Pregnancy outcomes,embryonic and fetal development in maternal exposure to chinese medicines

Chinese medicine is a common name for a collection of Chinese Materia Medica with therapeutic properties for medical treatment and healing. Similar to Western pharmaceuticals, Chinese medicines are not free of risk, and have the potential to cause adverse pregnancy outcomes and affect embryonic and fetal development. However, most clinical data concerning safety of maternal exposure to Chinese medicines during pregnancy are not available and the conclusion remains elusive. Some individual clinical trials of Chinese medicines reported some minor adverse effects during pregnancy, whereas few animal studies identified some adverse maternal and perinatal effects, as well as embryotoxic potentials. Basic research and mechanistic studies of the teratogenicity of Chinese medicines are still lacking. There is an urgent need for testing the safety of Chinese medicines before recommendation and commercialization. Until more reliable and scientific research data become available, clinicians should consider both the risks and benefits before recommending Chinese medicines to pregnant women. More systematic investigations of the safety implications of the use of Chinese medicines are highly recommended, in addition to more clinical trials with a larger sample size to confirm its safety during pregnancy. This review includes a critical overview of available clinical and experimental data and provides directions to study the safety issue of Chinese medicines for pregnancy. Birth Defects Research (Part C) 99:275–291, 2013. © 2013 Wiley Periodicals, Inc.     

Influence of maternal age, gestational age and fetal gender on expression of immune mediators in amniotic fluid

ABSTRACT: BACKGROUND: Variations in cytokine and immune mediator expression patterns in amniotic fluid due to gestational age, maternal age and fetal gender were investigated. METHODS: Amniotic fluid samples were obtained from 192 women, 82 with a mid-trimester amniocentesis (median gestational age 17 weeks) and 110 with a caesarean section not in labor (median gestational age 39 weeks). Amniotic fluid was screened by commercial ELISAs for the TH1/TH2/TH17 cytokines and immune mediators IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-15, IL-17, TNF alpha, GROalpha, MIP1alpha, MIP1beta, histone, and IP10. Analysis was by Bonferroni correction for multiple comparisons. RESULTS: None of the 15 examined cytokines revealed any differences in expression patterns regarding fetal gender and age of the mothers. Significant differences were found in IL-4, IL-10, IL-12 TNF- alpha and MIP1-beta with respect to gestational age. CONCLUSIONS: Cytokines utilized as biomarkers in the diagnosis of intrauterine infections are not influenced in their expression pattern by fetal gender or maternal age, but may vary with respect to gestational age.     

Persistently low natural killer cell activity, age, and environmental stress as predictors of infectious morbidity.

In recent studies of 'low natural killer (NK) cell syndrome', low NK activity was measured in individuals who were symptomatic, and therefore a causal relationship between low NK activity and infectious or other disease manifestations could not be concluded. However, preliminary work by members of our collaborative team (S.L. and R.H.) provided some indications for chronic low NK activity preceding and predicting subsequent infectious morbidity. This present study was designed to address this causal question in a larger sample, using a longitudinal design. Subjects were 106 healthy normal volunteers from the community. They were examined medically and psychosocially at baseline, and were then followed over a 6-month interval, with serial monthly assessments over the study period. The results supported our hypothesis that individuals who were currently healthy, but who exhibited a pattern of natural immunity characterized by persistently low NK cytotoxicity would be at risk for development of infectious sequelae over a 6-month follow-up period. The results also showed that younger age and the perception of more severe 'hassles' or stressors also predicted more infectious morbidity during the 6-month study period. Chronological age appeared to have both a direct, as well as indirect (via NK activity) association with illness outcome. Contrary to our expectation, the report of environmental stressors was directly associated with illness outcome, but not indirectly associated with outcome via natural immunity.     

Mediators of fetal inflammation in extremely low gestational age newborns

To establish levels of mediators of inflammation in cord blood and postnatal serum from extremely low gestational age newborns (ELGANs, < or =28 weeks), we measured sixteen markers of inflammation by recycling immunoaffinity chromatography in 15 ELGANs who had serum sampled at days 2-5. Median levels of IL-1, IL-6, IL-8, IL-11, IL-13, TNF-alpha, G-CSF, M-CSF, GM-CSF, MIP-1alpha, and RANTES were considerably higher than published values of these inflammatory mediators from term newborns. In three of eight ELGANS who had serial measurements taken, levels of IL-1, IL-6, IL-8, IL-11, TNF-alpha, G-CSF, and MIP-1alpha declined from initially very high levels to reach an apparent baseline towards the end of the first postnatal week. In these same three infants, GM-CSF and TGF-beta1 levels increased continuously during the first week. In the other five ELGANs, no consistent changes were observed. We speculate, that in some ELGANs, a fetal systemic inflammatory response is characterized by an antenatal wave of pro-inflammatory cytokines, followed by a second, postnatal wave of anti-inflammatory cytokines. Large epidemiologic studies are needed to clarify relationships among inflammation markers and their expression in the fetal and neonatal circulation over time. Such studies would also add to our understanding of the possible role of inflammatory mediators in the pathophysiology of the major complications of extreme prematurity.     

Down syndrome, water fluoridation, and maternal age

It has been claimed that there is a positive association between the frequency of Down syndrome and the fluoridation of drinking water. It has also been suggested that this association is most pronounced in young women. Recent congenital malformations data obtained from birth certificates from large U.S. cities have been analyzed. Some cities had fluoridated water supplies, while others had supplies deficient in fluoride. The rates of Down syndrome in the cities with fluoridated and in those with non-fluoridated water supplies were comparable. In addition, there was no indication of any maternal age-specific association.     

Organ and gestational age effects of maternal nutrient restriction on global methylation in fetal baboons

Background  A sub-optimal intrauterine environment alters the trajectory of fetal development with profound effects on life-time health. Altered methylation, a proposed epigenetic mechanism responsible for these changes, has been studied in non-primate species but not nonhuman primates. We tested the hypotheses that global methylation in fetal baboon demonstrates organ specificity, gestational age specificity, and changes with maternal nutritional status.
Methods  We measured global DNA methylation in fetuses of control fed (CTR) and nutrient restricted mothers fed 70% of controls (MNR) for brain, kidney, liver and heart at 0.5 and 0.9 gestation (G).
Results  We observed organ and gestation specific changes that were modified by maternal diet. Methylation in CTR fetuses was highest in frontal cortex and lowest in liver. MNR decreased methylation in 0.5G kidney and increased methylation in 0.9G kidney and frontal cortex.
Conclusion  These results demonstrate a potential epigenetic mechanism whereby reduced maternal nutrition has long-term programming effects on fetal organ development.     

The baboon model (Papio hamadryas) of fetal loss: maternal weight,age, reproductive history and pregnancy outcome

Background Several risk factors are associated with the incidence of human stillbirths. The prevention of stillbirths in women is a pressing clinical problem. Methods We reviewed 402 pathology records of fetal loss occurring in a large baboon (Papio spp.) colony during a 15‐year period. Clinical histories of 565 female baboons with one or more fetal losses during a 20‐year period were analyzed for weight, age, and reproductive history. Results Fetal loss was most common at term (35.57%) and preterm (28.61%) and less common in the first half of gestation (11.20%) and post‐term (5.22%). Greater maternal weight, older age, history of stillbirth and higher parity were independent predictors for stillbirth. An exponential increase in the incidence of fetal loss was observed beginning at age 14 years in baboons. Conclusions Fetal loss and maternal risk factors associated with stillbirths in baboons were similar to those documented in women.     

Causes of low utilization of amniocentesis by women of advanced maternal age

Abstract

The objectives of this study were to determine current usage of amniocentesis by women of advanced maternal age in a southwestern Ohio county and to determine potential usage levels by surveying women not utilizing the procedure to understand their reasons. For women age 35 and older giving birth in Hamilton County, Ohio, the estimated percentage using amniocentesis was 3.9 in 1978, 7.6 in 1979, and 13.3 in 1980. Approximately comparable statewide utilization rates were 7.0, 11.5, and 17.2 respectively. A telephone survey during the summer of 1980 of 81 Hamilton County women age 35 and older recently giving birth to a normal baby found four main reasons why they did not utilize amniocentesis: (1) they did not feel at an increased risk (29.6 per cent); (2) they had never heard of the test (24.7 per cent); (3) they were opposed to abortion (21.0 per cent); and (4) no one suggested they have the test done (19.8 per cent). Their physicians reported that 81 per cent of these women had received prenatal counseling. Thus, of those counseled, over two‐thirds apparently missed at least one essential message of the counseling they were presumably provided. These findings, coupled with 47.7 per cent of women who knew about amniocentesis saying they would most likely use it if they became pregnant again and their physician recommended it, indicate that utilization of prenatal diagnosis by at least 50 per cent of women age 35 and older is likely with greater public education and greater support of the procedure by obstetricians.     

Chromosome abnormalities and spontaneous fetal death following amniocentesis: Further data and associations with maternal age

The pooled results are presented of two North American surveys concerning spontaneous fetal deaths of conceptuses with cytogenetic abnormalities diagnosed prenatally whose mothers had declined elective abortion. The rate of fetal death of those with nonmosaic genotypes associated with Down syndrome was 30.1% (95% confidence interval of 19.0%–42.0%), which is almost identical with the difference of 30% previously estimated between rates observed at amniocentesis and in live births. The fetal death rate for (nonmosaic) 47,+18 was 68.0% (95% confidence interval of 46.5%–85.1%), close to the estimated difference of 75% between rates at amniocentesis and in live births for this genotype. For other nonmosaic genotypes, the rates (and 95% confidence intervals) were: 47,+13, 42.9% (9.9%–81.6%); 47,XXX, 0% (0%–9.0%); 47,XXY, 8.1% (0.8%–11.0%); 47,XYY, 3.0% (.08%–15.8%); for balanced translocations and inversions, 2.8% (0.3%–9.8%); and for markers, variants, and fragments, 0% (0%–12.8%). For 45,X, the rate was 75.0% (42.8%–94.5%), in contrast to the rate for 46,XX/45,X of 10.5% (1.3%–33.1%) and for structural X abnormalities associated with Turner syndrome of 0% (0%–60.2%). The rate for nonmosaic 45,X is significantly different from that for either of the other two categories associated with Turner syndrome. The maternal age of nonmosaic 47,+21 fetuses that survived to live birth was 39.1 ± 6.2, not significantly different from the rate for fetal deaths: 39.5 ± 3.8. The observations provide no support for opposing hypotheses by other groups that maternal age is positively or negatively associated with fetal death of 47,+21 conceptuses. For other chromosome abnormalities, maternal ages of fetal deaths are slightly lower than for live births, but none of the differences are significant. The rates of spontaneous fetal deaths derived here are likely to be pertinent to genetic counseling. Their use in adjusting the rates of abnormalities diagnosed at amniocentesis will enable derivation of predicted contemporary live-birth prevalence rates of abnormalities that would be observed in absence of selective abortion.     

Effectiveness of intrapartum fetal surveillance to improve maternal and neonatal outcomes: a systematic review and network meta-analysis

BACKGROUND:Cesarean delivery is the most common surgical procedure worldwide. Intrapartum fetal surveillance is routinely offered to improve neonatal outcomes, but the effects of different methods on the risk of emergency cesarean deliveries remains uncertain. We conducted a systematic review and network meta-analysis to evaluate the effectiveness of different types of fetal surveillance.METHODS:We searched MEDLINE, Embase and CENTRAL until June 1, 2020, for randomized trials evaluating any intrapartum fetal surveillance method. We performed a network meta-analysis within a frequentist framework. We assessed the quality and network inconsistency of trials. We reported primarily on intrapartum emergency cesarean deliveries and other secondary maternal and neonatal outcomes using risk ratios (RRs) and 95% confidence intervals (CIs).RESULTS:We included 33 trials (118 863 patients) evaluating intermittent auscultation with Pinard stethoscope/handheld Doppler (IA), cardiotocography (CTG), computerized cardiotocography (cCTG), CTG with fetal scalp lactate (CTG-lactate), CTG with fetal scalp pH analysis (CTG-FBS), CTG with fetal pulse oximetry (FPO-CTG), CTG with fetal heart electrocardiogram (CTG-STAN) and their combinations. Intermittent auscultation reduced the risk of emergency cesarean deliveries compared with other types of surveillance (IA v. CTG: RR 0.83, 95% CI 0.72–0.97; IA v. CTG-FBS: RR 0.71, 95% CI 0.63–0.80; IA v.CTG-lactate: RR 0.77, 95% CI 0.64–0.92; IA v. FPO-CTG: RR 0.75, 95% CI 0.65–0.87; IA v.FPO-CTG-FBS: RR 0.81, 95% CI 0.67–0.99; cCTG-FBS v. IA: RR 1.21, 95% CI 1.04–1.42), except STAN-CTG-FBS (RR 1.17, 95% CI 0.98–1.40). There was a similar reduction observed for emergency cesarean deliveries for fetal distress. None of the evaluated methods was associated with a reduced risk of neonatal acidemia, neonatal unit admissions, Apgar scores or perinatal death.INTERPRETATION:Compared with other types of fetal surveillance, intermittent auscultation seems to reduce emergency cesarean deliveries in labour without increasing adverse neonatal and maternal outcomes.

Cesarean delivery is the most common surgical procedure worldwide, performed to expedite delivery and avoid neonatal complications. Fetal surveillance is routinely offered to patients in labour to reduce the risk of adverse neonatal outcomes, as well as the risk of unnecessary emergency cesarean deliveries and other maternal interventions. Fetal surveillance aims to detect intrapartum hypoxia from acute or subacute adverse events in labour requiring medical intervention and to reduce the risk of serious complications such as neonatal cerebral palsy, hypoxic–ischemic encephalopathy or stillbirth.Monitoring the fetal heart rate to detect intrapartum hypoxia using simple surveillance techniques, such as the Pinard stethoscope, has been practised for decades.¹ Over the last 50 years, several newer surveillance methods have been evaluated, with varied uptake in practice.² Cardiotocography (CTG) remains the most common surveillance method used in high-risk pregnancies.³ However, given its limited accuracy, many researchers have evaluated its use in combination with other surveillance methods, such as fetal heart electrocardiogram (STAN), fetal scalp pH analysis (FBS) or fetal pulse oximetry (FPO), and with computer-aided decision models (cCTG) to improve its diagnostic value.^4–6 Despite extensive investment in clinical research, the overall effectiveness of such methods in improving maternal and neonatal outcomes remains debatable as stillbirth rates have plateaued worldwide, while cesarean delivery rates continue to rise.^7,8Existing meta-analyses evaluating different intrapartum fetal surveillance methods remain limited to head-to-head comparisons of monitoring techniques, without a comprehensive assessment of their effectiveness in improving maternal and neonatal pregnancy outcomes.^4,9–13 We conducted a systematic review of randomized trials and a network meta-analysis to evaluate the effectiveness of all available fetal surveillance methods in improving maternal and neonatal outcomes.     

Thrombosis in pregnancy and maternal outcomes

Pregnancy increases the risk of thrombosis four‐ to five‐fold. Seventy‐five to eighty percent of pregnancy‐related thrombotic events are venous and twenty to –twenty‐five percent are arterial. The main reason for the increased risk is hypercoagulability. Women are hypercoagulable because they have evolved so that they are protected against the bleeding challenges of pregnancy, miscarriage, or childbirth. Both genetic and acquired risk factors can further increase the risk of thrombosis. The maternal consequences of thrombosis of pregnancy include permanent vascular damage, disability, and death. While the maternal outcomes of thrombosis can be modified by anticoagulation therapy, management of thrombosis during pregnancy is the subject of another paper in this issue (see paper by B. Konkle). This review will focus on the epidemiology, pathophysiology, risk factors, and maternal consequences of thrombosis in pregnancy. Birth Defects Research (Part C) 105:159–166, 2015. © 2015 Wiley Periodicals, Inc.     

Cohesin and the maternal age effect

During meiosis in human oocytes, chromosome nondisjunction increases with maternal age, leading to disorders such as Down's syndrome. In a recent study in Nature Genetics, Hodges et al. (2005) show that mice with a mutation in the meiosis-specific cohesin protein SMC1beta exhibit age-dependent defects in meiosis. These defects are similar to those observed in oocytes of older human mothers. Their results implicate an age-dependent loss of function in SMC1beta (or related proteins) in the maternal age effect of humans.     

Effect of maternal age on the outcomes of in vitro fertilization and embryo transfer (IVF-ET)

This is a retrospective, observational study to evaluate the effect of maternal age on the outcomes of in vitro fertilization and embryo transfer (IVF-ET). 11830 IVF-ET cycles from 10268 women were included. Four groups of different maternal age periods were compared. The groups were 21?C30 years old group (4549 cycles), 31?C35 years old group (4424 cycles), 36?C40 years old group (2429 cycles), and over 40 years old group (428 cycles). The mean starting dose of Gn and mean total dose of Gn in each cycle were significantly higher (P<0.01), while the mean retrieved oocyte number was significantly lower (P<0.01) in groups of higher maternal age period than those in each of the lower groups. The biochemical pregnancy rate and the clinical pregnancy rate were significantly lower (P<0.01), while the miscarriage rate was significantly higher (P<0.01) in groups of higher maternal age period than those in the lower groups. No difference was found in two-pronuclear zygotes (2PN) rate and good quality embryo rate among different groups. Birth defect rate was also comparable in the born babies in different groups. In the group with patients?? age over 40 years old, the pregnancy rate was 26.87%, the clinical pregnancy rate was 19.39%, while the miscarriage rate after clinical pregnancy was 36.14%. To draw the conclusion, patients with higher maternal age had worse IVF outcomes. In women of fertile age, patients between 20 and 30 years old have the best IVF outcomes. Patients over 40 years old have poor IVF outcome and high miscarriage rate, which suggested the necessity of preimplantation genetic screening (PGS).     

Reduction of severe acute maternal morbidity and maternal mortality in Thyolo District, Malawi: the impact of obstetric audit

Background

Critical incident audit and feedback are recommended interventions to improve the quality of obstetric care. To evaluate the effect of audit at district level in Thyolo, Malawi, we assessed the incidence of facility-based severe maternal complications (severe acute maternal morbidity (SAMM) and maternal mortality) during two years of audit and feedback.

Methodology/Principal Findings

Between September 2007 and September 2009, we included all cases of maternal mortality and SAMM that occurred in Thyolo District Hospital, the main referral facility in the area, using validated disease-specific criteria. During two- to three-weekly audit sessions, health workers and managers identified substandard care factors. Resulting recommendations were implemented and followed up. Feedback was given during subsequent sessions. A linear regression analysis was performed on facility-based severe maternal complications. During the two-year study period, 386 women were included: 46 died and 340 sustained SAMM, giving a case fatality rate of 11.9%. Forty-five cases out of the 386 inclusions were audited in plenary with hospital staff. There was a reduction of 3.1 women with severe maternal complications per 1000 deliveries in the district health facilities, from 13.5 per 1000 deliveries in the beginning to 10.4 per 1000 deliveries at the end of the study period. The incidence of uterine rupture and major obstetric hemorrhage reduced considerably (from 3.5 to 0.2 and from 5.9 to 2.6 per 1000 facility deliveries respectively).

Conclusions

Our findings indicate that audit and feedback have the potential to reduce serious maternal complications including maternal mortality. Complications like major hemorrhage and uterine rupture that require relatively straightforward intrapartum emergency management are easier to reduce than those which require uptake of improved antenatal care (eclampsia) or timely intravenous medication or HIV-treatment (peripartum infections).