With the development of perinatal medicine in China for more than 30 years, great progress has been made in the fight against infectious diseases associated with pregnancy, including better knowledge, improved clinical treatment, and more effective preventive measures. This article reviews and prospects the prevention and treatment of infectious diseases in pregnancy in China from the four aspects: mother-to-child transmission of acquired immune deficiency syndrome, syphilis, and hepatitis B; toxoplasma, others, rubella virus, cytomegalovirus, and herpes simplex virus infection; influenza and novel coronavirus infection; and sepsis.

Sepsis and septic shock are obstetric emergencies, which bring clinical issues for obstetricians to pay attention to, such as early identification and emergency intervention before transferring the patients to intensive care. Physiological changes during pregnancy and puerperium result in difficulty in identifying the clinical features of sepsis. Simple bedside screening tools can be used for early identification and screening for possible sepsis. If initial sepsis screening is positive with suspected or evidence of infection, regardless of the presence of fever, further evaluation of organ damage is required for the diagnosis of sepsis. Bundle therapy should be initiated within 1 h after the identification of sepsis: For pregnant women or puerpera with suspected or confirmed sepsis, bacterial culture (blood, urine, respiratory tract, and other body fluids) and serum lactate level detection should be conducted promptly, moreover, empirical broad-spectrum antibiotics given within 1 h are recommended; For patients with sepsis complicated by hypotension or organ hypoperfusion, it is recommended to administer 1-2 L crystal solution as soon as possible for liquid resuscitation; For those with persistent hypotension and/or organ hypoperfusion despite fluid resuscitation, vasopressors are recommended to maintain mean arterial pressure ≥65 mmHg (1 mmHg=0.133 kPa), with norepinephrine as the first-line vasopressor. When sepsis is suspected or confirmed, the focus of infection should be actively sought to effectively control the source. Termination of pregnancy should be considered individually and comprehensively on the basis of obstetric indications, gestational age, and maternal and fetal conditions, but not depend on sepsis alone. If intrauterine infection is confirmed, pregnancy should be terminated immediately. Cesarean delivery usually requires general anesthesia for pregnant women with sepsis and intraspinal anesthesia is relatively contraindicated. The diagnosis and treatment of sepsis in pregnancy and puerperium should be individualized in accordance with the corresponding guidelines.

Neutrophils plays an essential role in innate immunity. Neutrophil extracellular traps (NETs) are released by activated neutrophils in response to infection. However, excessive NETs can result in body dysfunction and organ damage and participate in several pathological conditions. This paper mainly focuses on the formation, regulatory mechanism and role of NETs in obstetric diseases, such as preeclampsia, gestational diabetes mellitus and preterm birth, and listed the current medications used to block the formation of NETs in obstetrics.

Objective:To investigate the effects of neutrophil extracellular traps (NETs) on the proliferation and apoptosis of human amniotic epithelial cells.Methods:NETs were induced in vitro from the neutrophil cells obtained from the peripheral blood of normal pregnant women before elective cesarean section at full-term. Human amniotic epithelial cell lines (WISH cells) were cultured in vitro, and were divided into four groups:(1) control group: without any stimulus; (2) NETs group: WISH cells were stimulated with NETs (500 ng/ml); (3) NETs+SB203580 (p38 kinase inhibitor) group: WISH cells were pretreated with SB203580 (5 μmol/L) for 30 min and then NETs (500 ng/ml) was added; (4) SB203580 group: only SB203580 was added. After stimulating for 48 h, cell proliferation assay, lactate dehydrogenase(LDH) assay, and flow cytometry assay were used to detect the cell proliferation rate, LDH level of cell supernatant, and cell apoptosis rate among different groups. The results were analyzed and compared using one-way analysis of variance and LSD- t test. Results:(1) Cell proliferation: The cell proliferation ratio in the NETs group was lower than that in the control group [(9.379±0.775)% vs (36.560±1.208)%, LSD- t=20.78, P<0.001]; and the figure in the NETs+SB203580 group [(27.920±0.926)%] was higher than that in the NETs group (LSD- t=14.18, P<0.001). (2)LDH: There was an increased LDH level in the cell supernatant of the NETs group compared with the control group (1.518±0.038 vs 0.274±0.004, LSD -t=44.25, P<0.05), and the LDH level in the NETs+SB203580 group (0.857±0.009) was decreased than that in the NETs group (LSD -t=23.51, P<0.001). (3) Apoptosis: Compared with the control group, the cell apoptosis level of the NETs group was increased [(14.290±0.141)% vs (10.110±0.044)%, LSD- t=21.76, P<0.001]; but that in the NETs+SB203580 group [(10.500±0.218)%] was lower than in the NETs group (LSD- t=19.70, P<0.001). Conclusion:p38/mitogen-activated protein kinases signaling pathway may be involved in the process of NETs, inhibiting proliferation and promoting apoptosis of human amniotic epithelial cells.

Objective:Chemiluminescence immunoassay was used to detect the levels of anticardiolipin antibody (aCL) -IgA/IgG/IgM and anti-β2-glycoprotein Ⅰ antibody (aβ2GPⅠ) -IgA/IgG/IgM in healthy non-pregnant and pregnant women to explore the changes of antiphospholipid antibody in different pregnancy periods.Methods:This prospective study was conducted in Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, involving normal pregnant women who underwent prenatal examination and healthy non-pregnant women with no history of adverse pregnancy who underwent progestational eugenic health examination from April 2020 to August 2021. The levels of aCL-IgA/IgG/IgM and aβ2GPⅠ-IgA/IgG/IgM were detected using BIO-FLASH chemiluminescence immunoassay analyzer and P95 as well as P99 were calculated, respectively. The difference in the six data between non-pregnant and pregnant women was compared using Mann-Whitney U test. Kruskal-Wallis H test was used to compare the change of each antibody in different pregnancy periods and Spearman correlation was used to analyze the correlation between different trimester and the levels of aCL-IgA/IgG/IgM and aβ2GPⅠ-IgA/IgG/IgM. Results:A total of 454 cases met the inclusion criteria, and 435 cases were included in the analysis after excluding 19 cases, among them 110 were non-pregnant women and 325 were pregnant women, including 110 cases in the first trimester (≤13 +6 weeks), 110 cases in the second trimester(14 +0-27 +6 weeks), and 105 cases in the third trimester (≥28 weeks). P99 value of aCL-IgA/IgG/IgM and aβ2GPⅠ-IgA/IgG/IgM in the non-pregnant women were 7.31, 14.70, 7.92, 3.58, 13.60, and 4.95 CU, which in the pregnant women were 5.90, 12.78, 5.70, 1.60, 10.65, and 3.90 CU, and were all lower than the cut-off value of 20 CU that given by the analyzer manufacturer. The levels of aCL-IgA/IgG/IgM, and aβ2GPⅠ-IgG/IgM in the pregnant women were significantly decreased comparing with the non-pregnant women [aCL-IgA: 1.90 CU (1.40-2.70 CU) vs 2.90 CU (2.20-3.83 CU), Z=－7.14; aCL-IgG: 3.00 CU (2.20-4.50 CU) vs 6.10 CU (4.20-7.83 CU), Z=－10.26; aCL-IgM: 1.40 CU (1.10-2.30 CU) vs 2.65 CU (2.08-3.73 CU), Z=－8.87; aβ2GPⅠ-IgG: 3.50 CU (2.60-4.90 CU) vs 4.75 CU (3.60-5.93 CU), Z=－5.45; aβ2GPⅠ-IgM: 0.70 CU (0.50-1.20 CU) vs 1.00 CU (0.60-1.53 CU) , Z=－3.73; all P<0.001]. The aCL-IgA level in the third trimester was higher than those in the first and second trimester (both P<0.05). The levels of aCL-IgG/IgM in the second trimester and aβ2GPⅠ- IgG in the second and third trimesters were significantly decreased than those in the first trimester (all P<0.05). Spearman analysis showed that aCL-IgG/IgM, aβ2GPⅠ-IgA/IgM had no significant correlation with the pregnancy period (the first, second and the third trimester) (all P>0.05). However, a weak correlation between the aCL-IgA, aβ2GPⅠ- IgG and the pregnancy period was observed ( r=0.28 and－0.49, both P<0.001) Conclusions:P99 value of aCL-IgA/IgG/IgM and aβ2GPⅠ-IgA/IgG/IgM levels in normal pregnant women and non-pregnant women are lower than the cut-off value of 20 CU given by the analyzer manufacturer. The levels of aCL-IgA/IgG/IgM and aβ2GPⅠ-IgG/IgM during pregnancy are lower than those before pregnancy and fluctuate with the pregnancy period, but have no significant correlation with the pregnancy period. The clinical diagnosis of antiphospholipid syndrome should be made according to the cut-off values of aCL-IgA/IgG/IgM and aβ2GPⅠ-IgA/IgG/IgM determined by each laboratory.

Multifetal pregnancies with monochorionicity are more complicated, for which pregnancy monitoring and intrauterine intervention are of great importance. For dichorionic triamniotic triplets with MC twin, multifetal pregnancy reduction measures included cardiac injection of potassium chloride at 11 to 14 weeks of gestation for reduction to monochorionic singleton, and radiofrequency ablation after 16 weeks of gestation to preserve the dichorionic diamniotic twins. Moreover no significant difference was observed in the pregnancy outcomes between the two methods. Fetalscopic laser surgery can significantly improve the perinatal prognosis of multiple pregnancies complicated by twin-to-twin transfusion syndrome. Umbilical occlusion and transection can be used for the reduction of triplets containing monochorionic monoamniotic twins to avoid fetal death caused by entanglement of the umbilical cord. Cardiac injection of potassium chloride is appropriate for reducing the two fetuses in the same chorionic sac for trichorionic quadruamniotic pregnancy. Selective fetal reduction is applicable for MC triplets or quadruplets pregnancy, however, relevant studies are all with a small sample size, which requires full consultation and individualized treatment.

Objective:To explore the correlation between prenatal clinical data with etiological diagnosis and neonatal outcome in isolated fetal ascites.Methods:Totally, 36 pregnancy cases diagnosed as isolated fetal ascites by ultrasound in Provincial Hospital Affiliated to Shandong University from June 22nd, 2016 to September 28th, 2018 were collected. Invasive prenatal diagnosis was performed by taking fetal cord blood, amniotic fluid, and fetal ascites respectively for cytogenetics, molecular genetics and biochemical examination and the impact of intrauterine therapeutic procedures on neonatal outcomes was evaluated as well. The correlation among prenatal examination, pathogeny and prognosis was analyzed by Fisher′s exact test.Results:(1) The prognosis of isolated fetal ascites initially presenting ≥28 weeks was better than that before 28 weeks, survival rate of 1-year-old were 13/15 and 9/17,respectively, the difference was statistically significant ( P<0.05). (2) The etiologic diagnosis rate of ascites before delivery was 31%(11/36), which increased to 53%(19/36) totally after birth. Characteristics of cases which were defined prenatally were as follows: 8 cases of digestive tract diseases showed ultrasonic abnormalities, including echogenic bowel, bowel dilatation and polyhydramnios; platelet level in umbilical cord blood of fetuses infected with cytomegalovirus were below 100 × 10 9/L in 2 cases; 1 case of urinary system malformation showed megalocystis and hydronephrosis. Cases which were defined causes after birth included: 3 fetuses with chyloperitonium presented persistent fetal ascites; 3 cases of digestive-related causes were rectal duplication with infection, mesentery stenosis, and intestinal atresia; other causes included Pierre-Robin syndrome and Budd-Chiari syndrome. (3) The live birth rate was 72% (26/36) and survival rate of 1-year-old was 61% (22/36). And 9/10 of infants who underwent surgeries got good outcomes. Fetal ascites due to abdominal or pelvic factors turned well in 13/16 of cases. Conclusions:The pregnancy outcome of fetal isolated ascites depends mainly on primary causes. Gastrointestinal abnormality is one of the most common causes. Excluded intrauterine infection, chromosomal abnormality and abnormal systemic ultrasonic findings, fetus with reduced ascites as the pregnancy progresses will get good outcome.

Objective: To investigate the safety and effectiveness of radiofrequency ablation (RFA) for selective fetal reduction in complex multiple pregnancies and analyze factors affecting perinatal outcomes. Methods: This was a retrospective case series of 156 patients undergoing selective fetal reduction by RFA in Provincial Hospital Affiliated to Shandong University from July 22th, 2011 to September 12th, 2018. They were divided into five groups according to surgical indications, including 46 cases in the monochorionic twins discordant for fetal anomalies group, 42 cases in the multiple pregnancies for reducing fetal numbers group, 40 cases in the twin to twin transfusion syndrome (TTTS) group, 24 cases in the selective intrauterine growth restriction (sIUGR) group and 4 cases in the twin reversed arterial perfusion sequence (TRAPS) group. According to the gestational age at surgery, patients were divided into two groups: the gestational age at surgery <20 weeks group (75 cases) and the gestational age at surgery≥20 weeks group (81 cases). According to the cycles of RFA required for surgery, patients were divided into two groups: one cycle group (124 cases) and ≥2 cycles group (32 cases). Basic information of patients, surgical process, postoperative complications and pregnancy outcomes were recorded. The growth and development of survival newborns were also followed up. Factors affecting perinatal outcomes were analyzed. Results: (1) The median gestational age at procedure of 156 patients was 20 weeks (14⁺⁵- 29⁺¹ weeks). The median cycles of RFA was 1 cycle (1-3 cycles), of which one cycle accounted for 79.5% (124/156). (2) Eleven (7.1%, 11/156) patients experienced intrauterine fetal death, 27 (17.3%, 27/156) patients miscarried, and the overall survival rate was 75.6% (118/156). Premature birth rate before 34 weeks was 19.5% (23/118). There were 129 neonates. The median gestational age at delivery was 37⁺³ weeks (28⁺²- 41⁺¹ weeks) with a mean birth weight of (2 657±700) g. (3) Analysis of pregnancy outcomes based on surgical indications found that, the gestational age at delivery [38 weeks (30⁺¹-41⁺¹ weeks), 36⁺⁴ weeks (29- 39 weeks), 36⁺⁴ weeks (28⁺²-39⁺⁵ weeks), 38 weeks (31-39⁺⁶ weeks), 38⁺³ weeks (30⁺⁴-38⁺⁴ weeks)] and neonatal birth weight [(2 820±671), (2 435±416), (2 497±843), (2 998±718), (2 517±1 087) g] were significantly different among fetal anomalies group, reducing fetal numbers group, TTTS group, sIUGR group and TRAPS group, respectively (all P<0.05). There were no significant differences in the pregnancy outcomes between gestational age at surgery <20 weeks group and gestational age at surgery ≥20 weeks group, or between one cycle group and ≥2 cycles group, respectively (all P>0.05). Conclusions RFA is a safe and effective procedure in treating complex monochorionic multiple pregnancies. Surgical indications would affect the gestational age at delivery and neonatal outcomes.

Objective To investigate the safety and efficacy of radiofrequency fetal ablation (RFA) in the treatment of monozygotic triplet and quadruplet pregnancies. Methods We analyzed retrospectively the clinical data of eight gravidas, including seven monozygotic triplets and one monozygotic quadruplets admitted to the Department of Obstetrics, Shandong Provincial Hospital Affiliated to Shandong University from March 2014 to January 2017. All of the eight women accepted ultrasound-guided selective fetal reduction by RFA to reduce to twins. Descriptive methods were used to analyze the perioperative status of the gravidas, maternal and fetal outcomes and neonatal follow-up. Results (1) In seven cases, the fetuses were deprived of blood flow after one heating cycle of radiofrequency ablation, while in the other, blood flow was stopped after two heating cycles. Heart beats of the reduced fetuses slowed down gradually after RFA, and stopped at 10, 20-25 and 40 minutes after operation in one, four and three cases, respectively. The conserved fetus showed normal heartbeats. (2) All patients accepted regular obstetrical examination after RFA. One was diagnosed with gestational diabetes mellitus at 26 weeks, and hospitalized for 4 d because of preterm labor at 30+6weeks. One women was hospitalized to receive a two-week tocolysis treatment one day after surgery, and diagnosed with severe preeclampsia at 35 weeks. One patient who had a fever six days after surgery and was hospitalized for antiinfection treatment progressed to inevitable abortion on the day of admission. The other five pregnant women had no abnormalities. (3) Except for one miscarriage, the rest seven cases all continued the pregnancy until delivery by cesarean, among which two with preterm premature rupture of membranes eventually delivered before term (35+1and 33 weeks), one with severe preeclampsia also preterm delivered (35+4weeks) and four term deliveries. Apgar scores at 1 and 5 minutes of all newborns were over 7. Three of the 14 newborns were hospitalized and recovered, including one pathological jaundice, one laryngeal stridor and one premature. The last follow-up in September 2018 of all 14 babies did not show any abnormalities. Conclusions RFA is a feasible treatment for monozygotic triplets and quadruplets.

OBJECTIVETo assess the value of combined fetal karyotyping and chromosomal microarray analysis (CMA) for the verification of high-risk pregnancy signaled by noninvasive prenatal screening (NIPS) based on high-throughput sequencing.

METHODSOne hundred and fifty-one pregnant women with high risks for aneuploidies of chromosomes 13, 18, 21, X and Y or pathological copy number variations (CNVs) by NIPS were subjected to amniocytic karyotyping and CMA analysis.

RESULTSOne hundred and forty-two women were found to have a high risk for fetal chromosomal aneuploidies, which included 83 cases of trisomy 21, 17 cases of trisomy 18, 2 cases of trisomy 13, and 40 cases of sex chromosome aneuploidies. Amniocytic karyotyping and CMA analysis has confirmed 81 cases of trisomy 21, 15 cases of trisomy 18, 10 cases of 47,XXY, 4 cases of 47,XXX, 2 cases of 47,XYY and 1 case of 46,X,del(X)(q26.1). Two trisomy 21, two trisomy 18, 2 trisomy 13, and 23 cases of sex chromosomal aneuploidies were verified as false positives. For 9 women with pathological fetal CNVs detected by NIPS, combined fetal karyotyping and CMA has confirmed 1 case of chromosome 13 microdeletion, 1 case of chromosome 18 microduplication, and 1 case of chromosome 18 deletion. For a case with 30 Mb duplication of chromosome 2 and 25 Mb duplication of chromosome 8, CMA analysis had no positive finding, while fetal umbilical cord blood karyotyping has yielded a 46,XX,dup(2)(p23.1p25.3)[13]/46,XX[87] karyotype. The remaining 5 cases were confirmed as false positive results.

CONCLUSIONCombined fetal karyotyping and CMA has provided a powerful tool for verifying high-risk fetuses signaled by NIPS.

Aneuploidy ; DNA Copy Number Variations ; Down Syndrome ; Female ; High-Throughput Nucleotide Sequencing ; methods ; Humans ; Karyotyping ; Microarray Analysis ; Pregnancy ; Prenatal Diagnosis ; Trisomy 13 Syndrome ; Trisomy 18 Syndrome