Triply discordant triplets: probability, management options, and risks.

The spontaneous occurrence of triplets is rare. With increased utilization of "assisted reproductive technologies," multifetal gestations have become more common. The empiric fetal risk for major malformation is approximately 3%. In a triplet pregnancy each fetus independently carries this risk so that the probability of having at least one malformed fetus is approximately 9%. It is much less likely to have 2 or 3 simultaneously but discordantly malformed fetuses in a multizygotic triplet gestation (.09% and .0027% risk, respectively). We report on the first case, to our knowledge, of an ovulation-stimulated triplet pregnancy complicated by 3-way discordance for major malformations diagnosed in the late second trimester by ultrasound. Fetus A was affected by congenital diaphragmatic hernia and trisomy 21; fetus B had encephalocele, a midline facial defect, and a cleft palate; and fetus C had evidence of unilateral claw hand but an otherwise normal fetal survey. At 19 weeks of gestation, fetus A was found to have spontaneously died, and a selective termination of triplet B was performed. We conclude: (1) the finding of a single major malformation in one fetus should lead to extensive search for malformations in all members of the pregnancy, and (2) the simultaneous occurrence of major malformations in more than one member of a multifetal gestation is a circumstance under which multiple selective termination deserves consideration. In this article we discuss important issues and caveats in the performance of selective termination for abnormal members of multifetal gestations.     

超声多普勒检测晚孕期妊娠高血压综合征胎儿静脉导管血流的临床价值

目的探讨超声多普勒对晚孕期妊娠高血压综合征（PIH）胎儿静脉导管血流检测的临床价值。方法将临床确诊为PIH、孕周为32—40周的胎）L85例作为研究组,随机抽取相同孕周正常胎）LI32例为对照组。除外糖尿病、心脏病、胎儿畸形、多胎等影响因素。以超声多普勒检测胎儿静脉导管（DV）血流,分析每例胎儿的频谱波形变化,检测并计算相关的血流参数,并追踪每一例胎儿出生结局。结果研究组胎）LDV搏动指数（PI）、阻力指教（RI）、静脉前负荷指数（PLI）、S／a较对照组增高,两组比较有统计学意义。PIH胎儿不良出生结局组DV血流参数较正常出生结局组增高,两组比较有统计学意义。结论检测PIH胎儿DV血流参数可作为了解胎儿宫内情况及预测出生结局的有效指标,对指导围产期处理有重要临床价值。     

Assistierte Reproduktionstechniken aus pädiatrischer Sicht

The number of multiple gestation births has increased due to assisted reproduction techniques. There is a higher risk of maternal and fetal complications in multifetal pregnancies compared with singletons. Twins have a five- to tenfold risk of preterm birth, which is even greater in higher multiple gestations. Increased morbidity and mortality are mainly caused by respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, and retinopathy, all of which are due to prematurity. Last but not least, one should not forget the emotional stress that parents of multiples are subjected to during pregnancy and after birth. Considering all these problems, multifetal pregnancies due to assisted reproduction techniques should be avoided, and the delivery of preterm twins should take place in a specialized perinatal unit.     

孕中期胎儿心血管畸形超声检测NT值与染色体核型检测的关系探讨

目的探讨孕中期胎儿心血管畸形超声检测NT值与染色体核型检测的关系。方法选取2015年1月至2017年12月因胚胎发育不良(心脏发育畸形或异常)于本院行产前检测的孕妇108例,所有产妇均于孕24~35w行超声NT检查和经腹脐静脉穿刺术取胚胎绒毛组织的染色体核型检测,观察染色体核型检测情况,分析染色体核型检测正常与异常胎儿的超声NT值差异,并采用spearman相关性分析法分析胎儿超声NT值与染色体核型检测是否正常的相关性。结果108例病例中,染色体核型检测正常者30例(27.78%),染色体核型检测异常者78例(占比72.22%)。染色体核型检测正常胎儿心血管超声NT层厚值(3.83±0.54mm)低于染色体核型检测异常胎儿(4.64±0.63mm)(P<0.05)。spearman相关性分析显示,胎儿超声NT值与染色体核型检测是否正常具有明显的负相关性(r=0.871,P=0.018<0.05)。15例继续妊娠至分娩的胎儿中,10例(包括7例染色体核型检查异常胎儿)出生后心脏功能发育异常(或畸形),其余5例出生后未出现心脏功能发育异常(或畸形),且随访至12个月仍未出现心脏功能发育异常(或畸形)。结论通过染色体核型检测对心血管畸形胎儿绒毛组织进行染色体核型检测,可发现染色体中小至100Kb片段的缺失或重复,也可发现潜在致病基因序列,孕中期胎儿心血管超声检测NT值与染色体核型检测是否正常具有明显相关性,可作为心血管发育畸形胎儿染色体核型检查的参考指标,超声检测NT检查和染色体核型检测在胎儿心血管畸形的临床诊断中均具有良好的前景。     

Fetal ultrasound abnormalities: Correlation with fetal karyotype,autopsy findings,and postnatal outcome—five-year prospective study

A 5-year prospective prenatal study in 151 pregnancies with 152 malformed fetuses detected by ultrasound was evaluated cytogenetically. Thirty-five fetuses (23%) had abnormal karyotypes. Specific anatomical fetal malformations identified by ultrasound increase the risk for fetal chromosome abnormalities. Risks of abnormal chromosomes in the fetus are present with both single and multiple anomalies including amniotic fluid volume although the risk is increased with specific anatomical systems and multiple malformations. An abnormal fetal karyotype was present in 17% with a single anatomical abnormality and 30% when two or more anatomical systems were involved. Fetal hydrops, duodenal atresia, and omphalocele were the most specific single ultrasound anomalies; fetal hydrops, IUGR, holoprosencephaly, congenital heart disease, diaphragmatic hernia, duodenal atresia, and omphalocele were the most specific multiple anomalies with abnormal amniotic fluid volume. Termination of pregnancy occurred in 32/58 patients diagnosed prior to the 20th week of pregnancy with most (31/32) having a chromosomal anomaly or severe fetal anomaly. Fetuses terminated after the 20th week had chromosomal (7/18) or lethal fetal anomalies (11/18). The most common aneuploidies were trisomy 21, trisomy 18, and 45,X. The decision to terminate the pregnancy was based in most cases on the fetal ultrasound findings. Correlation of ultrasound and clinical findings is important for accurate genetic counselling. © 1992 Wiley-Liss, Inc.     

Fetal ultrasound abnormalities: correlation with fetal karyotype, autopsy findings, and postnatal outcome--five-year prospective study.

A 5-year prospective prenatal study in 151 pregnancies with 152 malformed fetuses detected by ultrasound was evaluated cytogenetically. Thirty-five fetuses (23%) had abnormal karyotypes. Specific anatomical fetal malformations identified by ultrasound increase the risk for fetal chromosome abnormalities. Risks of abnormal chromosomes in the fetus are present with both single and multiple anomalies including amniotic fluid volume although the risk is increased with specific anatomical systems and multiple malformations. An abnormal fetal karyotype was present in 17% with a single anatomical abnormality and 30% when two or more anatomical systems were involved. Fetal hydrops, duodenal atresia, and omphalocele were the most specific single ultrasound anomalies; fetal hydrops, IUGR, holoprosencephaly, congenital heart disease, diaphragmatic hernia, duodenal atresia, and omphalocele were the most specific multiple anomalies with abnormal amniotic fluid volume. Termination of pregnancy occurred in 32/58 patients diagnosed prior to the 20th week of pregnancy with most (31/32) having a chromosomal anomaly or severe fetal anomaly. Fetuses terminated after the 20th week had chromosomal (7/18) or lethal fetal anomalies (11/18). The most common aneuploidies were trisomy 21, trisomy 18, and 45,X. The decision to terminate the pregnancy was based in most cases on the fetal ultrasound findings. Correlation of ultrasound and clinical findings is important for accurate genetic counselling.     

胎儿脐膨出和腹裂的发生情况及胎儿结局比较

目的探讨并比较当前胎儿脐膨出和腹裂的发生情况及胎儿结局比较。方法对北京市海淀区妇幼保健院2005年1月1日至2008年12月31日期间20例诊断为胎儿脐膨出和腹裂的孕妇的临床资料进行回顾性分析。结果 （1）8例胎儿脐膨出,孕妇平均年龄32.60岁,12例胎儿腹裂,孕妇平均年龄29.4岁;胎儿脐膨出孕妇平均孕次2.2次,胎儿腹裂孕妇平均孕次3次,仅1例胎儿腹裂孕妇有1次自然流产史,其它无不良孕产史记录。在性别方面无差异,脐膨出发生率为1.8/万（8/44094）,胎儿腹裂的发生率为2.7/万（12/44094）。（2）4例脐膨出伴发其它结构异常（50%）,3例伴有心脏畸形,2例腹裂伴发其它结构异常（16.7%）;1例脐膨出胎儿染色体检查异常（12.5%）,无腹裂胎儿染色体检查异常。（3）脐膨出首次发现孕周为12～31周,腹裂首次发现孕周为14～37周,脐膨出产前B超诊断率100%,腹裂的诊断率为75%。3例诊断胎儿脐膨出时为死胎（37.5%）,其中1例为围产儿死亡（12.5%）,18例孕妇选择引产终止妊娠。结论脐膨出常伴有其他先天畸形及染色体异常,围产儿死亡率高。近年来胎儿腹裂的发生率高于脐膨出,由于腹裂胎儿预后好于脐膨出胎儿,应加强脐膨出与腹裂之间的B超鉴别诊断,从而降低围产儿死亡率。     

Retinoic acid embryopathy

Retinoic acid, an analogue of vitamin A, is known to be teratogenic in laboratory animals and has recently been implicated in a few clinical case reports. To study the human teratogenicity of this agent, we investigated 154 human pregnancies with fetal exposure to isotretinoin, a retinoid prescribed for severe recalcitrant cystic acne. The outcomes were 95 elective abortions, 26 infants without major malformations, 12 spontaneous abortions, and 21 malformed infants. A subset of 36 of the 154 pregnancies was observed prospectively. The outcomes in this cohort were 8 spontaneous abortions, 23 normal infants, and 5 malformed infants. Exposure to isotretinoin was associated with an unusually high relative risk for a group of selected major malformations (relative risk = 25.6; 95 per cent confidence interval, 11.4 to 57.5). Among the 21 malformed infants we found a characteristic pattern of malformation involving craniofacial, cardiac, thymic, and central nervous system structures. The malformations included microtia/anotia (15 infants), micrognathia (6), cleft palate (3), conotruncal heart defects and aortic-arch abnormalities (8), thymic defects (7), retinal or optic-nerve abnormalities (4), and central nervous system malformations (18). The pattern of malformation closely resembled that produced in animal studies of retinoid teratogenesis. It is possible that a major mechanism of isotretinoin teratogenesis is a deleterious effect on cephalic neural-crest cell activity that results in the observed craniofacial, cardiac, and thymic malformations.     

Utilization of genetic counseling by parents of a child or fetus with congenital malformation in North-East Italy

Congenital malformations (CM) affect 2-3% of all births, the cause of which, when known, is genetic in 80-90% of cases. A genetic consultation (GC) is indicated for the parents of a child affected by a CM. This study analyzes the parental utilization of genetic counseling (GCU) and its possible influencing factors after termination of pregnancy (TOP) because of fetal anomalies or after the birth of a child affected by a major malformation. The study concerns cases in North-East Italy where there is a CM registry and a center-satellite system for genetic counseling. The results of this analysis are also compared to other similar studies, which address the same topic. Between 1981 and 2000, 1,235 out of 14,888 GC were performed because of the presence of a CM in a child/fetus. In the same period, 4,933 births and 1,112 TOPs were registered. The overall GCU was 19%, with significant differences according to malformative phenotype, severity of the malformative condition, type of birth, and viability. Genetic counseling was performed significantly sooner following TOP than after the birth of a malformed child. GCU showed an unequal distribution according to the parents' place of residence, suggesting that easy and equal access to the genetic service was probably not well provided for. Our results suggest that genetic services should be integrated with related services, and that the public and physicians need a greater awareness of these services.     

657del5 mutation in the gene for Nijmegen breakage syndrome (NBS1) in a cohort of Russian children with lymphoid tissue malignancies and controls

Gershoni-Baruch syndrome is a multiple congenital malformation complex characterized by omphalocele, diaphragmatic hernia, cardiovascular abnormalities, and radial ray defects. Autosomal recessive inheritance is suggested. We describe two additional cases from a single family (sister and brother) delivered through termination at 23 and 9 weeks of gestation, respectively. The first fetus showed a spectrum of schisis defects without any limb involvement while the second bore mainly malformations of hands and feet. The occurrence of two different syndromes in the same family is highly improbable, but, considering both malformation complexes as possible manifestations of the same disease, a diagnosis of Gershoni-Baruch syndrome appears the most reasonable. These new familial cases bring further support to the hypothesis of an autosomal recessive inheritance of this syndrome.     

Usefulness of a registry of congenital malformations for genetic counseling and prenatal diagnosis

During three years, 39,924 infants born consecutively in the area covered by our registry of congenital malformations were surveyed; 775 had major congenital malformations. Recurrence risks for the major malformation was estimated and classified as high (greater than 10%, 5.3% of the cases), low (1 to 10%, 85.3% of the cases) or occasional (less than 1%, 9.4% of the malformed). Feasibility of prenatal diagnosis was considered. On the basis of the recurrence risk of 1% or higher and the feasibility of prenatal diagnosis, such a procedure should be considered in future pregnancies in 64.1% of the mothers. Genetic counseling has to be given to couples at risk of having a malformed child. For this purpose, as is shown in our study, the best way is the possibility of using a registry of congenital malformations.     

Ring chromosome 18 in a fetus with only facial anomalies

We report on a prenatally detected case of ring chromosome 18 [46,XX,r(18)] in amniotic fluid cells of a fetus with an abnormal facial profile on ultrasound as the only malformation. The chromosome 18 origin of the ring chromosome, of a supernumerary marker chromosome in some cells, and of micronuclei was demonstrated by fluorescent in situ hybridization with a whole chromosome 18 paint (Cambio) and 18 centromere probe L1.84. DNA investigations showed deletions of 18p as well as 18q material of r(18), which turned out to be of paternal origin. Autopsy of the fetus after termination of pregnancy at 20 weeks of gestation showed no additional malformations, in agreement with the previous ultrasound findings. © 1996 Wiley-Liss, Inc.     

The caudal regression syndrome in infants of diabetic mothers

Ultrasonography as part of the pre-natal diagnosis in high risk pregnancies may detect a number of fetal malformations that need to be re-evaluated for continuation or termination of pregnancy. Two fetuses, in two different patients with diabetes mellitus, were found to have significant intrauterine malformations detected by ultrasonography at 18 and 20 weeks gestational age, respectively. Post-mortem examination on both fetuses demonstrated the findings known as the caudal regression syndrome. The clinico-pathological features and obstetrical management of diabetic mothers whose pregnancies are complicated with this rare malformation are discussed.     

Clinical Practice Guidelines for Prenatal Aneuploidy Screening and Diagnostic Testing from Korean Society of Maternal-Fetal Medicine: (2) Invasive Diagnostic Testing for Fetal Chromosomal Abnormalities

The Korean Society of Maternal Fetal Medicine proposed the first Korean guideline on prenatal aneuploidy screening and diagnostic testing, in April 2019. The clinical practice guideline (CPG) was developed for Korean women using an adaptation process based on good-quality practice guidelines, previously developed in other countries, on prenatal screening and invasive diagnostic testing for fetal chromosome abnormalities. We reviewed current guidelines and developed a Korean CPG on invasive diagnostic testing for fetal chromosome abnormalities according to the adaptation process. Recommendations for selected 11 key questions are: 1) Considering the increased risk of fetal loss in invasive prenatal diagnostic testing for fetal genetic disorders, it is not recommended for all pregnant women aged over 35 years. 2) Because early amniocentesis performed before 14 weeks of pregnancy increases the risk of fetal loss and malformation, chorionic villus sampling (CVS) is recommended for pregnant women who will undergo invasive prenatal diagnostic testing for fetal genetic disorders in the first trimester of pregnancy. However, CVS before 9 weeks of pregnancy also increases the risk of fetal loss and deformity. Thus, CVS is recommended after 9 weeks of pregnancy. 3) Amniocentesis is recommended to distinguish true fetal mosaicism from confined placental mosaicism. 4) Anti-immunoglobulin should be administered within 72 hours after the invasive diagnostic testing. 5) Since there is a high risk of vertical transmission, an invasive prenatal diagnostic testing is recommended according to the clinician''s discretion with consideration of the condition of the pregnant woman. 6) The use of antibiotics is not recommended before or after an invasive diagnostic testing. 7) The chromosomal microarray test as an alternative to the conventional cytogenetic test is not recommended for all pregnant women who will undergo an invasive diagnostic testing. 8) Amniocentesis before 14 weeks of gestation is not recommended because it increases the risk of fetal loss and malformation. 9) CVS before 9 weeks of gestation is not recommended because it increases the risk of fetal loss and malformation. 10) Although the risk of fetal loss associated with invasive prenatal diagnostic testing (amniocentesis and CVS) may vary based on the proficiency of the operator, the risk of fetal loss due to invasive prenatal diagnostic testing is higher in twin pregnancies than in singleton pregnancies. 11) When a monochorionic twin is identified in early pregnancy and the growth and structure of both fetuses are consistent, an invasive prenatal diagnostic testing can be performed on one fetus alone. However, an invasive prenatal diagnostic testing is recommended for each fetus in cases of pregnancy conceived via in vitro fertilization, or in cases in which the growth of both fetuses differs, or in those in which at least one fetus has a structural abnormality. The guidelines were established and approved by the Korean Academy of Medical Sciences. This guideline is revised and presented every 5 years.     

胎儿后颅窝池扩张在产前超声诊断中的意义

目的探讨胎儿后颅窝池扩张（ECM）（≥10 mm）在产前诊断中的意义。方法对胎儿ECM 66例（0.42%）进行观察分析,21例行染色体检查,继续妊娠者追踪产后情况。结果胎儿ECM以妊娠29～32w最多见（31/66,47.0%）;胎儿CM扩张程度与结构畸形的发生率呈正比,其差异有统计学意义（P〈0.005）;发现3例18-三体,均合并结构畸形,其中2例Dandy-Walker畸形;未合并结构畸形ECM除2例（≥15mm）出现轻度脑发育迟缓,余生长发育未见明显异常。结论胎儿ECM于孕中晚期出现并以29～32w多见;CM扩张程度越大,畸形的发生率越高;合并结构畸形尤其是Dandy-Walker畸形可能与18-三体有关;不合并结构的ECM胎儿预后尚好。     

Concurrent IVF and spontaneous conception resulting in a quadruplet pregnancy.

Blastocyst transfer of just one or two embryos has been used to help limit the number of high-order gestations. In this case report we describe the occurrence of a quadruplet pregnancy after the transfer of only two blastocysts during IVF. Sonographic examination showed four fetuses and what appeared to be quadriamniotic/quadrichorionic sacs, suggesting that a concomitant spontaneous conception had occurred. Definite confirmation of zygosity was obtained by genetic testing using DNA microsatellite polymorphism determinations after the birth of one boy and three girls at 32 weeks gestation. Although this event has not been reported previously, the possibility of its occurrence should be kept in mind. IVF patients with patent Fallopian tubes should be cautioned against intercourse late in their controlled ovarian stimulation, especially if they would decline multifetal reduction.     

Fetal gonadal histology in XXXXY, XYY and XXX syndromes

During a 3-year period in which 1500 amniotic fluid samples were studied, six cases of sex chromosome abnormality were detected antenatally: two with XXX, three with XYY and one with XXXXY sex chromosome constitution. After careful counselling, the parents in each case chose termination of the pregnancy, which was performed at the 20th week of gestation. All fetuses appeared normal and showed no gross malformations. Histologic investigation of the gonads of the XXXXY, one XYY and one XXX fetus showed a normal overall picture. The number of spermatogonia in the seminiferous tubules of the XXXXY male fetus was markedly reduced and the testes of the XYY fetus also contained less spermatogonia than testes from control fetuses.     

First trimester diagnosis of conjoined twins in a triplet pregnancy after IVF and ICSI: case report

A case of conjoined twins in a triplet pregnancy after in-vitro fertilization and intracytoplasmic sperm injection is described. The diagnosis was made by high-resolution vaginal sonography, as early as the eighth week of gestation. The third fetus, of different chorionicity, was normal. Selective termination was successfully done at 12 weeks. The possible association between assisted reproduction and conjoined twinning is discussed. The importance of expert early vaginal sonography of pregnancy resulting from assisted reproduction technology is emphasized.     

Pregnancy outcome after multifetal pregnancy reduction to twins compared with spontaneously conceived twins

Multifetal pregnancy reduction (MFPR) appears to be an efficaciousmethod for improving the perinatal outcome of ‘high order’multifetal gestations. The present study was undertaken to evaluatepregnancy outcomes after MFPR to twins in comparison with spontaneouslyconceived twins. In all, 10 patients with quadruplet gestations(group 1) and 30 patients with triplet gestations (group 2),who underwent MFPR to twins, were prospectively enrolled. Pregnancycomplications, gestational age at delivery, mode of deliveryand birthweights were compared with 30 consecutive spon-taneoustwin gestations (group 3) matched by maternal age and parity.Mean gestational age at delivery and mean birthweights weresignificantly lower in group 1, compared with groups 2 and 3(33.2, 35.9, 36.9 weeks, and 1843, 2209, 2361 g respectively).The incidence of pregnancy complications was significantly higherin group 1 compared with group 3. There was also a clear trendof increased incidence of specific pregnancy complications ingroup 1 compared with groups 2 and 3, especially premature contractions(PMC; 50, 27 and 13% respectively), and pregnancy-induced hypertension(PIH; 40, 23 and 7% respectively). In conclusion, the initialnumber of fetuses before reduction was inversely correlatedwith gestational age at delivery and birthweight, and positivelycorrelated with pregnancy complications. Contrary to previousstudies, we found a higher incidence of pregnancy complicationsafter MFPR compared with spontaneous twins, especially PMC andPIH.     

Attitudes of German infertile couples towards multiple births and elective embryo transfer

BACKGROUND: In Germany, embryo screening programmes combined with elective embryo transfer are illegal, but there is controversial debate about their legalization. Studies about the attitudes of infertile couples towards multiples, elective embryo transfer and multifetal reduction may help to illuminate how this law shapes patient choices. METHODS: A survey of 265 German infertile couples was conducted. Different logistic regression analyses were performed to assess independent factors associated with the parity for multiple births, approval for elective embryo transfer and multifetal reduction. RESULTS: Despite prior information about the risk of multiple births, 81% of respondents saw no risk in twin pregnancies and a sizable minority saw no risk even in triplet pregnancies. Eighty-nine percent of the respondents rated a twin pregnancy as desirable, whereas 35% rated a triplet birth as desirable. When presented with a choice of having multiple births versus having no biological children, 99% of the respondents endorsed twins, 84% triplets and 58% quadruplets. Seventy-four percent of the respondents approve of legalizing embryo screening programmes to select a good-quality embryo combined with elective embryo transfer. Ninety-two percent of the respondents rejected fetal reduction of twins. CONCLUSIONS: German infertile couples might conceivably be more willing to accept elective embryo transfer if screening for viable embryos was permitted.