What proportion of couples with a history of recurrent pregnancy loss and with a balanced rearrangement in one parent can potentially be identified through cell-free DNA genotyping?

BACKGROUND: Balanced chromosome aberrations are reported in about 1:30 couples with recurrent pregnancy loss (RPL). Karyotyping of both parents is necessary to identify these aberrations. Genome-wide non-invasive prenatal testing (NIPT) in case of recurrent pregnancy loss could be a more efficient way to identify couples at increased risk for carrying a balanced chromosome rearrangement. The aim of this study was to evaluate whether the potential fetal imbalances caused by parental balanced aberrations detected in our center are large enough to be detectable by genome-wide non-invasive prenatal testing (NIPT). MATERIAL AND METHODS: From January 1970 until May 2020 our laboratory received 30,863 unique requests for karyotyping due to RPL. We have identified 16,045 couples and evaluated all abnormal cytogenetic results to assess the minimal size of the involved chromosomal segments in potential unbalanced products of the rearrangements. RESULTS: In the presented cohort we detected 277 aberrant balanced translocations/inversions in females and 185 in males amongst 16,045 couples with RPL, which can be translated to a risk of 1:35 (2.9%, 95% CI 2.6-3.2%). Our study showed that the vast majority (98.7%, 95% CI 97.1-99.5%) of these balanced aberrations will potentially cause a fetal imbalance > 10 Mb, which is detectable with genome-wide NIPT if it was performed during one of the miscarriages. CONCLUSIONS: Our study suggests that genome-wide NIPT is able to reveal most unbalanced products of balanced chromosomal rearrangements carried by couples with RPL and therefore can potentially identify balanced chromosomal aberration carriers. Moreover, our data suggest that these couples can be offered NIPT in case they decline invasive testing in future pregnancies.

Levothyroxine in euthyroid thyroid peroxidase antibody positive women with recurrent pregnancy loss (T4LIFE trial): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Women positive for thyroid peroxidase antibodies (TPO-Ab) have a higher risk of recurrent pregnancy loss. Evidence on whether levothyroxine treatment improves pregnancy outcomes in women who are TPO-Ab positive women with recurrent pregnancy loss is scarce. The aim of this study was to determine if levothyroxine increases live birth rates in women who were TPO-Ab positive with recurrent pregnancy loss and normal thyroid function. METHODS: The T4LIFE trial was an international, double-blind, placebo-controlled, phase 3 study done in 13 secondary and tertiary hospitals in the Netherlands, one tertiary hospital in Belgium, and one tertiary hospital in Denmark. Women (18-42 years) who were TPO-Ab positive, had two or more pregnancy losses, and had a thyroid stimulating hormone (TSH) concentration within the institutional reference range were eligible for inclusion. Women were excluded if they had antiphospholipid syndrome (lupus anticoagulant, anticardiolipin IgG or IgM antibodies, or ß2-glycoprotein-I IgG or IgM antibodies), other autoimmune diseases, thyroid disease, previous enrolment in this trial, or contraindications for levothyroxine use. Before conception, women were randomly assigned (1:1) to receive either levothyroxine or placebo orally once daily. The daily dose of levothyroxine was based on preconception TSH concentration and ranged from 0·5-1·0 µg/kg bodyweight. Levothyroxine or placebo was continued until the end of pregnancy. The primary outcome was live birth, defined as the birth of a living child beyond 24 weeks of gestation measured in the intention-to-treat population. The trial was registered within the Netherlands Trial Register, NTR3364 and with EudraCT, 2011-001820-39. RESULTS: Between Jan 1, 2013, and Sept 19, 2019, 187 women were included in the study: 94 (50%) were assigned to the levothyroxine group and 93 (50%) were assigned to the placebo group. The trial was prematurely stopped when 187 (78%) of the 240 predefined patients had been included because of slow recruitment. 47 (50%) women in the levothyroxine group and 45 (48%) women in the placebo group had live births (risk ratio 1·03 [95% CI 0·77 to 1·38]; absolute risk difference 1·6% [95% CI -12·7 to 15·9]). Seven (7%) women in the levothyroxine group and seven (8%) in the placebo group reported adverse events, none of them were directly related to the study procedure. INTERPRETATION: Compared with placebo, levothyroxine treatment did not result in higher live birth rates in euthyroid women with recurrent pregnancy loss who were positive for TPO-Ab. On the basis of our findings, we do not advise routine use of levothyroxine in women who are TPO-Ab positive with recurrent pregnancy loss and normal thyroid function. FUNDING: Dutch Organization for Health Research and Development, Fonds NutsOhra, Dutch Patient Organization of Thyroid Disorders, the Jan Dekkerstichting and Dr Ludgardine Bouwmanstichting, and a personal donation through the Dutch Patient Organization of Thyroid Disorders.

Balloon catheter for induction of labor in women with one previous cesarean and an unfavorable cervix.

INTRODUCTION: When women with a previous cesarean section and an unfavorable cervix have an indication for delivery, the choice is to induce labor or to perform a cesarean section. This study aims to assess the effectiveness and safety of a balloon catheter as a method of induction of labor in women with one previous cesarean section and an unfavorable cervix compared with an elective repeat cesarean section. MATERIAL AND METHODS: We performed a prospective cohort study in 51 hospitals in the Netherlands on term women with one previous cesarean section, a live singleton fetus in cephalic position, an unfavorable cervix and an indication for delivery. We recorded obstetric, maternal and neonatal characteristics. We compared the outcome of women who were induced with a balloon catheter with the outcome of women who delivered by elective repeat cesarean section. Main outcomes were maternal and neonatal morbidity. Mode of delivery was a secondary outcome for women who were induced. Adjusted odds ratios (aOR) were calculated using logistic regression, adjusted for potential confounders. RESULTS: Analysis was performed on 993 women who were induced and 321 women who had a repeat cesarean section (August 2011 until September 2012). Among the women who were induced, 560 (56.4%) delivered vaginally and 11 (1.1%) sustained a uterine rupture. Composite adverse maternal outcome (uterine rupture, severe postpartum hemorrhage or postpartum infection) occurred in 73 (7.4%) in the balloon and 14 (4.5%) women in the repeat cesarean section group (aOR 1.58, 95% confidence interval [CI] 0.85-2.96). Composite adverse neonatal outcome (Apgar score <7 at 5 minutes or umbilical pH <7.10) occurred in 57 (5.7%) and 10 (3.2%) neonates, respectively (aOR 1.40, 95% CI 0.87-3.48). Women who were induced had a shorter postpartum admission time (2.0 vs 3.0 days (P < 0.0001)). CONCLUSIONS: In women with a previous cesarean section and a need for delivery, induction of labor with a balloon catheter does not result in a significant increase in adverse maternal and neonatal outcomes as compared with planned cesarean section.

The diagnostic value of routine antenatal ultrasound in screening for congenital uropathies.

BACKGROUND: Antenatal hydronephrosis (ANH) is characteristic for congenital obstructive abnormalities of the urinary tract (COAUT). COAUT is the most common cause of urinary tract infections (UTI's) in newborns. The prognosis of mild to moderate ANH is unclear. The aim of this study was to determine the diagnostic value of antenatal ultrasound screening for ANH in order to inform patients correctly. METHODS: A retrospective cohort study over the period 2009-2011, evaluating all structural ultrasounds and proven cases of ANH. Also, evaluation of all patients diagnosed with UTIs caused by COAUT in the same period. RESULTS: About 7003 children underwent antenatal screening. Of them, 0.7% (n = 47) were diagnosed with ANH. In the same period, 257 children without ANH had a proven UTI. Of them, 4.3% (n = 11) were diagnosed with COAUT, which was not found during antenatal screening. The predictive value of the antenatal ultrasound was higher in the third trimester than the second trimester (sensitivity 0.97 versus 0.62, respectively). CONCLUSION: Antenatal ultrasound screening is a reliable method in diagnosing ANH. Third trimester scanning is more specific for diagnosing ANH than second trimester scanning. Our findings allow collaborating gynecologists and pediatricians to inform patients more accurately in the future after the antenatal detection of COAUT.

Cervical cancer in 2 women with a Mirena(R)-pitfalls in the assessment of irregular bleeding: a case series.

INTRODUCTION: The levonorgestrel-releasing intra-uterine device (Mirena(R)) is an effective, long term form of contraception that leads to a significant reduction of menstrual bleeding among majority of women. However, irregular bleeding is quite common in initial Mirena(R) users and may thereby mask underlying cervical pathology. CASE PRESENTATION: Two women with cervical cancer and a Mirena(R) initially presented with irregular bleeding, posing a diagnostic pitfall which resulted in doctor and patient delay. CONCLUSION: Proper evaluation of irregular vaginal bleeding, including cervical cytology, should be a prerequisite among all women opting for a Mirena(R) and must be repeated in case of persisting symptoms.

Dutch community midwives' views on preconception care.

OBJECTIVE: to explore the opinions of midwives on the desirability of preconception care for all couples contemplating pregnancy, their willingness to introduce preconception care to midwifery practice and, if it were to be implemented, the necessary conditions, including knowledge, postgraduate education and referral possibilities for successful implementation in the community. PARTICIPANTS: all community midwives (n = 129) working in 49 midwifery practices that refer their high-risk clients to the Erasmus University Medical Centre, Rotterdam (the Netherlands). SETTING: Rotterdam and its immediate surrounding communities. DESIGN: midwives working at the midwifery practices were recruited by telephone. All agreed to participate, and subsequently received a questionnaire by post. FINDINGS: 102 (79%) questionnaires were returned. Ninety-five (93%) of the 102 midwives were familiar with the concept of preconception care, and 71 (70%) of them already provided it to some extent. Of the 102 respondents, 84 (83%) seemed to be willing to provide such care in the future, and 56 (55%) felt that preconception care should be part of their professional domain. Midwives, however, lack time and knowledge to do so. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: community midwives already provide counselling, although not on a structural basis, and usually not earlier than in the first trimester of pregnancy. Midwives seem willing to play an active role in the provision of preconception care in the future. There is, however, great need for postgraduate training.

Preconception care: preliminary estimates of costs and effects of smoking cessation and folic acid supplementation.

OBJECTIVE: To assess costs and effectiveness of preconception counseling for all women planning pregnancy in The Netherlands with regard to folic acid supplementation and smoking cessation counseling. STUDY DESIGN: Costs and effects were estimated based on 200,000 women approached yearly and uptake rates of 50% and 75%. Effectiveness and potential savings were based on hospital costs of neural tube defects, low birth weight, very low birth weight and perinatal death attributable to maternal smoking. RESULTS: Total costs were estimated at dollar 5.1 million and dollar 7.2 million at uptake rates of 50% and 75%, respectively. If 50% of women would seek preconception counseling, 22 neural tube defects, 98 low-birth-weight infants, 10 very-low-birth-weight infants and 7 perinatal deaths could be avoided. At 75% uptake, 33 neural tube defects, 146 low- and 15 very-low-birth-weight infants, and 11 perinatal deaths could be avoided. CONCLUSION: Net costs of preconception counseling amount to dollar 3.7 million and dollar 5.0 million when considering cases prevented and subsequent potential savings in costs of neural tube defects and smoking-related morbidity only. However, in light of many other preventable adverse outcomes and the potential of preconception counseling to prevent significant lifetime costs for affected children, the net costs may ultimately result in a favorable cost-savings balance. Moreover, the importance of a healthy child cannot be expressed in terms of costs and savings alone.

Health-related quality-of-life in patients with morbid obesity after gastric banding for surgically induced weight loss.

BACKGROUND: Physical, emotional, and social functioning are impaired in obesity. It is unknown whether and, if so, to what extent and in which domain obese subjects who lose weight may catch up to normal-weight levels. Our objective was to compare the health-related quality-of-life (HRQL) of obese subjects with that of a normal-weight reference group before and 1 year after a weight loss program that centered around laparoscopic and open gastric banding. METHODS: An HRQL questionnaire consisting of a battery of both generic and specific measures was administered to 50 morbidly obese subjects on 2 occasions and to 100 healthy, normal-weight subjects, matched for age, gender, education, and vocational training. In addition to weight loss and health gain, the influences of achieved weight loss goals, satisfaction with outcome and operative approach (laparoscopy/laparotomy) were assessed. RESULTS: Quality-of-life was significantly impaired in obese subjects. With a substantial weight loss of 35 kg and 42% loss of excessive weight, and correction of disturbed metabolic parameters, they significantly improved in general well-being, health distress, and perceived attractiveness, approaching halfway the values of a normal-weight reference group. Improvement in values for depression and self-regard lagged behind. In physical activity, they bypassed the reference group. Days of sick leave decreased to the level of the reference group. Improvements in HRQL paralleled the rate of weight loss. Personal satisfaction and surgical approach were of minor influence. CONCLUSIONS: The obese subjects' impaired physical and social functioning improved considerably, catching up midway to normal-weight reference values after weight loss. Psychologic amelioration lagged behind. Whether the latter will catch up later and physical/social improvements will be maintained is the subject of further studies.

Preconception nutritional intake and lifestyle factors: first results of an explorative study.

OBJECTIVE: To describe nutritional intake and lifestyle factors in women planning pregnancy. STUDY DESIGN: A semi-quantitative, 1-month food frequency questionnaire and a questionnaire on health practices and personal views were filled out at home and verified by telephone interview. RESULTS: One hundred and one women agreed to participate and data of 69 women were eligible for evaluation. Women planning pregnancy (n=46) consumed significantly more saturated fats and proteins, less carbohydrates and higher median intakes of Vitamin A, thiamin, riboflavin, calcium, selenium, magnesium and iron than controls (n=23; P<0.05). However, the percentage of women planning pregnancy with intakes below recommended dietary allowances was 74% for iron, 59% for selenium, 48% for Vitamin A and 91% for copper. Ninety-six percent and 20% of them reported alcohol use and smoking, respectively. CONCLUSIONS: Nutritional intake of women in the preconception period appears to be inadequate. Efforts to increase awareness of a healthy diet and lifestyle before and throughout pregnancy should be continued.

Validation of the dutch short form of the state scale of the Spielberger State-Trait Anxiety Inventory: considerations for usage in screening outcomes.

OBJECTIVE: To validate the six-item short form of the state scale of the Spielberger State-Trait Anxiety Inventory (STAI) for usage in screening outcomes in a Dutch population receiving preconception counseling. METHODS: Men and women completed the 20-item full form of the STAI before (n = 310) and after preconception counseling (n = 147). Prorated scores of the six-item form were compared to the full form using Pearson's correlation coefficients and paired t tests. RESULTS: Cronbach's alpha for the Dutch translation of the short-form of the STAI-state was 0.83. The short form highly correlates with the full form (r = 0.95). The short form was able to discriminate between different levels of anxiety and was sensitive to change. CONCLUSION: The Dutch translation of the short form of the STAI-state has good reliability and validity and was found to be useful as a quick tool to evaluate the effectiveness of screening programs on anxiety levels. We believe our results will be applicable to other populations, although this needs to be confirmed in other studies.

Variation of serum and urine cotinine in passive and active smokers and applicability in preconceptional smoking cessation counseling.

This study assessed the applicability of serum and urine cotinine as a biochemical marker of self-reported smoking habits for use in a preconceptional smoking cessation program. The variation of serum and urine cotinine over the course of the day was investigated in a sample of 21 smokers and 8 passive smokers who reported their smoking habits and exposure to smoke daily in a questionnaire for 10 consecutive days. Blood and urine samples were collected on two sampling days, 1 week apart. Both serum and urine cotinine assay could distinguish between passive and active smokers, but not between higher categories of smokers (10-19 and > or = 20 cigarettes per day) due to significant intersubject overlap. In serum, no significant differences were found between morning and afternoon cotinine concentrations on either day, in contrast to urine cotinine (with lower excretions observed in the morning). An overall coefficient of variation of 22% was observed for both specimens in smokers. Because serum cotinine is subject to lower variability over the course of the day, it is more practical for use in a clinical setting where appointments are scheduled throughout the day in order to confirm smoking status.

Preconception care: a screening tool for health assessment and risk detection.

BACKGROUND: Identification of risk factors for adverse pregnancy outcome is a main component of preconception care, but requires adequate time and knowledge. This study compares self-administered questionnaires to history taking by a physician to evaluate the reliability of such a screening tool for prepregnancy risk detection. METHODS: One hundred ninety-three women from the outpatient clinic of Obstetrics and Gynecology of the University Medical Center Nijmegen, The Netherlands, were included in a study on preconception care. A Preconceptional Health Assessment form with risk variables pertaining to social, nutritional, medical, infectious disease, medication, reproductive and family history, and two Family History surveys (for the woman and her partner) were completed by 186 couples at home. A physician then orally verified the written answers. Agreement between the written and the oral answers was calculated using kappa statistic. RESULTS: An excellent agreement level was found for all sections of the Preconceptional Health Assessment form (overall kappa = 0.88) except for nutritional history (kappa = 0.70). The Family History surveys also showed a high agreement level (kappa = 0.92 for women and kappa = 0.90 for men). CONCLUSIONS: The questionnaires are an accurate screening tool for preconceptional risk factors. We advocate their implementation in various settings to facilitate the provision of preconception care.

Preconception counseling improves folate status of women planning pregnancy.

OBJECTIVE: To assess whether counseling women planning pregnancy to start or continue folic acid supplementation improves folate status. METHODS: Women and their partners reported folic acid supplement intake in a preconceptional health questionnaire, and the women were categorized as reported "users" or "nonusers" of supplements before counseling. The use of periconceptional folic acid was addressed at a subsequent preconceptional consultation. Differences between reported supplement users and nonusers before counseling as well as between assumed users and nonusers of folic acid (with precounseling red cell and serum folate levels above and below 590 nmol/L and 20 nmol/L, respectively) were analyzed. RESULTS: A total of 111 (66%) of 168 eligible women participated. Estimated mean red cell folate levels of women who reported no use of folic acid supplements before counseling increased significantly after 4 months from 540 nmol/L to 680 nmol/L. Red cell folate levels of women who reported taking supplements (44%) remained stable up to 1 year after counseling. Women with low precounseling folate levels showed a highly significant mean increase in red cell folate from 475 nmol/L to 689 nmol/L 4 months after counseling. CONCLUSION: Addressing periconceptional folic acid use at a preconceptional consultation improves folate status among women planning to conceive.

The past and present practices and continuing controversies of preconception care.

Preconception care, a long-established concept for primary prevention of maternal and perinatal morbidity and mortality through detection and reduction of modifiable risks, has been widely propagated for the last decades. This article provides an overview of the various goals and practices described in the literature in different parts of the world, including issues and controversies pertaining to the provision and implementation of preconception care in different health care settings.