Low-dose aspirin for primary prevention of adverse pregnancy outcomes in twin pregnancies: an observational cohort study based on propensity score matching.

BACKGROUND: Since the effectiveness of low-dose aspirin (LDA) in twin pregnancies is uncertain, we aimed to preliminarily assess whether LDA is beneficial in preventing preeclampsia in twin pregnancies. METHODS: This study is an observational study in two hospitals in China. Among 932 women, 277 in the First Affiliated Hospital of Chongqing Medical University were routinely treated with aspirin (100 mg daily) from 12 to 16 weeks to 35 weeks of gestational age, while 655 in Chongqing Health Center for Women and Children were not taking aspirin during pregnancy. We followed each subject and the individual details were recorded. RESULTS: LDA significantly reduced the risk of preeclampsia (RR 0.48; 95% CI 0.24-0.95) and preterm birth 34 weeks (RR 0.50; 95% CI 0.29-0.86) and showed possible benefits to lower the rate of SGA babies (RR 0.74; 95% CI 0.55-1.00). Moreover, the risk of postpartum hemorrhage was not increased by LDA (RR 0.89; 95% CI 0.35-2.26). CONCLUSIONS: Treatment with low-dose aspirin in twin pregnancies could offer some protection against adverse pregnancy outcomes in the absence of significantly increased risk of postpartum hemorrhage. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR); ChiCTR-OOC-16008203 , Retrospectively registered date: April 1st, 2016.

Twin pregnancy outcome following teriflunomide treatment in a relapsing-remitting multiple sclerosis patient: A case report.

RATIONALE: Teriflunomide is a disease-modifying drug that has been approved for treatment of relapsing-remitting multiple sclerosis. Due to its teratogenic effect in animals, however, it is not recommended during pregnancy. For this reason, effective contraception must be used during its administration. When an unscheduled pregnancy occurs during therapy, patients must undergo a cholestyramine procedure for rapid flushing of the drug. PATIENT CONCERNS: We describe the case of a 35-year-old female patient suffering diagnosed with relapsing-remitting multiple sclerosis at the age of 20. The patient as a result of side effects of previous therapies started taking teriflunomide. DIAGNOSIS: Despite recommendations for the use of contraceptives, the patient became pregnant during drug therapy. Pregnancy occurred 12 months after initiating teriflunomide treatment. INTERVENTIONS: Therapy with teriflunomide was immediately suspended and cholestyramine was prescribed (8 g 3 times a day, for 11 days) to flush out any residual drug from the body. OUTCOMES: Despite an 8-week exposure to teriflumomide during gestation, the patient gave birth to healthy twin girls at 35 week. Controls carried out after birth did not reveal any malformation or genetic and chromosomal abnormality. At a 5-month pediatric specialist check both babies were healthy and growing regularly. CONCLUSION: This shows that even if there is evidence of teratogenic effects in animals, an 8-week exposure to teraflunomide >0.02 mg/L did not have effects on the newborn.

Maternal ABVD chemotherapy for Hodgkin lymphoma in a dichorionic diamniotic pregnancy: a case report.

BACKGROUND: Hodgkin lymphoma (HL) is the most common hematological malignancy during pregnancy. The first-line treatment for HL in pregnancy is the standard ABVD regimen without any drug and/or dose adjustment. However, data on chemotherapy during twin pregnancies are sparse, and a better understanding of the mechanisms involved in exposure to and the toxic effects of anticancer drugs in the fetuses is needed. CASE PRESENTATION: A 41-year-old dichorionic diamniotic pregnant patient was given ABVD treatment for HL at a gestational age of 28 weeks and 3 days. The patient received 2 cycles of chemotherapy with a 15-day therapeutic window including an actual 25 mg/m2 dose of doxorubicin per cycle. Unlike the female twin, the male twin presented four days after birth a left cardiac dysfunction. Doxorubicin cardiotoxicity in the male newborn was also supported by high blood levels of troponin. At one month of age, echocardiography findings were normal. We investigated literature data on physiological aspects of pregnancy that may influence doxorubicin pharmacokinetics, and pharmacodynamic and pharmacokinetic data on the use of doxorubicin in pregnancy. We detailed the role of the transporters in doxorubicin placenta distribution, and tried to understand why only one fetus was affected. CONCLUSIONS: Fetal safety depends at least on maternal doxorubicin pharmacokinetics.Because of drug interactions (i.e. drug metabolism and drug transport), care should always be taken to avoid maternal pharmacokinetic variability. The toxic effects were discrepant between the dizygotic twins, suggesting additional fetus-specific pharmacokinetic/pharmacodynamic factors in doxorubicin toxicity.

Association of histological chorioamnionitis and magnesium sulfate treatment in singleton and dichorionic twin pregnancies with preterm premature rupture of membranes: preliminary observations.

Objective To evaluate the possible association between antenatal magnesium sulfate treatment with histological chorioamnionitis in patients with singleton or dichorionic twins that had preterm premature rupture of the membranes. Methods This was an observational study performed in patients admitted to the hospital with rupture of membranes before 34 weeks' gestation. The primary outcome was histological chorioamnionitis and the primary predictor was antenatal magnesium sulfate treatment. A logistic regression model was used without consideration of other antenatal medical treatments. Results Among 107 patients with preterm deliveries, 57 were admitted to the hospital before 34 weeks' gestation with preterm premature rupture of membranes. Fifty-cases were excluded from the analysis because they were admitted after 34 weeks' gestation, delivered before 24 weeks' gestation or had intrauterine fetal demise or monochorionic twins. The logistic regression analysis adjusting for maternal age, gravidity, parity, multiple gestation, gestational age at delivery, and birthweight, indicated that patients with singleton pregnancies and histological chorioamnionitis had received magnesium sulfate antenatally more frequently (χ2=6.46; P=0.01). The association between histological chorioamnionitis and magnesium sulfate treatment was not found among patients with dichorionic twin pregnancies with one intact gestational sac. Conclusions In this cohort of patients with preterm premature rupture of membranes admitted to the hospital before 34 week's gestation, those with singleton pregnancies treated antenatally with magnesium sulfate for neonatal neuroprotection had a greater rate of histological chorioamnionitis.

Antagonist protocol versus clomiphene in unexplained infertility: A randomized controlled study.

OBJECTIVE: The primary purpose of this randomized controlled trial study was to compare clinical pregnancy rates and ovulation parameters in female patients of unexplained infertility undergoing intrauterine insemination (IUI) using an antagonist protocol versus a conventional clomiphene citrate protocol. MATERIALS AND METHODS: This was a multicenter parallel randomized controlled, open-label trial. A central randomization center used computer generated tables to allocate treatments. We conducted the study in two centers: Saudi Center and Samir Abbas and Assisted Reproductive Techniques Center of Cairo University, Cairo, Egypt between January 2011 and January 2014. Six hundred and twenty-two couples with unexplained infertility were randomized into two equal groups with 27 excluded after randomization: the antagonist protocol group and the clomiphene group. Antagonist protocol: human menopausal gonadotropins were given to 298 patients from Day 2 to reach a dominant follicle of 18-22 mm, intramuscularly. Then, orgalutrone (0.25 mg) was subcutaneously started from Day 6 or Day 7 until the day of human chorionic gonadotropins (hCG; that was given in the dose of 10,000 IU, intramuscularly) when follicles reached 18-22 mm. Afterward, the IUI of 0.5 mL was done from 34 hours to 36 hours using IUI catheter without guidance of ultrasonography and with an empty urinary bladder. The clomiphene citrate protocol was clomiphene citrate given 100 mg/d to 297 patients from Day 2 to Day 6 and follow up until day of hCG. The clinical pregnancy rate detected with ultrasound confirmed fetal heart pulsations at 6-weeks' gestation (4 weeks after IUI). The number of dominant follicles, level of serum estradiol, and luteinizing hormone at the day of hCG injection and the incidence of twin or triplet pregnancies in both groups were secondary outcome measures. RESULTS: The clinical pregnancy rate in the antagonist protocol group was significantly (p < 0.001) higher than in the clomiphene group. It was 80 patients (27%) in the antagonist protocol group versus 41 patients (14%) in the clomiphene group. The mean number of dominant follicles was significantly (p < 0.001) greater in the antagonist protocol group (4.36 ± 1.36 dominant follicles) compared with the clomiphene group (2.71 ± 0.96 dominant follicles). In addition, the rate of twin pregnancies was 15 cases in the antagonist protocol group versus six cases only in the clomiphene group (p = 0.047). The luteinizing hormone also was significantly lower in the antagonist group (2.1 ± 1.3) compared with that in the clomiphene group (9.5 ± 3.6). CONCLUSION: IUI clinical pregnancy rates were significantly higher by antagonist protocol.

Relation between time interval from antenatal corticosteroids administration to delivery and neonatal outcome in twins.

AIM: The aim of this study was to evaluate the perinatal outcome in twins, who were administered one complete course of antenatal corticosteroids (ACS) depending on the time interval from corticosteroids to delivery. METHODS: We carried out a retrospective analysis of medical data of women with twins who received a course of ACS and delivered before 34 weeks within or beyond 7 days after ACS were given. Among 652 twin deliveries between 2006 and 2014, 106 met the criteria (50 patients delivered <7 days and 56 ≥ 7 days after ACS administration). RESULTS: There were no differences in the mean gestational age at labor, mean birthweight, perinatal mortality or newborns' general condition between women who delivered <7 and ≥7 days after corticosteroids. Newborns in the ≥7 days group suffered from respiratory disorders significantly more often (74.1% vs 54.5%, P = 0.003) and were hospitalized longer (42.6 ± 19.1 vs 33.4 ± 21.7 days, P < 0.001). Significantly more infants in the <7 days group were administered antibiotics (55.6% vs 25%, P = 0.001). In the multiple logistic regression analysis, the only factors significantly influencing the incidence of respiratory complications in twins were delivery following ACS therapy within 7 days (adjusted odds ratio, 0.16; 95% confidence interval, 0.02-0.90) and female sex (adjusted odds ratio, 0.71; 95% confidence interval 0.40-0.90). CONCLUSION: There is a relation between neonatal outcomes in twins and time interval between ACS administration and birth. Therefore, a single ACS course should be administered with caution in order to allow for the completion of the treatment without exceeding an interval of 7 days to delivery. © 2016 Japan Society of Obstetrics and Gynecology.

Glycemic control in twin pregnancies with gestational diabetes: are we improving or worsening outcomes?

OBJECTIVE: To estimate the association between glycemic control and adverse outcomes in twin pregnancies with gestational diabetes (GDM). STUDY DESIGN: A cohort of patients with twin pregnancies and GDM were identified from one maternal-fetal medicine practice from 2005 to 2014. Patients with prepregnancy diabetes were excluded. First, outcomes were compared between patients with GDMA1 and GDMA2 (gestational age at delivery, birthweight, small for gestational age (SGA, birthweight <10th percentile), preeclampsia, and cesarean delivery). Then, finger stick glucose logs were reviewed and correlated with the risk of SGA and preeclampsia. Abnormal finger stick values were defined as: fasting ≥ 90 mg/dL, 1-h postprandial ≥ 140 mg/dL, 2-h postprandial ≥ 120 mg/dL. RESULTS: Sixty-six patients with twin pregnancies and GDM were identified (incidence 9.1%). Comparing the 43 patients with GDMA1 to the 23 patients with GDMA2, outcomes were similar, aside from patients with GDMA1 having lower birthweight of the smaller twin (2184 ± 519 g versus 2438 ± 428 g, p = 0.040). The risk of preeclampsia was not associated with glycemic control. Patients with SGA had lower mean fasting values (83.3 ± 5.5 versus 87.2 ± 7.7 mg/dL, p = 0.033), and a lower percentage of abnormal fasting values (24.0% versus 36.9%, p = 0.040), abnormal post-breakfast values (9.9% versus 27.1%, p = 0.003), and total abnormal values (20.1% versus 27.7%, p = 0.055). CONCLUSION: In twin pregnancies with GDM, improved glycemic control is not associated with improved outcomes, and is associated with a higher risk of SGA. Prospective trials in twin pregnancies should be performed to establish goals for glycemic control in twin pregnancies.

Epirubicin: a new entry in the list of fetal cardiotoxic drugs? Intrauterine death of one fetus in a twin pregnancy. Case report and review of literature.

BACKGROUND: Current knowledge indicate that epirubicin administration in late pregnancy is almost devoid of any fetal cardiotoxicity. We report a twin pregnancy complicated by breast cancer in which epirubicin administration was causatively linked to the death of one twin who was small for gestational age (SGA) and in a condition of oligohydramnios and determined the onset of a transient cardiotoxicity of the surviving fetus/newborn. CASE PRESENTATION: A 38-year-old caucasic woman with a dichorionic twin pregnancy was referred to our center at 20 and 1/7 weeks for a suspected breast cancer, later confirmed by the histopathology report. At 31 and 3/7 weeks, after the second chemotherapy cycle, ultrasound examination evidenced the demise of one twin while cardiac examination revealed a monophasic diastolic ventricular filling, i.e. a diastolic dysfunction of the surviving fetus who was delivered the following day due to the occurrence of grade II placental abruption. The role of epirubicin cardiotoxicity in the death of the first twin was supported by post-mortem cardiac and placental examination and by the absence of structural or genomic abnormalities that may indicate an alternative etiology of fetal demise. The occurrence of epirubicin cardiotoxicity in the surviving newborn was confirmed by the report of high levels of troponin and transient left ventricular septal hypokinesia. CONCLUSION: Based on our findings we suggest that epirubicin administration in pregnancy should be preceded by the screening of some fetal conditions like SGA and oligohydramnios that may increase its cardiotoxicity and that, during treatment, the diastolic function of the fetal right ventricle should be specifically monitored by a pediatric cardiologist; also, epirubicin and desamethasone for lung maturation should not be closely administered since placental effects of glucocorticoids may increase epirubicin toxicity.

[Progesterone and prevention of preterm birth]. / Progestérone et prévention de l'accouchement prématuré.

The literature confirms the interest of progesterone for prevention of preterm delivery in specific indications for patients carrying a singleton pregnancy. In contrast, randomized trials have shown no benefit using progesterone in the prevention of prematurity in twins and even an adverse effect.

Candida glabrata sepsis associated with chorioamnionitis in an IVF twin pregnancy: Should we deliver?

We report a case of in vitro fertilization (IVF)-acquired Candida glabrata chorioamnionitis successfully treated through systemic maternal antifungal treatment prior to delivery. To the best of our knowledge, this is the first case of its kind in the literature. C. glabrata chorioamnionitis in pregnancy is rare, but the current literature suggests a very high fetal fatality in such cases. It is known to have an association with cervical stitch, amniocentesis, chorionic villous sampling, and assisted reproductive techniques such as IVF. Given the increasing global use of artificial reproductive techniques, it is important to raise awareness of this condition and highlight its potential complications. Early recognition of possible fetal infection could enable early initiation of systemic antifungal treatment. It would be prudent to consider early delivery once fetal maturity is achieved despite normal fetal monitoring.

[Hungarian twin studies: results of four decades]. / Magyarországi ikerkutatások: négy évtized eredményei.

Twin studies play a role in examining the contribution of genetic variations and environmental factors responsible for the determination of phenotypic variables and of genetic linkage between genotypes. Hungarian twin studies, supported by three twin registries (among them two twin-database), date back to 1970s. Studies mainly focused on various congenital abnormalities, the effect of contraceptive pills and folic acid on the frequency of twin pregnancies, as well as psychosexual and alcohol consumptional behaviors. Monogenic Mendelian inheritance of lactose (mal)absorption was demonstrated for the first time. Hungarian Twin Registry was founded in 2007, which contributed to the current understanding on the background of several disorders, e.g. metabolic syndrome and atherosclerosis. As part of an international twin study, among others, arterial stiffness, central blood pressure, carotid intima/media thickness, venous biomechanics, body composition, lung function and smoking characteristics were also assessed. Absence of genetic background in non-alcoholic fatty liver disease and high inheritance of carotid plaque characteristics were demonstrated for the first time. The review also aims to summarize future plans of the Hungarian Twin Registry.

Reproductive hormone concentrations in pregnancy and neonates: a systematic review.

Although much research focuses on hormones during gestation, little is known about the actual hormone concentrations within the fetal surroundings. The aim of this study was to combine all available oestrogen, androgen, sex hormone-binding globulin (SHBG), anti-Müllerian hormone (AMH), inhibin, gonadotrophin and dehydroepiandrosterone sulphate (DHEAS) concentrations during gestation and post partum into graphical representations reporting weighted mean hormone values. A systematic search was performed in Pubmed and Embase from inception to March 2012. Studies were evaluated by two reviewers; manuscripts were included if the actual hormone concentrations were reported together with the gestational age at time of sampling. A total of 97 articles were found eligible for this review. Maternal serum oestrogens, inhibin A, SHBG, androstenedione and testosterone rise during gestation, which is followed by a rapid decline in the post-partum period. For AMH and DHEAS, an inverse relationship is found, while gonadotrophin concentrations are negligible during gestation. For girls cord blood oestriol and post-partum FSH concentrations are higher, while for boys cord blood FSH and neonatal testosterone, inhibin B, LH and AMH concentrations are higher. In conclusion, longitudinally measured endocrine data during gestation and in the peri- and post-natal period are lacking, especially for twin pregnancies.

Relationship between 17-hydroxyprogesterone caproate concentrations and gestational age at delivery in twin gestation.

OBJECTIVE: We sought to evaluate in women with twin gestation the relationship between 17-hydroxyprogesterone caproate (17-OHPC) concentration and gestational age at delivery and select biomarkers of potential pathways of drug action. STUDY DESIGN: Blood was obtained between 24-28 weeks (epoch 1) and 32-35 weeks (epoch 2) in 217 women with twin gestation receiving 17-OHPC or placebo. Gestational age at delivery and concentrations of 17-OHPC, 17-hydroxyprogesterone, progesterone, C-reactive protein (CRP), and corticotrophin-releasing hormone were assessed. RESULTS: Women with higher concentrations of 17-OHPC delivered at earlier gestational ages than women with lower concentrations (P < .001). Women receiving 17-OHPC demonstrated significantly higher (P = .005) concentrations of CRP in epoch 1 than women receiving placebo but CRP values were similar in epoch 2 in both groups. A highly significant (P < .0001) positive relationship was observed between 17-OHPC concentration and progesterone and 17-hydroxyprogesterone concentrations at both epochs. Corticotropin-releasing hormone concentrations did not differ by treatment group. CONCLUSION: 17-OHPC may adversely impact gestational age at delivery in women with twin gestation.

Placenta share discordance and umbilical artery Doppler change after antenatal betamethasone administration in monochorionic twins with selective intrauterine growth restriction: is there a link?

This study was designed to evaluate the degree of placenta share discordance in relation to the betamethasone-induced return of positive end-diastolic flow in monochorionic twin pregnancies with selective intrauterine growth restriction (sIUGR) and abnormal umbilical artery Doppler. Monochorionic twins with sIUGR was defined as one twin having an estimated fetal weight below the 10th percentile combined with an estimated fetal weight discordance >25%. The umbilical artery Doppler directly prior to (D0) and 24 hours (D1) and 48 hours (D2) after the first dose of betamethasone administration was recorded. The estimated individual placental weight in monochorionic twins was obtained by cutting the placenta along the vascular equator into two territories; the placenta share discordance was calculated as [(estimated individual placental weight of appropriated for gestational age twin- estimated individual placental weight of growth restricted twin)/estimated individual placental weight of appropriated for gestational age twin] × 100%. Six (23.1%) of the 26 included cases achieved betamethasone-induced return of positive umbilical artery end-diastolic flow. The difference of placenta share discordance and birth weight discordance were not significantly different between twins with and without betamethasone-induced return of positive umbilical artery end-diastolic flow. Thus, according to our study results, it was proposed that although the placenta share discordance correlated with the abnormal umbilical artery Doppler in the IUGR fetus in monochorionic twin, the betamethasone-induced return of positive umbilical artery end-diastolic flow, however, did not reveal the similar relationship with the severity of placenta share discordance.

Progestogens to prevent preterm birth in twin pregnancies: an individual participant data meta-analysis of randomized trials.

BACKGROUND: Preterm birth is the principal factor contributing to adverse outcomes in multiple pregnancies. Randomized controlled trials of progestogens to prevent preterm birth in twin pregnancies have shown no clear benefits. However, individual studies have not had sufficient power to evaluate potential benefits in women at particular high risk of early delivery (for example, women with a previous preterm birth or short cervix) or to determine adverse effects for rare outcomes such as intrauterine death. METHODS/DESIGN: We propose an individual participant data meta-analysis of high quality randomized, double-blind, placebo-controlled trials of progestogen treatment in women with a twin pregnancy. The primary outcome will be adverse perinatal outcome (a composite measure of perinatal mortality and significant neonatal morbidity). Missing data will be imputed within each original study, before data of the individual studies are pooled. The effects of 17-hydroxyprogesterone caproate or vaginal progesterone treatment in women with twin pregnancies will be estimated by means of a random effects log-binomial model. Analyses will be adjusted for variables used in stratified randomization as appropriate. Pre-specified subgroup analysis will be performed to explore the effect of progestogen treatment in high-risk groups. DISCUSSION: Combining individual patient data from different randomized trials has potential to provide valuable, clinically useful information regarding the benefits and potential harms of progestogens in women with twin pregnancy overall and in relevant subgroups.

Thyroid aplasia in male sibling of heterozygotic twins born to the hyperthyroid mother treated with propylthiouracil during pregnancy (case report).

UNLABELLED: A 30-year-old pregnant female was diagnosed to have thyrotoxicosis (TSH= 0.005 µU/ml) at 13th week of gestation. Propylthiouracil (PTU; 200 mg daily) was prescribed to her and four weekly follow ups by the endocrinologist and obstetrician were ensured. At each examination TSH, FT4 and FT3 levels were normal and she became symptom free. Repeated ultrasound examination throughout the pregnancy did not reveal any fetal abnormality. The lady normally delivered heterozygotic twins. Umbilical cord blood of the baby boy twin showed a high TSH (541 µU/ml; reference range 0.270 - 4.20 µU/ml). He was started on thyroxine therapy (50 µg once daily). Ultrasound reported the absence of the thyroid gland. One month later TSH was within normal range and thyroxine dose was adjusted to 25 µg once daily. Repeated ultrasound confirmed the absence of thyroid gland. TSH was repeatedly normal. The boy is currently doing well on thyroxine replacement therapy. The other non-identical twin was a healthy girl with normal thyroid function tests and always thereafter. This case report suggested that PTU could be a hazardous drug to the fetus, since the mother gave birth to a baby with thyroid aplasia. KEYWORDS: PTU, Thyroid aplasia, Thyrotoxicosis, TSH.

Pharmacokinetics of 17-hydroxyprogesterone caproate in multifetal gestation.

OBJECTIVE: The purpose of this study was to define the pharmacokinetic parameters of 17-hydroxyprogesterone caproate (17-OHPC) in multifetal gestation. STUDY DESIGN: Blood was obtained at 24-28 weeks' gestation and at 32-35 weeks gestation in 97 women with twin and 26 women with triplet gestation who were receiving 17-OHPC. Six of the women with twins had daily blood sampling for 7 days between 24 and 28 weeks' gestation, and pharmacokinetic parameters were estimated with the use of noncompartmental analysis. Modeling was applied to estimate the population parameters and to simulate various treatment scenarios. RESULTS: The apparent half-life of 17-OHPC was 10 days. Body mass index significantly impacted 17-OHPC concentrations, but fetal number and parity did not. Apparent clearance was significantly greater in African American than in white women (P = .025). CONCLUSION: This is the first pharmacokinetic analysis of 17-OHPC in pregnant women. Determination of half-life, covariates that affect plasma 17-OHPC concentrations, and the modeling of drug behavior provide insights into this drug's pharmacologic properties during multifetal pregnancy.