Prenatal use of indomethacin for preterm labor and renal function among very low birth weight infants.

BACKGROUND: Indomethacin is administered as a tocolytic agent for threatening preterm labor <28weeks of gestation. Only a few, not conclusive, studies have investigated its nephrotoxicity in very low birth weight (VLBW) infants. We investigated whether indomethacin increases the incidence of acute kidney injury (AKI) among VLBW infants. METHODS: This is a retrospective study including all VLBW infants born at our center between January 1, 2005, and December 31, 2013. Indomethacin was administered to women with preterm labor and intact membranes. Neonatal AKI was defined according to KDIGO classification. Univariate analyses were performed comparing VLBW infants exposed to and not exposed to indomethacin. In the multivariable model, the association of indomethacin and AKI was adjusted for patent ductus arteriosus, use of nephrotoxic medications, birth weight, and gestational age. RESULTS: Five hundred seventy-five VLBW infants were included, 49 (8.5%) of whom were exposed to indomethacin in utero. The univariate analysis showed that infants exposed to indomethacin had lower birth weight, lower gestational age, and higher incidence of AKI than infants not exposed. The multivariable model adjusted for confounding factors confirmed an increased risk of AKI in relation to gestational age at birth <27 weeks, but not to indomethacin. CONCLUSIONS: Our data suggest that extreme prematurity, but not the use of indomethacin, is associated with AKI.

Neonatal hyperkalemia associated with maternal ritodrine: A retrospective study.

BACKGROUND: We recently reported on a late preterm infant born at 36 weeks' gestation with serious arrhythmia due to hyperkalemia associated with long-term maternal ritodrine administration. It is unknown whether ritodrine alone increases the risk of neonatal hyperkalemia in infants born at 34-36 weeks' gestation. METHODS: This single-center, retrospective, cohort study enrolled late preterm infants (34-36 gestational weeks) born between 2004 and 2018. Cases with maternal magnesium sulfate use were not sufficient for statistical analysis and so were excluded from the study. Risk factors for the occurrence of hyperkalemia were determined based on clinical relevance and previous reports. RESULTS: In all, 212 late preterm infants with maternal ritodrine use and 400 infants without tocolysis were included in the study. Neonatal hyperkalemia occurred in 5.7% (12/212) in the ritodrine group and 1.8% (7/400) in the control group. The risk of neonatal hyperkalemia was significantly increased by maternal ritodrine administration with a crude odds ratio (OR) of 3.37 (95% confidence interval [CI]: 1.30-8.69; p < 0.01) and an adjusted OR of 3.71 (95% CI: 1.41-9.74; p < 0.01) on multivariable analysis. Long-term tocolysis (≥28 days) with ritodrine increased the risk of neonatal hyperkalemia with 9.3% (11/118) of infants developing hyperkalemia (adjusted OR 4.86; 95% CI: 1.59-14.83; p < 0.01). Neonatal hyperkalemia was not found within 2 weeks of ritodrine administration. CONCLUSION: This research suggests that late preterm infants born after long-term ritodrine administration are at risk of neonatal hyperkalemia and require special attention.

Nicotine ameliorates inflammatory mediators in RU486 induced preterm labor model through activating cholinergic anti-inflammatory pathway.

BACKGROUND: Preterm birth is a global public health threat. Inflammatory reaction is thought to mediate preterm birth. The role of nicotine, an anti-inflammatory agent that is mediated by cholinergic anti-inflammatory pathways (CAP), remains unclear in the pathogenesis. METHODS: Pregnant rats were randomly divided into four groups (20 rats each): pregnant control group (P), RU486-treated group (PTL), RU486 and nicotine-treated group (PTL + N), RU486, nicotine and α-BGT treated group (PTL + N + A). Rats were administered RU486 (1.0 mg/kg) by subcutaneous injection on gestational day (GD) 18 to establish PTL model. Subcutaneous injection of nicotine (1 mg/kg) was administered daily from GD 16 to 18. α-BGT (1 µg/kg) was administrated subcutaneously in two sessions and each session was 30 min prior to nicotine. TNF-α, IL-1ß, IL-4, IL-6, IL-10 in myometrium and serum were detected by Luminex. Macrophage infiltration and α7nAChR were detected by IHC. RESULTS: We established a RU486-induced preterm labor rat model. Preterm labor was associated with a striking upregulation inflammatory mediators and increased macrophage infiltration. Nicotine significantly prolonged gestation (P < 0.05) and α-BGT treatment reversed the prolonged interval (P < 0.05). The cytokines all markedly elevated at 12 h, but deceased after delivery (P < 0.05). The IL-1ß and TNF-α in serum were significantly increased in PTL group vs P group (P < 0.05), and decreased after nicotine treatment (P < 0.05). The cytokines IL-1ß, IL-4, IL-6, IL-10 and TNF-α in myometrium increased as the same trend as in serum. Nicotine treatment also downregulated the expression of α7nAChR in pregnant tissue. CONCLUSION: We confirmed the increased inflammation in preterm birth. Nicotine was able to down-regulate the inflammatory mediates and prolong the pregnant duration in PTL model, which might be induced by activating α7nAChR through CAP. This study provides a novel evidence supporting the future development of therapeutic target for preterm birth.

Four kinds of tocolytic therapy for preterm delivery: Systematic review and network meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Premature birth affects more than 15 million infants, as well as mothers and families around the world. With the relaxation of the two-child policy, the problem of premature birth has become relatively prominent in China. According to statistics, China had a birth population of 15.23 million in 2018, with a considerably large number of premature births. This study aims to evaluate the efficacy and safety of tocolysis in the treatment of preterm delivery, provide clinical evidence for medical staff and promote the self-management of patients with premature births. METHODS: Four English databases (PubMed, Embase, Cochrane Library and Web of Science) were retrieved by computer, the retrieval time was from the establishment of each database to November 2021, and the randomized controlled trials for the treatment of preterm delivery were screened according to the pre-set natriuretic exclusion criteria. After literature screening, data selection and risk of bias evaluation were independently conducted by two researchers. R 4.1.1 and Stata 17.0 software were used for statistical analysis. RESULTS AND DISCUSSION: A total of 44 RCTs were included, including 6939 patients. The results of network meta-analysis reveal that in terms of effectiveness, indomethacin was the most effective intervention measure, followed by nifedipine, and the difference was statistically significant; regarding safety, nifedipine was the safest intervention measure, followed by indomethacin, and the difference was statistically significant; and in respect of adverse reactions, ritodrine had the highest probability, and the difference was statistically significant. WHAT IS NEW AND CONCLUSION: Nifedipine may be better for delayed delivery and less likely to produce adverse pregnancy outcomes, followed by indomethacin. Limited by the number and quality of recipient studies, the aforementioned conclusions need to be verified through more high-quality studies. At the same time, the focus should be on patients with twin pregnancy and patients with clinical manifestations of extreme preterm delivery.

Preterm Labor Using Tocolysis as a Possible Risk Factor for Postpartum Depression: A 14-Year Population-Based Study in Taiwan.

Postpartum depression (PPD) is associated with negative physical and mental health outcomes for the mother and infant. Women often experience elevated symptoms of PPD, and the incidence of PPD has increased in recent years. There were lack of studies to investigate the effects of medications during pregnancy. Herein, we focused on the most common obstetric medical therapies used in labor and determined whether the medical therapies cause mental stress in pregnant women. This 14-year retrospective population-based nationwide study was based on the National Health Insurance Research Database. Univariate and multivariate logistic regression analyses were used to evaluate unadjusted and adjusted odds ratios and 95% confidence intervals for each tocolytic and uterotonic treatments during pregnancy and common medical illnesses. In comparing the effects of tocolytic and uterotonic medications on maternal PPD, tocolysis with the injection form of ritodrine resulted in a significantly higher risk of PPD based on multivariate analysis. This study supports existing research demonstrating an association between tocolysis with ritodrine and PPD. Ritodrine treatment for preterm labor was a significant risk factor for PPD, especially the injection form. This information provides obstetricians and health policy providers to pay attention to maternal mental health outcomes among high-risk pregnant women.

Differences in environmental factors contributing to preterm labor and PPROM - Population based study.

BACKGROUND: Previous reports indicate an association between ambient temperature (Ta) and air pollution exposure during pregnancy and preterm birth (PTB). Nevertheless, information regarding the association between environmental factors and specific precursors of spontaneous preterm birth is lacking. We aimed to determine the association between Ta and air pollution during gestation and the precursors of spontaneous preterm parturition, i.e. preterm labor (PTL) and preterm prelabor rupture of membranes (PPROM). METHODS: From 2003 to 2013 there were 84,476 deliveries of singleton gestation that comprised the study cohort. Exposure data during pregnancy included daily measurements of temperature and particulate matter <2.5 µm and <10 µm, PM2.5 and PM10, respectively. Deliveries were grouped into PPROM, PTL and non-spontaneous preterm and term deliveries. Exposure effect was tested in windows of a week and two days prior to admission for delivery and adjusted to gestational age and socio-economic status. Poisson regression models were used for analyses. RESULTS: There is an association of environmental exposure with the precursors of spontaneous preterm parturition; PPROM was more sensitive to Ta fluctuations than PTL. This effect was modified by the ethnicity, Bedouin-Arabs were susceptible to elevated Ta, especially within the last day prior to admission with PPROM (Relative Risk (RR) =1.19 [95% CI, 1.03; 1.37]). Jews, on the other hand, were susceptible to ambient pollutants, two (RR=1.025 [1.010; 1.040]) and one (RR= 1.017 [1.002; 1.033]) days prior to spontaneous PTL with intact membranes resulting in preterm birth. CONCLUSION: High temperature is an independent risk factor for PPROM among Bedouin-Arabs; ambient pollution is an independent risk factor for spontaneous PTL resulting in preterm birth. Thus, the precursors of spontaneous preterm parturition differ in their association with environmental factors.

Aspects of Anesthesia for Breast Surgery during Pregnancy.

Non-obstetric surgery is needed in 0.75-2% of pregnant women, and safety of anesthesia for mother and child are key points at this time. Some breast diseases need to be approached in a short time interval, and surgery must be performed during pregnancy . In these cases, the technique of anesthesia regarding local, regional or general anesthesia and type of anesthetic medicine are selected based on the extent of the procedure, gestational age, and condition of the mother and child. The ideal timing for any surgery during pregnancy is in the second trimester because the risk of fetal adverse effects as well as preterm labor are lower. However, surgery of breast cancer during pregnancy is performed in any trimester as guided by treatment guidelines and is not deferred based on anesthesia preferences. Various types of anesthesia for breast surgery during pregnancy , preoperative and postoperative considerations are discussed in this chapter.

The comparison of side effects of methyldopa, amlodipine, and metoprolol in pregnant women with chronic hypertension.

OBJECTIVE: The aim of the study was to compare the complication of Antihypertensive drug; in pregnant women with chronic hypertension. METHOD: This retrospective cohort study was performed on 300 pregnant women  with chronic hypertension. Results:  a relative risk of preeclampsia among methyldopa group was 3.45 times higher than the metoprolol, the relative risk of preterm labor was not significantly between methyldopa and metoprolol group, LBW, and IUGR in methyldopa and amlodipine groups . CONCLUSION: Methyldopa and amlodipine are associated with the least side effects in pregnant women treated for chronic hypertension.the incidence of preeclampsia was greater in methyldopa group.

Quercetin Prevents Lipopolysaccharide-Induced Experimental Preterm Labor in Mice and Increases Offspring Survival Rate.

Premature labor is still a worldwide problem, causing serious social economic burden and family burden. Currently, there is no effective way to prevent preterm labor. Since inflammation increases the risk of preterm birth and quercetin is reported to have anti-inflammation, immune-enhancement, and antioxidative effects, this study aims to explore whether quercetin exerts inhibitory effect on preterm labor in mice and increases offspring survival. Lipopolysaccharide (LPS) is one of the commonly used drugs in the inflammatory animal model of preterm birth. On day 15 of pregnancy, mice received a dose of vehicle phosphate-buffered saline (PBS) or a dose of quercetin (low concentration, 30 mg/kg; medium concentration, 90 mg/kg; high concentrations, 150 mg/kg) via oral gavage. After 2 h, mice received a dose of LPS (50 µg/kg) or vehicle intraperitoneally (i.p.). In the absence of quercetin, a 100% incidence of preterm labor was observed in LPS-treated mice, and the fetuses were all died. Medium concentration of quercetin significantly prevented 63.5% of LPS-induced inflammatory preterm labor, and the survival rate of pups on day 22 was 83.76%. Specifically, quercetin significantly inhibited LPS-induced upregulation of NF-kappa-B/P65(RELA), AP-1/C-JUN(JUN), cyclooxygenase-2(PTGS2), and interleukin 6(IL6) in mice myometrium on mRNA level and inhibited the upregulation of P65 and C-JUN on protein level. Based on these observations, we concluded that quercetin exerts inhibitory effect on LPS-induced experimental mice preterm labor and increases offspring survival through a mechanism involving NF-κB/AP-1 pathway.

[Non-caloric sweeteners in women of reproductive age - A consensus document]. / Edulcorantes no calóricos en la mujer en edad reproductiva: documento de consenso.

INTRODUCTION: Non-nutritive sweeteners (NNS) are food additives that have been used as a possible tool to reduce energy and sugar intake. There is a scientific debate around the real benefits of their use. NNS are substances widely evaluated in the scientific literature. Their safety is reviewed by international regulatory health agencies. Health professionals and consumers often lack education and objective information about food additives based on the best scientific evidence. NNS have been used as a substitute for sucrose, especially by people with diabetes mellitus and obesity. However, concerns related to their possible association with preterm birth have been raised, and also with their use during pregnancy and lactation because of the possibility of metabolic or other consequences in both the mother and offspring. This analysis of the evidence in gynecology and obstetrics presents a review of the most commonly asked questions regarding this matter by health professionals and their patients. This document evaluates a diversity of scientific publications under the sieve of evidence-based medicine and the regulatory framework for food additives to elucidate whether the use of NNS in women in these critical stages of pregnancy and breastfeeding represents a potential risk.

INTRODUCCIÓN: Los edulcorantes no calóricos (ENC) son aditivos de alimentos que se utilizan para sustituir azúcares y potencialmente para reducir la ingesta energética. Existe un debate científico en torno a los beneficios reales de su uso. Los ENC son sustancias ampliamente evaluadas en la literatura científica. Su seguridad es revisada por las agencias regulatorias internacionales del campo de la salud. Los profesionales de la salud y los consumidores con frecuencia carecen de educación e información rigurosa, objetiva y sustentada en la evidencia científica y el juicio clínico sobre el uso de aditivos en los alimentos. Los ENC se han empleado como sustitutos de la sacarosa, en especial por las personas con diabetes mellitus y obesidad. Sin embargo, se han planteado inquietudes relacionadas con su posible asociación con el parto pretérmino y con su uso durante el embarazo y la lactancia, ante la posibilidad de consecuencias metabólicas o de otra índole en la madre o en el neonato. Este análisis de la evidencia en ginecología y obstetricia presenta una revisión que intenta responder a preguntas que habitualmente se hacen al respecto los profesionales de la salud y sus pacientes. En este documento se evalúan diversas publicaciones científicas bajo el tamiz de la medicina basada en la evidencia y del marco regulatorio para aditivos de alimentos con el fin dilucidar si el uso de ENC en las mujeres durante las etapas críticas del embarazo y la lactancia supone o no un posible riesgo.

CCR2 mediates the adverse effects of LPS in the pregnant mouse.

In our earlier work, we found that intrauterine (i.u.) and intraperitoneal (i.p.) injection of LPS (10-µg serotype 0111:B4) induced preterm labor (PTL) with high pup mortality, marked systemic inflammatory response and hypotension. Here, we used both i.u. and i.p. LPS models in pregnant wild-type (wt) and CCR2 knockout (CCR2-/-) mice on E16 to investigate the role played by the CCL2/CCR2 system in the response to LPS. Basally, lower numbers of monocytes and macrophages and higher numbers of neutrophils were found in the myometrium, placenta, and blood of CCR2-/- vs. wt mice. After i.u. LPS, parturition occurred at 14 h in both groups of mice. At 7 h post-injection, 70% of wt pups were dead vs. 10% of CCR2-/- pups, but at delivery 100% of wt and 90% of CCR2-/- pups were dead. Myometrial and placental monocytes and macrophages were generally lower in CCR2-/- mice, but this was less consistent in the circulation, lung, and liver. At 7 h post-LPS, myometrial ERK activation was greater and JNK and p65 lower and the mRNA levels of chemokines were higher and of inflammatory cytokines lower in CCR2-/- vs. wt mice. Pup brain and placental inflammation were similar. Using the IP LPS model, we found that all measures of arterial pressure increased in CCR2-/- but declined in wt mice. These data suggest that the CCL2/CCR2 system plays a critical role in the cardiovascular response to LPS and contributes to pup death but does not influence the onset of inflammation-induced PTL.

Pro-inflammatory cytokine-induced microRNA-212-3p expression promotes myocyte contraction via methyl-CpG-binding protein 2: a novel mechanism for infection-related preterm parturition.

Preterm labour is a common pregnancy complication contributing to major maternal and fetal morbidity and mortality. We have found microRNA (miR)-212-3p, a potential infection-associated molecule, was significantly over-expressed during human preterm labour. However, the mechanism remains unknown. In this study, we have adopted a lipopolysaccharide (LPS)-induced Institute of Cancer Research murine preterm model to examine the role of miR-212-3p in the infection-induced preterm labour. Myometrial miR-212-3p expression was increased by nearly 4-fold in the term labour group (P = 0.10) and 12-fold (P = 0.03) in the LPS-induced preterm labour group compared with the non-labour group. In vitro cellular experiments confirmed that a series of pro-inflammatory cytokines, including interleukin (IL)1B (P = 0.02) and IL-6 (P = 0.01), rather than LPS (P = 0.08) itself could significantly upregulate miR-212-3p expression in human myometrial smooth muscle cells. Methyl-CpG-binding protein 2 (MeCP2), as a target gene of miR-212-3p confirmed by our dual luciferase assay, influenced myocyte contractility and connexin 43 expression which is an important contraction-associated protein. Therefore, we conclude that miR-212-3p may be involved in infection-induced preterm labour through MeCP2 and it is a promoting molecule and novel target for the diagnosis and treatment of preterm labour in the future.

Inhibition of the NLRP3 inflammasome can prevent sterile intra-amniotic inflammation, preterm labor/birth, and adverse neonatal outcomes†.

Sterile intra-amniotic inflammation is commonly observed in patients with spontaneous preterm labor, a syndrome that commonly precedes preterm birth, the leading cause of perinatal morbidity and mortality worldwide. However, the mechanisms leading to sterile intra-amniotic inflammation are poorly understood and no treatment exists for this clinical condition. Herein, we investigated whether the alarmin S100B could induce sterile intra-amniotic inflammation by activating the NLRP3 inflammasome, and whether the inhibition of this pathway could prevent preterm labor/birth and adverse neonatal outcomes. We found that the ultrasound-guided intra-amniotic administration of S100B induced a 50% rate of preterm labor/birth and a high rate of neonatal mortality (59.7%) without altering the fetal and placental weights. Using a multiplex cytokine array and immunoblotting, we reported that S100B caused a proinflammatory response in the amniotic cavity and induced the activation of the NLRP3 inflammasome in the fetal membranes, indicated by the upregulation of the NLRP3 protein and increased release of active caspase-1 and mature IL-1ß. Inhibition of the NLRP3 inflammasome via the specific inhibitor MCC950 prevented preterm labor/birth by 35.7% and reduced neonatal mortality by 26.7%. Yet, inhibition of the NLRP3 inflammasome at term did not drastically obstruct the physiological process of parturition. In conclusion, the data presented herein indicate that the alarmin S100B can induce sterile intra-amniotic inflammation, preterm labor/birth, and adverse neonatal outcomes by activating the NLRP3 inflammasome, which can be prevented by inhibiting such a pathway. These findings provide evidence that sterile intra-amniotic inflammation could be treated by targeting the NLRP3 inflammasome.

Repurposing simvastatin as a therapy for preterm labor: evidence from preclinical models.

Preterm birth (PTB), the leading cause of neonatal morbidity and mortality, urgently requires novel therapeutic agents. Spontaneous PTB, resulting from preterm labor, is commonly caused by intrauterine infection/inflammation. Statins are well-established, cholesterol-lowering drugs that can reduce inflammation and inhibit vascular smooth muscle contraction. We show that simvastatin reduced the incidence of PTB in a validated intrauterine LPS-induced PTB mouse model, decreased uterine proinflammatory mRNA concentrations (IL-6, Cxcl1, and Ccl2), and reduced serum IL-6 concentration. In human myometrial cells, simvastatin reduced proinflammatory mediator mRNA and protein expression (IL-6 and IL-8) and increased anti-inflammatory cytokine mRNA expression (IL-10 and IL-13). Critically, simvastatin inhibited myometrial cell contraction, basally and during inflammation, and reduced phosphorylated myosin light chain concentration. Supplementation with mevalonate and geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate, abolished these anticontractile effects, indicating that the Rho/Rho-associated protein kinase pathway is critically involved. Thus, simvastatin reduces PTB incidence in mice, inhibits myometrial contractions, and exhibits key anti-inflammatory effects, providing a rationale for investigation into the repurposing of statins to treat preterm labor in women.-Boyle, A. K., Rinaldi, S. F., Rossi, A. G., Saunders, P. T. K., Norman, J. E. Repurposing simvastatin as a therapy for preterm labor: evidence from preclinical models.

Maternal serum arsenic level during pregnancy is positively associated with adverse pregnant outcomes in a Chinese population.

Arsenic is an environmental toxicant. The association of gestational arsenic exposure with adverse pregnant outcomes remains controversial. This study was to investigate the association of serum As level with adverse pregnant outcomes in a large Chinese cohort population. Total 3194 mother-and-infant pairs were recruited from the China-Anhui Birth Cohort Study. Maternal serum arsenic (As) concentration was measured using hydride generation-atomic fluorescence spectrometry. Subjects were divided into L-As group and H-As group in accordance to the 75th percentile of serum As concentration. The associations of serum As level during gestation with adverse pregnant outcomes were analyzed. The incidence of small-for-gestational-age (SGA) newborns was elevated in H-As group compared to L-As group (9.9% vs 7.6%, P = .044). After controlling confounders and stratified analysis, the adjusted OR for SGA was significant only in girls with H-As but not in boys. Moreover, the incidence of preterm delivery (PTD) was elevated in H-As group compared to L-As group (7.0% vs 4.8%, P = .016). Further analysis found that the adjusted OR for moderate-to-late PTD was 1.47 (95%CI: 1.03, 2.09; P = .034) in H-As group as compared with L-As group. These results indicate that maternal serum As level during gestation is positively associated with adverse pregnant outcomes.

Interleukin 22 prevents lipopolysaccharide- induced preterm labor in mice.

Preterm birth is widespread and causes 35% of all neonatal deaths. Infants who survive face potential long-term complications. A major contributing factor of preterm birth is infection. We investigated the role of interleukin 22 (IL22) as a potential clinically relevant cytokine during gestational infection. IL22 is an effector molecule secreted by immune cells. While the expression of IL22 was reported in normal nonpregnant endometrium and early pregnancy decidua, little is known about uterine IL22 expression during mid or late gestational stages of pregnancy. Since IL22 has been shown to be an essential mediator in epithelial regeneration and wound repair, we investigated the potential role of IL22 during defense against an inflammatory response at the maternal-fetal interface. We used a well-established model to study infection and infection-associated inflammation during preterm birth in the mouse. We have shown that IL22 is upregulated to respond to an intrauterine lipopolysaccharide administration and plays an important role in controlling the risk of inflammation-induced preterm birth. This paper proposes IL22 as a treatment method to combat infection and prevent preterm birth in susceptible patients.

Pregnancy outcome following in utero exposure to azathioprine: A French comparative observational study.

AIM OF THE STUDY: To evaluate whether azathioprine exposure during pregnancy increases the risk of birth defects and prematurity. METHOD: Prospective comparative observational study using the French pregnancy database TERAPPEL. To evaluate birth defects, outcomes of pregnancies exposed to azathioprine during the 1st trimester were prospectively assessed and compared to that of pregnancies exposed to another drug used for the same indications. Secondly, the rate of preterm births was compared between fetuses exposed to azathioprine at least during the third trimester and those exposed during the first trimester only. RESULTS: From 447 requests for a risk assessment for women receiving azathioprine during pregnancy, 193 pregnancies meet inclusion criteria. One hundred and twenty-four of them were exposed to azathioprine during the 1st trimester and were compared to that of 124 pregnancies exposed to another drug used for the same indication. Azathioprine use during the first trimester was not statistically associated with the risk of all birth defects ([7.3% vs. 5.4%]; [OR=1.36; 95%CI: 0.44-4.20]) nor with major birth defects (5.2% vs. 1.8% [OR=2.96; 95%CI: 0.56-15.64]). The rate of preterm births (22.5% vs. 27.3%, P=0.579) was similar regardless of the exposure period to azathioprine (at least during the third trimester or during the first trimester only). CONCLUSIONS: This study confirms that first trimester exposure to azathioprine is not associated with an elevated rate of birth defects and that the high rate of preterm births among women exposed to azathioprine is probably explained by the underlying maternal disease.

Behcet's disease and pregnancy: what to expect?

The relationship between Behcet's disease (BD) and pregnancy is only reported in limited number of studies. We retrospectively collected data of 26 women with BD diagnosis and their 66 pregnancies. We analysed patients according to disease activity, age at BD diagnosis, age at first/last pregnancy, obstetric history, obstetric complications, neonatal birthweight, associated foetal abnormalities and pregnancy-related complications. Sixteen miscarriages (24.2%), two intrauterine deaths (3%) and 48 live births (72.8%) were identified. Preterm labour was observed in 12 (24%) of 50 deliveries. Colchicine was used in six pregnancies, however, there was no drug treatment for BD in the remaining 59. There was a higher rate of preterm labour and low birthweight in patients using colchicine. BD was in remission in 60 (90.9%) of 66 pregnancies, and disease flared up only in six cases. In conclusion, BD patients with altered symptoms during pregnancy carry an increased risk of obstetric complications. IMPACT STATEMENT What is already known on this subject: There are limited and conflicting data about the interaction between BD and gestation. What the results of this study add: Our findings indicated that patients who were in an active symptomatic phase of BD and were being treated with colchicine had an increased risk of preterm delivery and low birthweight. What the implications are of these findings for clinical practice and/or further research: Clinicians should consider increased obstetric complication risk among patients with active BD.

Fetal growth and premature delivery in pregnant women on antiepileptic drugs.

OBJECTIVE: To evaluate the effects of epilepsy and antiepileptic drugs (AEDs) used during pregnancy on fetal growth and preterm delivery. METHODS: This study included singleton liveborn infants born to women enrolled in the North American Antiepileptic Drug Pregnancy Registry between 1997 and 2016. Data were collected prospectively through telephone interviews. The prevalence of preterm birth (<37 weeks) and small for gestational age status (SGA) among infants exposed prenatally to AEDs when used by women with epilepsy (WWE) or women without epilepsy (WWOE) was compared with that among infants unexposed to AEDs and born to WWOE. Multivariate log-binomial regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: The study population included infants born to 6,777 AED-WWE, 696 AED-WWOE, and 486 no-AED-WWOE. The risk of prematurity was 6.2% for no-AED-WWOE, 9.3% for AED-WWE (RR = 1.5, 95% CI = 1.0-2.1), and 10.5% for AED-WWOE (RR = 1.5, 95% CI = 1.0-2.4). Prenatal exposure to AEDs in WWE and WWOE was associated with a mean lower birth weight of 110 and 136g, respectively, as compared to no-AED-WWOE. The prevalence of SGA was 5.0% for no-AED-WWOE, 10.9% for AED-WWE (RR = 2.0, 95% CI = 1.3-3.0), and 11.0% for AED-WWOE (RR = 1.9, 95% CI = 1.2-2.9). Within users of AEDs in monotherapy, the prevalence of SGA ranged from 7.3% for lamotrigine to 18.5% for topiramate. INTERPRETATION: Women on AEDs during pregnancy, whether for epilepsy or for other neuropsychiatric indications, are at a higher risk of delivering prematurely and giving birth to SGA newborns. The risk may vary by drug. Ann Neurol 2017;82:457-465.

Maternal administration of melatonin exerts short- and long-term neuroprotective effects on the offspring from lipopolysaccharide-treated mice.

Preterm birth is a major contributor to early and delayed physical and cognitive impairment. Epidemiological and experimental data indicate that maternal infections are a significant and preventable cause of preterm birth. Recently, melatonin has been suggested to exert neuroprotective effects in several models of brain injury. Here, we sought to investigate whether the administration of melatonin is able to prevent lipopolysaccharide (LPS)-induced fetal brain damage in a model of LPS-induced preterm labor. For this purpose, 15-day pregnant BALB/c mice received intraperitoneally 2 doses of LPS or vehicle: the first one at 10:00 hours (0.26 mg/kg) and the second at 13:00 hours (0.52 mg/kg). On day 14 of pregnancy, a group of mice was subcutaneously implanted with a pellet of 25 mg melatonin. This experimental protocol resulted in 100% of preterm birth and pup death in the LPS group and a 50% of term birth and pup survival in the melatonin + LPS group. In the absence of melatonin, fetuses from LPS-treated mothers showed histological signs of brain damage, microglial/macrophage activation, and higher levels of IL-1ß, inducible nitric oxide synthase (NOS), and neuronal NOS mRNAs as well as increased histone acetyltransferase activity and histone H3 hyperacetylation. In contrast, antenatal administration of melatonin prevented LPS-induced fetal brain damage. Moreover, when behavioral traits were analyzed in the offspring from control, melatonin, and melatonin + LPS, no significant differences were found, suggesting that melatonin prevented LPS-induced long-term neurodevelopmental impairments. Collectively, our results suggest that melatonin could be a new therapeutic tool to prevent fetal brain damage and its long-term consequences induced by maternal inflammation.