthweight infants and number of secondary care consultations.

OBJECTIVES: To determine whether integrated maternity care is associated with reduced preterm births (PTB) and fewer small-for-gestational-age infants (SGA), and whether its implementation leads to a reduction of secondary care consultations. DESIGN: Retrospective study. SETTING: Integrated maternity care organisation in the southwestern region of the Netherlands. PARTICIPANTS: All singleton pregnancies (≥24 weeks) within integrated maternity care organisation Annature between 2015 and 2020. INTERVENTION: Implementation of a shared maternity record in primary and secondary care. METHODS: Data of 20 818 women were derived from patient records and from the Netherlands Perinatal Registry. Intervention was the introduction of integrated maternity care in January 2018. Through multivariate logistic regression and segmented regression analysis we assessed the combined prevalence of SGA and PTB (SGA-PTB) before (2015-2017), and after the intervention (2018-2020). Regional rates were contrasted with nationwide rates (n=782 176). MAIN OUTCOME MEASURES: SGA-PTB prevalence and mean number of secondary care consultations per pregnancy. RESULTS: SGA-PTB prevalence declined from 618/3443 (17.9%) in 2015 to 560/3501 (16.0%) in 2017 to 507/3459 (14.7%) in 2020 (p<0.005). Mean number of secondary care consultations declined from six per pregnancy in 2015 to three in 2020. Logistic regression demonstrated a significant decline in odds of SGA-PTB (OR 0.83 (95% CI 0.77 to 0.89)) between 2015-2017 and 2018-2020 adjusted for changes in sociodemographic characteristics over time. A statistically significant average monthly 7.3% (p=0.05) reduction in SGA-PTB prevalence and 12.4% (p<0.005) mean monthly reduction in secondary care consultations were demonstrated for 2015-2017. Immediately after the intervention, mean monthly prevalence of SGA-PTB dropped non-significantly to 14.7%. Between 2018 and 2020 a significant 15.2% (p<0.005) reduction in secondary care consultations was shown. CONCLUSION: Our results suggest that implementation of integrated maternity care was associated with reduced PTBs and/or low birth weight, and fewer secondary care consultations. These encouraging findings were observed in a less favourable sociodemographic profile and should be confirmed in other regions with sufficiently large populations, and the possibility to test individual components of integrated maternity care.

Delayed cord clamping vs cord milking in elective cesarean delivery at term: a randomized controlled trial.

BACKGROUND: Delayed cord clamping has significant beneficial effects on the neonate and its transition to extrauterine life and, therefore, is common practice at vaginal births in the Netherlands. In 2015, 16% of neonates were born via cesarean delivery; moreover, in 81% of these cases, the umbilical cord was clamped and cut immediately. Neonatal benefits of delayed cord clamping are an increased circulating volume of 25 to 30 mL/kg, leading to a higher preload of both the right and left ventricles during the transition from umbilical circulation to pulmonary circulation, thus maintaining a stable left ventricle output, and to higher neonatal hemoglobin and hematocrit levels 24 to 48 hours after birth. Currently, little is known about whether the abovementioned neonatal benefits of delayed cord clamping could apply to neonates delivered by cesarean delivery. In these cases, possible negative effects on neonatal outcomes (ie, neonatal hypothermia, lower Apgar scores, and hyperbilirubinemia) and maternal outcomes (ie, increased maternal blood loss and higher postoperative infection rate) should also be taken into consideration. OBJECTIVE: This study aimed to determine whether clamping the umbilical cord after 2 minutes is superior to cord milking during elective cesarean deliveries at term, taking both short- and long-term neonatal and maternal outcomes into consideration, and to determine whether cord milking could be an appropriate alternative to delayed cord clamping. STUDY DESIGN: A randomized controlled trial was conducted in a large secondary care center in the Netherlands (Amphia Hospital in Breda) from October 2020 to April 2022. A total of 115 patients who underwent an elective cesarean delivery between 37 0/7 and 41 6/7 weeks of gestation were included. The primary outcomes were neonatal hemoglobin and hematocrit levels at 48 hours after birth. The secondary outcomes were divided into neonatal and maternal outcomes. RESULTS: After randomization, 58 participants were treated with cord milking, and 57 participants were treated with delayed cord clamping. There was no significant difference in demographic characteristics between both groups. There was no significant difference in the primary outcomes, with a mean hemoglobin level 48 hours after birth of 12.1 mmol/L in the delayed cord clamping group and 12.2 mmol/L in the cord milking group (P=.80). Regarding our secondary outcomes, there was no significant difference regarding Apgar score, neonatal body temperature, maternal blood loss, and postoperative infection rate between our intervention groups. CONCLUSION: Hemoglobin and hematocrit levels at 48 hours after birth showed no significant difference when comparing delayed cord clamping with cord milking. Delayed cord clamping did not lead to increased maternal blood loss or postoperative infections compared with a method with a much shorter timeframe between delivery and clamping of the umbilical cord, namely, cord milking. In addition, delayed cord clamping did not lead to a lower Apgar score or neonatal temperature compared with cord milking. Our research suggests that delayed cord clamping can be safely performed during elective cesarean deliveries at term. If intraoperative circumstances do not allow for delayed cord clamping, cord milking can be an appropriate alternative for the neonate at term.

Home-based monitoring of ovulation to time frozen embryo transfers in the Netherlands (Antarctica-2): an open-label, nationwide, randomised, non-inferiority trial.

BACKGROUND: The growing field of assisted reproductive techniques, including frozen-thawed embryo transfer (FET), should lead the way to the best sustainable health care without compromising pregnancy chances. Correct timing of FET is crucial to allow implantation of the thawed embryo. Nowadays, timing based on hospital-controlled monitoring of ovulation in the natural cycle of a woman is the preferred strategy because of the assumption of favourable fertility prospects. However, home-based monitoring is a simple method to prevent patient travel and any associated environmental concerns. We compared ongoing pregnancy rates after home-based monitoring versus hospital-controlled monitoring with ovulation triggering. METHODS: This open-label, multicentre, randomised, non-inferiority trial was undertaken in 23 hospitals and clinics in the Netherlands. Women aged between 18 and 44 years with a regular ovulatory menstrual cycle were randomly assigned in a 1:1 ratio via a web-based randomisation program to home-based monitoring or hospital-controlled monitoring. Those who analysed the data were masked to the groups; those collecting the data were not. All endpoints were analysed by intention to treat and per protocol. Non-inferiority was established when the lower limit of the 90% CI exceeded -4%. This study was registered at the Dutch Trial Register (Trial NL6414). FINDINGS: 1464 women were randomly assigned between April 10, 2018, and April 13, 2022, with 732 allocated to home-based monitoring and 732 to hospital-controlled monitoring. Ongoing pregnancy occurred in 152 (20·8%) of 732 in the home-based monitoring group and in 153 (20·9%) of 732 in the hospital-controlled monitoring group (risk ratio [RR] 0·99 [90% CI 0·81 to 1·22]; risk difference [RD] -0·14 [90% CI -3·63 to 3·36]). The per-protocol analysis confirmed non-inferiority (152 [21·0%] of 725 vs 153 [21·0%] of 727; RR 1·00 (90% CI 0·81 to 1·23); RD -0·08 [90% CI -3·60 to 3·44]). INTERPRETATION: Home-based monitoring of ovulation is non-inferior to hospital-controlled monitoring of ovulation to time FET. FUNDING: The Dutch Organisation for Health Research and Development.

Comparing the cumulative live birth rate of cleavage-stage versus blastocyst-stage embryo transfers between IVF cycles: a study protocol for a multicentre randomised controlled superiority trial (the ToF trial).

INTRODUCTION: In vitro fertilisation (IVF) has evolved as an intervention of choice to help couples with infertility to conceive. In the last decade, a strategy change in the day of embryo transfer has been developed. Many IVF centres choose nowadays to transfer at later stages of embryo development, for example, transferring embryos at blastocyst stage instead of cleavage stage. However, it still is not known which embryo transfer policy in IVF is more efficient in terms of cumulative live birth rate (cLBR), following a fresh and the subsequent frozen-thawed transfers after one oocyte retrieval. Furthermore, studies reporting on obstetric and neonatal outcomes from both transfer policies are limited. METHODS AND ANALYSIS: We have set up a multicentre randomised superiority trial in the Netherlands, named the Three or Fivetrial. We plan to include 1200 women with an indication for IVF with at least four embryos available on day 2 after the oocyte retrieval. Women are randomly allocated to either (1) control group: embryo transfer on day 3 and cryopreservation of supernumerary good-quality embryos on day 3 or 4, or (2) intervention group: embryo transfer on day 5 and cryopreservation of supernumerary good-quality embryos on day 5 or 6. The primary outcome is the cLBR per oocyte retrieval. Secondary outcomes include LBR following fresh transfer, multiple pregnancy rate and time until pregnancy leading a live birth. We will also assess the obstetric and neonatal outcomes, costs and patients' treatment burden. ETHICS AND DISSEMINATION: The study protocol has been approved by the Central Committee on Research involving Human Subjects in the Netherlands in June 2018 (CCMO NL 64060.000.18). The results of this trial will be submitted for publication in international peer-reviewed and in open access journals. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL 6857).

Pregnancy before recurrent pregnancy loss more often complicated by post-term birth and perinatal death.

INTRODUCTION: The cause of recurrent pregnancy loss often remains unknown. Possibly, pathophysiological pathways are shared with other pregnancy complications. MATERIAL AND METHODS: All women with secondary recurrent pregnancy loss (SRPL) visiting Leiden University Medical Center (January 2000-2015) were included in this retrospective cohort to assess whether women with SRPL have a more complicated first pregnancy compared with control women. SRPL was defined as three or more consecutive pregnancy losses before 22 weeks of gestation, with a previous birth. The control group consisted of all Dutch nullipara delivering a singleton (January 2000-2015). Information was obtained from the Dutch Perinatal Registry. Outcomes were preeclampsia, preterm birth, post-term birth, intrauterine growth restriction, breach position, induction of labor, cesarean section, congenital abnormalities, perinatal death and severe hemorrhage in the first ongoing pregnancy. Subgroup analyses were performed for women with idiopathic SRPL and for women ≤35 years. RESULTS: In all, 172 women with SRPL and 1 196 178 control women were included. Women with SRPL were older and had a higher body mass index; 29.7 years vs. 28.8 years and 25.1 kg/m2 vs. 24.1 kg/m2 , respectively. Women with SRPL more often had a post-term birth (OR 1.86, 95% CI 1.10-3.17) and more perinatal deaths occurred in women with SRPL compared with the control group (OR 5.03, 95% CI 2.48-10.2). Similar results were found in both subgroup analyses. CONCLUSIONS: The first ongoing pregnancy of women with (idiopathic) SRPL is more often complicated by post-term birth and perinatal death. Revealing possible links between SRPL and these pregnancy complications might lead to a better understanding of underlying pathophysiology.

Association between miscarriage and cardiovascular disease in a Scottish cohort.

OBJECTIVE: To assess if miscarriage, whether consecutive or not, is associated with an increased risk of subsequent cardiovascular disease. METHODS: A cohort study was performed using women with at least one miscarriage or live birth recorded from 1950 to 2010 in the Aberdeen Maternity and Neonatal Databank. The exposed groups consisted of women with non-consecutive, two consecutive or three or more consecutive miscarriages; the unexposed group consisted of all women with at least one live birth and no miscarriages. Women were linked to Scottish Morbidity Records for hospital admissions for cardiovascular conditions, cardiac surgery and death registrations. Main outcome measures were ischaemic heart disease, cerebrovascular disease and a composite outcome of any disease of circulatory system. A sensitivity analysis was performed dividing the women into those who had one, two or three or more miscarriages irrespective of whether these events were consecutive or not. RESULTS: After excluding women with pre-existing hypertension, type 1 diabetes mellitus, kidney disease and 'disease of circulatory system', 60,105 women were analysed; 9419 with non-consecutive, 940 with two consecutive, 167 with three or more consecutive miscarriages and 49,579 with no miscarriage. In the multivariate analyses, a significant association was found between ischaemic heart disease and women with two (HRs 1.75 (95% CI 1.22 to 2.52)) or three or more (HR 3.18 (95% CI 1.49 to 6.80)) consecutive miscarriages. Similar patterns of risk were observed in the sensitivity analysis. CONCLUSION: Women with a history of two or more miscarriages, irrespective of whether consecutive or not, appear to have an increased risk of ischaemic heart disease.

ALIFE2 study: low-molecular-weight heparin for women with recurrent miscarriage and inherited thrombophilia--study protocol for a randomized controlled trial.

BACKGROUND: A large number of studies have shown an association between inherited thrombophilia and recurrent miscarriage. It has been hypothesized that anticoagulant therapy might reduce the number of miscarriages and stillbirth in these women. In the absence of randomized controlled trials evaluating the efficacy of anticoagulant therapy in women with inherited thrombophilia and recurrent miscarriage, a randomized trial with adequate power that addresses this question is needed. The objective of the ALIFE2 study is therefore to evaluate the efficacy of low-molecular-weight heparin (LMWH) in women with inherited thrombophilia and recurrent miscarriage, with live birth as the primary outcome. METHODS/DESIGN: Randomized study of LMWH plus standard pregnancy surveillance versus standard pregnancy surveillance alone. STUDY POPULATION: pregnant women of less than 7 weeks' gestation, and confirmed inherited thrombophilia with a history of 2 or more miscarriages or intra-uterine fetal deaths, or both. SETTING: multi-center study in centers from the Dutch Consortium of Fertility studies; centers outside the Netherlands are currently preparing to participate. INTERVENTION: LMWH enoxaparin 40 mg subcutaneously once daily started prior to 7 weeks gestational age plus standard pregnancy surveillance or standard pregnancy surveillance alone. Main study parameters/endpoints: the primary efficacy outcome is live birth. Secondary efficacy outcomes include adverse pregnancy outcomes, such as miscarriage, pre-eclampsia, syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP syndrome), fetal growth restriction, placental abruption, premature delivery and congenital malformations. Safety outcomes include bleeding episodes, thrombocytopenia and skin reactions. DISCUSSION: After an initial period of slow recruitment, the recruitment rate for the study has increased. Improved awareness of the study and acknowledgement of the need for evidence are thought to be contributing to the improved recruitment rates. We aim to increase the number of recruiting centers in order to increase enrollment into the ALIFE2 study. The study website can be accessed via www.ALIFE2study.org. TRIAL REGISTRATION: The ALIFE2 study was registered on 19 March 2012 under registration number NTR3361.

Hormonal versus non-hormonal contraceptives in women with diabetes mellitus type 1 and 2.

BACKGROUND: Adequate contraceptive advice is important in both women with diabetes mellitus type 1 and type 2 to reduce the risk of maternal and infant morbidity and mortality in unplanned pregnancies. A wide variety of contraceptives are available for these women. However, hormonal contraceptives might influence carbohydrate and lipid metabolism and increase micro- and macrovascular complications, so caution in selecting a contraceptive method is required. OBJECTIVES: To investigate whether progestogen-only, combined estrogen and progestogen or non-hormonal contraceptives differ in terms of effectiveness in preventing pregnancy, in their side effects on carbohydrate and lipid metabolism, and in long-term complications such as micro- and macrovascular disease when used in women with diabetes mellitus. SEARCH METHODS: The search was performed in CENTRAL, MEDLINE, EMBASE, POPLINE, CINAHL, WorldCat, ECO, ArticleFirst, the Science Citation Index, the British Library Inside, and reference lists of relevant articles. The last search was performed in January 2013. In addition, experts in the field and pharmaceutical companies marketing contraceptives were contacted to identify published, unpublished or ongoing studies. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials that studied women with diabetes mellitus comparing: 1. hormonal versus non-hormonal contraceptives; 2. progestogen-only versus estrogen and progestogen contraceptives; 3. contraceptives containing < 50 µg estrogen versus contraceptives containing ≥ 50 µg estrogen; and 4. contraceptives containing first-, second- and third-generation progestogens, drospirenone and cyproterone acetate. The principal outcomes were contraceptive effectiveness, diabetes control, lipid metabolism and micro- and macrovascular complications. DATA COLLECTION AND ANALYSIS: Two investigators evaluated the titles and abstracts identified from the literature search. Quality assessment was performed independently with discrepancies resolved by discussion or consulting a third review author. Because the trials differed in studied contraceptives, participant characteristics and methodological quality, we could not combine the data in a meta-analysis. The trials were therefore examined on an individual basis and narrative summaries were provided. MAIN RESULTS: Four randomised controlled trials were included. No unintended pregnancies were reported during the study periods. Only one trial was of good methodological quality. It compared the influence of a levonorgestrel-releasing intrauterine device (IUD) versus a copper IUD on carbohydrate metabolism in women with type 1 diabetes mellitus. No significant difference was found between the two groups. The other three trials were of limited methodological quality. Two compared progestogen-only pills with different estrogen and progestogen combinations, and one also included the levonorgestrel-releasing IUD and copper IUD. The trials reported that blood glucose levels remained stable during treatment with most regimens. Only high-dose combined oral contraceptives and 30 µg ethinylestradiol + 75 µg gestodene were identified as slightly impairing glucose homeostasis. The three studies found conflicting results regarding lipid metabolism. Some combined oral contraceptives appeared to have a minor adverse effect while others appeared to slightly improve lipid metabolism. The copper IUD and progestogen-only oral contraceptives also slightly improved lipid metabolism and no influence was seen while using the levonorgestel-releasing IUD. Only one study reported on micro- and macrovascular complications. It observed no signs or symptoms of thromboembolic incidents or visual disturbances, however study duration was short. Only minor adverse effects were reported in two studies. AUTHORS' CONCLUSIONS: The four included randomised controlled trials in this systematic review provided insufficient evidence to assess whether progestogen-only and combined contraceptives differ from non-hormonal contraceptives in diabetes control, lipid metabolism and complications. Three of the four studies were of limited methodological quality, sponsored by pharmaceutical companies and described surrogate outcomes. Ideally, an adequately reported, high-quality randomised controlled trial analysing both intermediate outcomes (that is glucose and lipid metabolism) and true clinical endpoints (micro- and macrovascular disease) in users of combined, progestogen-only and non-hormonal contraceptives should be conducted. However, due to the low incidence of micro- and macrovascular disease and accordingly the large sample size and long follow-up period needed to observe differences in risk, a randomised controlled trial might not be the ideal design.

Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. HABENOX: a randomised multicentre trial.

Recurrent miscarriage affects 1-2% of women. In more than half of all recurrent miscarriage the cause still remains uncertain. Thrombophilia has been identified in about 50% of women with recurrent miscarriage and thromboprophylaxis has been suggested as an option of treatment. A randomised double-blind (for aspirin) multicentre trial was performed among 207 women with three or more consecutive first trimester (<13 weeks) miscarriages, two or more second trimester (13-24 weeks) miscarriages or one third trimester fetal loss combined with one first trimester miscarriage. Women were analysed for thrombophilia. After complete work-up, women were randomly allocated before seven weeks' gestation to either enoxaparin 40 mg and placebo (n=68), enoxaparin 40 mg and aspirin 100 mg (n=63) or aspirin 100 mg (n=76). The primary outcome was live-birth rate. Secondary outcomes were pregnancy complications, neonatal outcome and adverse effects. The trial was ended prematurely because of slow recruitment. A live birth rate of 71% [relative risk (RR) 1.17, 95% confidence interval (CI) 0.92-1.48] was found for enoxaparin and placebo and 65% [RR 1.08, 95% CI 0.83-1.39] for enoxaparin and aspirin when compared to aspirin alone (61%, reference group). In the whole study group the live birth rate was 65% (95% CI 58.66-71.74) for women with three or more miscarriages (n=204). No difference in pregnancy complications, neonatal outcome or adverse effects was observed. No significant difference in live birth rate was found with enoxaparin treatment versus aspirin or a combination of both versus aspirin in women with recurrent miscarriage.