Outcome of twin-to-twin transfusion syndrome in monochorionic monoamniotic twin pregnancy: systematic review and meta-analysis.

OBJECTIVES: To explore the outcome of monochorionic monoamniotic (MCMA) twin pregnancies affected by twin-to-twin transfusion syndrome (TTTS). METHODS: MEDLINE and EMBASE databases were searched for studies reporting the outcome of MCMA twin pregnancies complicated by TTTS. The primary outcome was intrauterine death (IUD); secondary outcomes were miscarriage, single IUD, double IUD, neonatal death (NND), perinatal death (PND), survival of at least one twin, survival of both twins and preterm birth (PTB) before 32 weeks' gestation. Outcomes were assessed in MCMA twins affected by TTTS not undergoing intervention and in those treated with amniodrainage, laser therapy or cord occlusion. Subgroup analysis was performed including cases diagnosed before 24 weeks. Random-effects meta-analysis of proportions was used to analyze the data. RESULTS: Fifteen cohort studies, including 888 MCMA twin pregnancies, of which 44 were affected by TTTS, were included in the review. There was no randomized trial comparing the different management options in MCMA twin pregnancies complicated by TTTS. In cases not undergoing intervention, miscarriage occurred in 11.0% of fetuses, while the incidence of IUD, NND and PND was 25.2%, 12.2% and 31.2%, respectively. PTB complicated 50.5% of these pregnancies. In cases treated by laser surgery, the incidence of miscarriage, IUD, NND and PND was 19.6%, 27.4%, 7.4% and 35.9%, respectively, and the incidence of PTB before 32 weeks' gestation was 64.9%. In cases treated with amniodrainage, the incidence of IUD, NND and PND was 31.3%, 13.5% and 45.7% respectively, and PTB complicated 76.2% of these pregnancies. Analysis of cases undergoing cord occlusion was affected by the very small number of included cases. Miscarriage occurred in 19.2%, while there was no case of IUD or NND of the surviving twin. PTB before 32 weeks occurred in 50.0% of these cases. CONCLUSIONS: MCMA twin pregnancies complicated by TTTS are at high risk of perinatal mortality and PTB. Further studies are needed in order to elucidate the optimal type of prenatal treatment in these pregnancies. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Low-dose aspirin for pre-eclampsia prevention in twins with elevated human chorionic gonadotropin.

OBJECTIVE: The objective of the study is to evaluate low-dose aspirin (LDA) for pre-eclampsia prevention in twin gestations with elevated maternal serum human chorionic gonadotropin (hCG). STUDY DESIGN: Secondary analysis of the Maternal-Fetal Medicine Units High-Risk Aspirin trial for pre-eclampsia prevention. A threshold hCG level for predicting pre-eclampsia was identified in placebo-randomized patients. Pre-eclampsia incidence and time of onset were compared between treatment groups, overall and by hCG threshold category. RESULTS: Pre-eclampsia incidence was lower with LDA than with placebo (6% vs 16%, OR 0.32, 95% CI 0.12 to 0.82). An hCG threshold of 29.96 IU ml(-1) best predicted pre-eclampsia. In patients with hCG <29.96 IU ml(-1), the differences in pre-eclampsia incidence or time of onset were not significant. In patients with hCG >29.96 IU ml(-1), LDA was associated with lower pre-eclampsia incidence than placebo (6% vs 23%, OR 0.21, 95% CI 0.06 to 0.79) and delayed onset. CONCLUSION: Twin gestations with elevated hCG levels may benefit from LDA for pre-eclampsia prevention.

The impact of low-dose aspirin on preterm birth: secondary analysis of a randomized controlled trial.

OBJECTIVE: The objective of this study is to determine whether low-dose aspirin (LDA) reduced the rate of preterm birth (PTB) in a cohort of women at high risk for preeclampsia. STUDY DESIGN: Secondary analysis of the Maternal-Fetal Medicine Units High-Risk Aspirin trial. Preterm births were categorized by phenotype: indicated, spontaneous or due to preterm premature rupture of membranes (PPROMs). RESULTS: Of 1789 randomized women, 30.5% delivered before 37 weeks (18.5% indicated, 5.8% spontaneous and 6.2% following preterm PPROMs). Among women randomized to LDA, we observed a trend favoring fewer PTBs due to spontaneous preterm labor and preterm PPROMs, odds ratio (OR: 0.826 (0.620, 1.099)); the incidence of indicated PTBs appeared unchanged, OR: 0.999 (0.787, 1.268). CONCLUSION: Although not reaching significance, we observed an effect size similar to other studies of both low- and high-risk women. These results support findings from other studies assessing LDA as a PTB prevention strategy.

Early initiation of low-dose aspirin for reduction in preeclampsia risk in high-risk women: a secondary analysis of the MFMU High-Risk Aspirin Study.

OBJECTIVE: Early initiation of low-dose aspirin (LDA) may reduce preeclampsia risk. We sought to determine whether LDA was beneficial when initiated <17w0d, within a trial of high-risk women enrolled <26w0d. STUDY DESIGN: Secondary analysis of the Maternal-Fetal Medicine Units High-Risk Aspirin study, including women enrolled <17w0d, randomized to LDA (60 mg day(-1)) or placebo with chronic hypertension (CHTN, n=186), diabetes (n=191) or prior preeclampsia (n=146). The primary outcome was preeclampsia at any time in pregnancy, secondary outcomes were early preeclampsia (<34w0d), late preeclampsia (⩾34w), small for gestational age (SGA; neonatal birthweight <10th %) and composite (early preeclampsia or SGA). Outcomes were compared by exact Χ(2)-tests. RESULTS: Baseline characteristics were similar between treatment groups. Aspirin was associated with a lower rate of late-onset preeclampsia ⩾34w (17.36% vs 24.42%, P=0.047), with a 41% reduction in women with CHTN (18.28% vs 31.18%, P=0.041). There were no other significant differences in the outcome. CONCLUSION: Aspirin initiated <17w0d reduced the risk for late-onset preeclampsia by 29% supporting the practice of early initiation of aspirin in high-risk women.

Cutting edge: regulation of uterine NKT cells by a fetal class I molecule other than CD1.

The peri-implantation uterus contains an expanded population of NK1.1(+) V alpha 14(+) TCR(int) (NKT) lymphocytes. Although these cells bear the above features in common with other NKT cells populations in thymus, bone marrow, liver, and spleen, they differ from these other populations in terms of an altered V beta repertoire and absence of a CD4(+) component. In this study, we demonstrate that the uterine population also differs from other NKT cell populations because they recognize a class I/class I-like molecule other than CD1, whereas most previously described V alpha 14(+) NKT cells are CD1-restricted. Moreover, the class I/class I-like molecule leading to the uterine NKT cell expansion may be supplied by the fetus. These data demonstrate a novel mechanism whereby the fetus is capable of modulating the maternal immune system.

Delayed-interval delivery: extended series from a single maternal-fetal medicine practice.

OBJECTIVE: Our purpose was to review the extended experience of a single maternal-fetal medicine practice with delayed-interval delivery. STUDY DESIGN: We completed a retrospective review of our maternal-fetal medicine practice database from January 1991 through March 1999. Patients were derived from both primary and consultative practices. All patients were managed with tocolysis, antibiotics, and cerclage after delivery of the first fetus(es). Retained siblings were investigated by amniocentesis to exclude intra-amniotic infection. RESULTS: Twenty-four consecutive patients had attempted delayed-interval delivery. Exclusion criteria for delayed-interval delivery included monochorionicity, abruptio placentae, severe preeclampsia, and the need for hysterotomy. The mean latency interval was 36 days, with a range of 3 to 123 days. Additionally, patients with previous cerclage(s) had significantly shorter mean latency intervals than patients without previous cerclage(s). Patients with long latency intervals (> or =49 days) had earlier births of the first fetus. CONCLUSION: Selected multichorionic pregnancies may benefit from delayed-interval delivery. Patients with previous cervical cerclage(s) during the index pregnancy are less likely to achieve significant latency intervals. Even modest intervals between births of siblings at critical gestational ages can improve neonatal survival and decrease neonatal morbidity.

Natural killer 1.1(+) alpha beta T cells in the periimplantation uterus.

When the developing embryo implants into the uterine wall, resident maternal immune cells may encounter antigens present on the fetal tissues. The nature and constituents of the ensuing maternal immune response, and its regulation, are of considerable interest in understanding normal and abnormal pregnancy. Here, we report the presence of natural killer (NK)1.1(+) alpha beta T cells in the murine periimplantation uterus. These cells account for a large portion of both the T-cell and natural killer cell populations in early pregnancy, while their numbers in the non-pregnant uterus and later in pregnancy are greatly reduced. Phenotypically, these NK1.1+ alpha beta T cells belong to a previously described subset of cells that bear a V alpha 14-J alpha 281-encoded T-cell receptor. Unlike other organs, where both CD4(+) and CD4(-)/CD8(-) NK1.1(+) alpha beta T cells are found, the placental/decidual population appears to be entirely CD4(-)/CD8(-). The V beta repertoire of the placental/decidual population is also altered from that of other organs, with a majority of cells expressing V beta 3. Together, these features suggest the possibility of local development. NK1.1(+) alpha beta T cells are known to recognize the class I-like CD1 molecule. Consistent with this association, we demonstrate CD1 expression by tissues within the pregnant uterus. Our findings define an additional organ-specific immune environment where NK1.1(+) alpha beta T cells may play a role, and continue to demonstrate the specialized nature of the maternal intrauterine immune system during pregnancy.

Preeclampsia prevention: lessons from the low-dose aspirin therapy trials.

The ability of low-dose aspirin therapy to prevent preeclampsia is controversial. The 19 randomized, placebo-controlled trials of low-dose aspirin therapy reported in the literature were categorized according to the risk factors of the women studied-nulliparity, underlying medical illness, poor obstetric history, and multiple gestation. Low-dose aspirin therapy reduced the incidences of preeclampsia among women with poor obstetric histories and among high-risk nulliparous women but was ineffective among women with underlying medical illness. It was marginally effective among low-risk nulliparous women, and benefits for women with multiple gestations are unclear. More research is needed to better identify high-risk nulliparous women who might benefit from the use of low-dose aspirin therapy and to define potential benefits for women with multiple gestations. The differential effects of low-dose aspirin therapy in the various risk groups are probably a result of varying roles in the groups of abnormal arachidonic acid metabolism in mediating preeclampsia. It is premature to abandon the use of low-dose aspirin therapy for preeclampsia prevention.

Reversal of Ballantyne syndrome by selective second-trimester fetal termination. A case report.

BACKGROUND: Ballantyne syndrome (mirror syndrome, triple edema) describes the unusual association of fetal and placental hydrops with maternal preeclampsia. In most cases, the poor fetal prognosis and associated maternal risks warrant delivery regardless of gestational age. We used novel therapy for Ballantyne syndrome in a twin pregnancy. CASE: Ballantyne syndrome occurred at 16 weeks' gestation due to severe, unexplained hydrops in one of dichorionic twins. Selective termination of the affected fetal twin resulted in reversal of the preeclamptic findings in the mother, and the surviving twin was born uneventfully at term. CONCLUSION: This case strengthens the association of fetal and placental hydrops with preeclampsia and suggests selective fetal termination for Ballantyne syndrome due to hydrops in one of multichorionic fetuses.

Selective delivery in a twin gestation.

One or more infants of a multifetal pregnancy occasionally require delivery selectively because of in utero risk of fetal death in circumstances in which the sibling fetus appears well. At 26 weeks 5 days of gestation a small fundally placed twin in a dichorionic gestation had an estimated fetal weight of 650 g with decreased amniotic fluid and ominous Doppler velocity findings in his umbilical artery. A normally grown presenting sibling had reassuring fetal surveillance data. Over a 2-week interval the growth-restricted twin showed no growth, and his status deteriorated. He was selectively delivered by hysterotomy. Selective delivery may offer parents of multifetal gestations an additional option when 1 or more of their fetuses are at high risk for in utero death.

Delayed-interval delivery in multifetal pregnancy.

OBJECTIVE: Our goal was to review a single subspecialty practice experience with a uniform approach to delayed-interval delivery. STUDY DESIGN: A 66-month retrospective review of our maternal-fetal medicine practice database was completed. Fifty-nine sets of twins or triplets delivered at < 30 weeks' gestation were identified. No cases of twins or triplets who came to our care, either in consultation or as primary providers, were excluded. RESULTS: Forty-three patients were excluded as candidates for delayed-interval delivery because of monochorionicity, abruptio placentae, severe preeclampsia, and the need for hysterotomy. Sixteen pregnancies were identified as candidates for delayed-interval delivery, and we actually attempted to delay delivery in 9 of them. The details of the interval deliveries are summarized; there was a mean latency interval of 34 days with a range of 3 to 76 days. Pregnancies in which delayed-interval deliveries wer attempted were significantly less mature at the time of presentation than those managed by delivery of all infants initially. Perinatal mortality was significantly lower in the retained fetuses. CONCLUSIONS: This retrospective consecutive case review from a single maternal-fetal practice documents that selected multichorionic pregnancies may benefit from delayed-interval delivery. Modest intervals between siblings during critical gestational ages can improve newborn survival and decrease neonatal morbidity.

Interleukin-10 in amniotic fluid at midtrimester: immune activation and suppression in relation to fetal growth.

OBJECTIVE: Low birth weight remains the leading cause of perinatal morbidity and mortality, but mechanisms mediating impaired fetal growth are poorly understood. To further define the role of abnormal immune activation and suppression in mediating impaired fetal growth, we measured levels of interleukin-10, a potent immunosuppressive cytokine not previously identified in association with pregnancy, in amniotic fluid samples obtained at genetic amniocentesis. STUDY DESIGN: In a case-control study with an enzyme-linked immunoassay we compared amniotic fluid levels of interleukin-10 in midtrimester samples obtained from appropriate-for-gestational age (n = 42) and small-for-gestational-age (n = 24) pregnancies. RESULTS: Interleukin-10 levels in small-for-gestational-age samples were elevated (median 78 pg/ml) compared with levels in control samples (median < 40 pg/ml), p = 0.02. In small-for-gestational-age pregnancies elevated levels were associated with nulliparity, p = 0.003. CONCLUSION: Our data support the role of abnormal immune activation, as opposed to inadequate immune suppression, in mediating impaired fetal growth.

Pregnancy specific beta 1 glycoprotein (SP-1) in maternal serum and amniotic fluid; pre-eclampsia, small for gestational age fetus and fetal distress.

Pregnancy specific beta 1 glycoprotein (SP-1) levels have been suggested to correlate with certain obstetrical complications. We compared maternal serum SP-1 levels in normal pregnancies (N = 82), and pregnancies complicated by pre-eclampsia (N = 37), small for gestational age fetuses (N = 8) and fetal distress (N = 13). We also compared levels of this protein in mid-trimester amniotic fluid samples obtained from normal (N = 47) and small for gestational age fetuses (N = 25). Despite trends towards low maternal serum and amniotic fluid SP-1 values in complicated pregnancies, there were no statistically significant differences in their levels as compared with normal gestational age matched controls (P > 0.05). These data do not support the use of SP-1 values in clinical practice.

Characterization of gamma delta T lymphocytes at the maternal-fetal interface.

A specific subset of gamma delta T lymphocytes bearing a V gamma 6V delta 1-encoded TCR is known to populate the normal nonpregnant murine uterine and vaginal epithelium. However, gamma delta T lymphocytes residing at the maternal-fetal interface during pregnancy have not yet been investigated. Using mAb and cytofluorographic analysis, we analyzed gamma delta TCR-bearing lymphocytes obtained from placental/decidual tissues of allogeneic (C57B1/10 X BALB/c and BALB/c X C57B1/10) pregnancies. Gestations were analyzed at several time points during the second half of pregnancy, with lymphocytes from both maternal spleen and nonpregnant C57B1/10 uteri analyzed as controls. We found that all gamma delta T lymphocytes at the maternal-fetal interface are maternally derived. Relative to the total T lymphocyte population, the percentage of gamma delta TCR-bearing T lymphocytes at the maternal-fetal interface is enriched three- to four-fold compared with maternal spleen, and twofold compared with nonpregnant uteri. Although one-third of gamma delta T lymphocytes from pregnant animals express a cell-surface marker associated with activation (IL-2R), gamma delta cells from uteri of nonpregnant mice fail to express IL-2R. In terms of absolute numbers, we estimate that reproductive-tract gamma delta T cells are increased nearly 100-fold in pregnant animals compared with nonpregnant animals. To characterize the TCR-gamma delta repertoire in the placenta/decidua, we generated 21 TCR-gamma delta-bearing hybridomas from lymphocytes in this tissue. Analysis of these hybridomas revealed at least six distinct gamma delta receptor types expressed at the maternal-fetal interface, with V gamma 6V delta 1 encoded TCR representing the predominant population. As specific resident constituents of the reproductive tract, gamma delta T lymphocytes may be involved in regulating a variety of physiologic and pathophysiologic events in reproductive biology.

Tumor necrosis factor-alpha in midtrimester amniotic fluid is associated with impaired intrauterine fetal growth.

OBJECTIVE: To investigate whether abnormal immune system activation is involved in the pathogenesis of some instances of impaired fetal growth, we compared tumor necrosis factor-alpha levels in midtrimester amniotic fluid samples obtained from appropriate-for-gestational-age and small-for-gestational-age pregnancies. STUDY DESIGN: In a case-control study with the sensitive and specific WEHI cell assay, bioactive tumor necrosis factor-alpha levels in amniotic fluid samples from 24 gestations resulting in small-for-gestational-age infants were compared with levels in 35 samples obtained from gestations resulting in the birth of a term, appropriate-for-gestational-age infant. The two groups were not significantly different with regard to indication for amniocentesis, maternal age, race, smoking history, parity, or other factors. RESULTS: Elevated amniotic fluid tumor necrosis factor-alpha activity was associated with small-for-gestational-age birth, p = 0.028. With a threshold of 10 pg/ml, elevated amniotic fluid tumor necrosis factor-alpha had a sensitivity of 48% for the detection of small-for-gestational-age birth, with a specificity of 83%. CONCLUSION: Elevated tumor necrosis factor-alpha in midtrimester amniotic fluid is associated with impaired intrauterine fetal growth. Abnormal immune system activation, as manifested by increased amniotic fluid tumor necrosis factor-alpha activity, may mediate impaired fetal growth in some cases.

Renal artery stenosis during pregnancy: a review.

Renal artery stenosis in pregnancy may present as chronic hypertension with superimposed preeclampsia or as recurrent isolated preeclampsia. Renal angiography is the most sensitive and specific diagnostic technique available for this lesion, and therapeutic percutaneous transluminal angioplasty may be carried out in conjunction with angiography. We report a patient with renal artery stenosis diagnosed and treated with percutaneous transluminal angioplasty at 26 3/7 weeks gestation. The literature on renal artery stenosis in pregnancy is reviewed.

Prolongation of premature gestation in women with hemolysis, elevated liver enzymes and low platelets. A report of five cases.

Severe pregnancy-induced hypertension complicated by hemolysis, elevated liver enzymes and low platelets (HELLP) is considered an indication for immediate delivery, often resulting in premature or even previable infants. In five cases, temporary reversal of the HELLP syndrome was achieved using low-dose aspirin and corticosteroids. Pregnancy was prolonged an average of 4 weeks; three pregnancies were prolonged, beginning at less than or equal to 25 weeks, for an average of 5.5 weeks. Two of seven infants died, one from pulmonary hypoplasia due to oligohydramnios and the other from complications of prematurity. No long-term maternal morbidity was encountered, though one patient had peripartum disseminated intravascular coagulation and a seizure. A review of the literature supports the usefulness of low-dose aspirin in this setting; the impact of corticosteroids as part of the reversal strategy has not been discussed previously.