Version May 2024
INTRODUCTION — Multifetal gestations are often complicated by spontaneous preterm birth. When this occurs before or proximate to the lower gestational age limit of ex utero survival, the neonates are at high risk for prolonged hospitalization, serious morbidity, and/or mortality. Although all the fetuses of a multiple gestation are typically born within a short interval, sometimes the interval between births can be safely and substantially extended and this delay may improve survival and morbidity for the neonates who are born later. This is called delayed-interval delivery (also asynchronous delivery), which can be defined as >24 hours between the firstborn and secondborn of a multiple gestation.
This topic will discuss selection of candidates for delayed-interval delivery and management of these pregnancies. Interpretation of available information is challenging because the evidence base consists of case reports, small case series, and literature reviews, but no randomized trials. Ascertainment bias is a significant problem as cases with successful outcomes are often reported, while many cases with unsuccessful outcomes go unreported.
The routine management of twin and triplet births are reviewed separately.
●(See "Twin pregnancy: Labor and delivery".)
●(See "Triplet pregnancy".)
KEY PRINCIPLES — The best approach for achieving a delayed-interval delivery is unclear. The authors' approach is based upon our early experience with over 50 delayed-interval deliveries [1,2], our ongoing experience with delayed-interval delivery, and our insights from case series reported in the literature [3-14]. The key principles of our approach are:
●Appropriate selection of candidates
●Informed consent
●Exclusion of intraamniotic infection in undelivered fetus(es)
●Medication-induced uterine relaxation
●Antibiotic prophylaxis
●Cerclage placement
●Administration of antenatal glucocorticoids
●Close follow-up of the pregnancy
SELECTING CANDIDATES — Delayed-interval delivery is a rare event and a complex clinical decision because it is difficult to objectively quantify and compare the potential risks and benefits for the various stakeholders. As a result, no high-quality data are available to inform decision-making for selecting or excluding candidates and generally accepted guidelines based on limited data and expert opinion have not been published.
Our criteria — In our practice, we discuss the option of delayed-interval delivery with patients who meet all the following criteria:
●An obstetric factor (eg, cervical insufficiency) results in the birth of one fetus (usually) of a multiple gestation [12,15-17])
●The other fetus(es) of the multiple gestation is not affected by the factor
●Concurrent delivery of the other fetus(es) would likely result in its death or severe morbidity
Within this group, the best candidates appear to be pregnancies with firstborns who deliver vaginally at <24 weeks [6], typically because of cervical insufficiency, prelabor rupture of membranes, preterm labor, or intrauterine demise. Patients with uterus didelphys with an affected fetus in one uterine horn and an unaffected fetus in the other horn are good candidates, but only a dozen such pregnancies with delayed-interval-delivery have been reported [18].
Contraindications — We do not offer delayed-interval delivery in the following scenarios; however, there is variation among clinicians at other centers.
●Pregnancies ≥28 weeks of gestation. Neonatal outcome at our institution, and similar institutions with an appropriate level of neonatal care, is generally good at this gestational age. A minority of clinicians elsewhere have reported offering the procedure to patients with pregnancies ≤32 weeks [4].
●Pregnancy complications associated with a high risk of serious maternal or fetal morbidity/mortality in ongoing pregnancies. Examples include preeclampsia with severe features, placental abruption, intraamniotic infection or abnormal fetal testing (eg, heart rate or biophysical profile score) of the nonpresenting fetus(es), and placenta previa.
In our practice, the finding of intraamniotic infection involving the first-born fetus or the requirement for oxytocin augmentation to facilitate its delivery does not exclude the option of a delayed-interval delivery as long as laboratory studies on amniotic fluid (obtained by amniocentesis) from the other fetus(es) show no evidence of infection. Infection of the other fetus(es) would be a contraindication to this approach and would require delivery of the entire pregnancy. (See 'Evaluation for infection' below.)
●Monochorionicity with the firstborn. Vascular anastomoses in the retained placenta may cause complications of the undelivered fetus(es), although successful delayed-interval delivery has been reported in monochorionic twins [19,20].
●Operative delivery of the firstborn is a relative contraindication; however, a few cases of selective hysterotomy [18,21,22] or transcervical evacuation using Sopher forceps [23] for delivery of the firstborn with successful outcomes for the delayed secondborns have been reported. There is also a case report of cesarean birth of the first twin (birth weight 530 g) at 22+4 weeks followed 10 days later (24+0 weeks) by cesarean birth of the secondborn (birth weight 600 g); unexpectedly, the first twin survived, and the secondborn died on day 2 of life of cardiovascular and respiratory failure [14]. These are rare cases requiring individualized decision-making that will not be addressed in this topic.
In our practice, if the presenting fetus is in breech presentation, at a gestational age compatible with newborn survival, and the parents desire cesarean birth with neonatal resuscitation, then we generally perform the cesarean birth and do not attempt delayed-interval delivery of the remaining fetus(es). Hysterotomy in ongoing pregnancies was associated with high rates of preterm prelabor rupture of membranes (PPROM), abruption, preterm labor, and uterine dehiscence in studies involving hysterotomy for fetal surgery [24].
●Other – Fetal anomaly in the nonpresenting fetus is not an absolute contraindication to delayed-interval delivery. We manage these pregnancies on a case-by-case basis, with consideration of the fetal/neonatal prognosis and the parents' values and preferences.
INFORMED CONSENT — The focus of informed consent is the potential benefits and risks of delayed-interval delivery and the range of potential outcomes. Key points include:
●Discussion of all options – Delayed-interval delivery is an option, but not the only option. Regardless of gestational age, parents may choose to deliver the entire pregnancy when one fetus of a multiple gestation is born.
●Risk of infection – Delaying delivery increases the risk for infection (maternal, fetal, and/or neonatal) and, in turn, the potential sequelae of infection. For the mother, this includes sepsis, localized infection, and infertility. For the secondborn, this includes periviable or preterm birth, sepsis, neurodevelopmental impairment, or death. (See 'Outcome' below and 'Evaluation for infection' below.)
●Issues related to latency
•The duration of latency is difficult to predict, with wide ranges reported in the literature.
•The potential benefit of delaying delivery depends on both the gestational age of the firstborn and latency duration. For instance, if the firstborn is 22 or 23 weeks, a three-week latency interval has a substantial survival benefit over contemporaneous delivery of secondborns; however, if the firstborn delivers at 18 weeks, three weeks would be insufficient to improve the chances of survival of the secondborn.
•Delaying delivery may extend the duration of pregnancy from a previable to a periviable gestational age at secondborn delivery [6,7,25]. A neonatology consultation may assist in providing information on potential pediatric outcomes. Patients who meet criteria for delayed-interval delivery at a previable gestational age may elect not to attempt an approach that increases the possibility of birth of an extremely preterm infant who survives with significant long-term morbidity. These patients can reasonably choose to deliver all the fetuses in conjunction with the birth of the firstborn. (See "Periviable birth (limit of viability)" and "Overview of the long-term complications of preterm birth".)
●Risks associated with cerclage – Since we generally perform a cerclage, we review the risks of the procedure. (See "Transvaginal cervical cerclage".)
EVALUATION FOR INFECTION — The potential for serious infectious morbidity is a major concern when delivery is delayed. We have avoided this complication over the years by using an active, preemptive approach to identifying infection:
●We always perform an amniocentesis on the undelivered fetus(es) to analyze amniotic fluid for evidence of subclinical intraamniotic infection, which would exclude the pregnancy from consideration of delayed-interval delivery [7,26,27]. Rarely, we are forced to complete delivery of the presenting fetus (including cerclage placement) and then perform the amniocentesis(es) immediately thereafter. We have not had to remove the cerclage and deliver an unexpectedly infected retained sibling in these rare instances.
●The amniotic fluid is sent to the laboratory for Gram stain, culture, leukocyte count, and glucose concentration. We consider one or more of the following findings suggestive of intraamniotic infection: amniotic fluid leukocyte count >50 cells/mm3, glucose concentration <20 mg/dL (1.1 mmol/L), or bacteria on Gram stain. As there is no universal standard, practice variation exists in criteria for intraamniotic infection. Available evidence is discussed separately. (See "Clinical chorioamnionitis", section on 'When to perform amniocentesis to test amniotic fluid'.)
•If the initial laboratory results strongly suggest infection (ie, they are not just "borderline"), we do not attempt to delay delivery.
•If initial laboratory results do not suggest infection but the culture (which is checked daily) is positive, then the initial attempt at delaying delivery is terminated, and the undelivered fetus is delivered.
•If laboratory results show no evidence of infection but the firstborn has suspected or confirmed infection, we administer broad-spectrum antibiotics with anaerobic coverage and proceed with delayed-interval delivery (in parents who have chosen this approach) (see "Clinical chorioamnionitis", section on 'Antibiotic therapy'). In a few case reports, delayed-interval delivery was successful despite clinical chorioamnionitis of the firstborn [18,28-30]. Presumably the infection was limited to the firstborn's sac and was cleared with delivery and maternal administration of antibiotics. Importantly, if maternal signs of clinical chorioamnionitis do not resolve within 24 hours after birth of the firstborn and initiation of antibiotic therapy, we repeat the amniocentesis and testing for intraamniotic infection in the undelivered fetus(es), and proceed with delivery if results suggest infection.
MANAGEMENT
Deliver the presenting fetus — The firstborn usually delivers as a result of spontaneous preterm labor. Rarely, labor is augmented or induced. In this rare setting, we would augment/induce labor with oxytocin, as needed. After fetal expulsion, we avoid cord traction and we clamp, cut, and ligate the cord with absorbable suture as high as possible (ie, as close to the placental insertion site as possible). The placenta is left in situ. We do not obtain cord cultures.
Induce uterine quiescence — As soon as the firstborn delivers, we stop oxytocin if used for augmentation/induction. Sometimes the uterus spontaneously ceases to contract after the firstborn has delivered. If not, we begin nitroglycerin intravenously to promptly initiate uterine quiescence [31]. We also administer an oral tocolytic, such as indomethacin, for 24 to 48 hours postoperatively, depending on uterine activity. (See "Inhibition of acute preterm labor", section on 'Cyclooxygenase inhibitors (eg, indomethacin)'.)
Administer local and systemic antibiotic prophylaxis — We irrigate the lower uterine segment with 500 to 1000 mL of an antibiotic solution (eg, cefazolin 1 gram in a liter of saline) after the delivery. To accomplish this, the patulous cervix is grasped with ring forceps and placed on gentle traction, then an irrigating syringe is used to direct the solution into the lower uterine cavity.
We also administer broad-spectrum antibiotics (eg, gentamicin and clindamycin or ampicillin-sulbactam) intravenously for a three-day course, followed by a cephalosporin (eg, cephradine 500 mg orally every six hours) plus metronidazole 500 mg orally every eight hours orally for four days.
Use of antibiotics has not been evaluated in comparative studies. In a systematic review of case reports and small series, delayed-interval delivery typically involved cleansing the vagina and cervical canal using antiseptic solution and administering prophylactic broad spectrum antibiotics [32].
Place a cerclage — We generally perform a cerclage in all patients attempting delayed-interval delivery because it is usually impossible to exclude the possibility that cervical insufficiency was the underlying cause or a contributing factor to the early delivery of the firstborn. Cerclage may forestall the birth of the secondborn and is a common intervention in this setting [19,26,27,33-39]. Even if cervical insufficiency was not initially a contributing factor, reapproximation of the cervix after delivery of the presenting fetus may prevent later prolapse of fetal membranes and decrease the chances of intraamniotic infection. However, there are numerous reports of successful delayed-interval deliveries without placement of a cerclage [7,23,40,41] and no data from comparative studies.
If membranes from an undelivered fetus are prolapsed, we gently retract them cephalad using standard maneuvers (see "Transvaginal cervical cerclage", section on 'Replace prolapsed membranes, if present'). We place a McDonald cerclage using #2 monofilament nonabsorbable suture swaged onto a medium taper needle. Either nylon or polypropylene can be used based on the surgeon’s personal preference (eg, ease of handling). Two sutures are initially placed; the second is offset by 45 degrees so as not to be placed directly on top of the first suture.
Repeat cerclage is unlikely to be successful in pregnancies in which a cerclage had been placed earlier in pregnancy before delivery of the firstborn [2]. This group of patients has a more guarded prognosis due to a particularly foreshortened latency.
Administer a course of antenatal corticosteroids (ACS) — We administer ACS administration at the gestational age at which parents who have been counseled by the neonatology service desire aggressive support of the newborn if delivered. This is typically between 22 and 24 weeks. Rescue steroids are offered two weeks later. Evidence regarding risks and benefits of ACS and rescue ACS are reviewed separately. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)
Administer anti-D immune globulin to RhD-positive patients — Anti-D immune globulin is administered to RhD-negative mothers after delivery of the firstborn. RhD-negative candidates for anti-D immune globulin, including indications for repeat administration later in pregnancy, are described in detail separately. (See "RhD alloimmunization: Prevention in pregnant and postpartum patients".)
Postdelivery inpatient monitoring
●We hospitalize patients for a minimum of seven days to closely monitor for complications requiring delivery. Approximately 50 percent of these pregnancies deliver within this seven-day period [5].
●If urgent delivery for an abnormal fetal heart rate pattern would be considered, we perform electronic fetal heart rate monitoring per unit protocol while the patient is in the hospital. Abnormal findings such as recurrent decelerations, persistent loss of previous heart rate variability, or tachycardia should prompt further assessment (eg, ultrasound, amniocentesis and retesting for intraamniotic infection) and/or intervention (delivery).
Outpatient care and monitoring — Many patients will need to remain hospitalized until delivery, but discharge can be considered in some cases. Ideal candidates for hospital discharge are those with minimal uterine activity or bleeding, proven adherence to medical care, and minimal barriers to seeking appropriate care for questions or emergencies. They are discharged to home with instructions to limit physical activity to light activities in the home (eg, self-care) and to avoid sexual intercourse. They are also counseled to be aware of contractions, discharge, fever, or abdominal tenderness and to call if any of these symptoms occur.
We schedule office visits weekly and perform transvaginal ultrasound evaluation approximately every two weeks to evaluate the cervix and the integrity of the cerclage. If the plane of the cerclage is broken by membrane prolapse, especially in patients with some uterine activity, then we readmit the patient for closer surveillance and proximity to the labor unit. We remove the cerclage if preterm prelabor rupture of membranes (PPROM) or preterm labor occurs.
LATENCY DURATION — Achieving an extended time interval between births of fetuses at critical gestational ages is the basis for improved neonatal survival and reduced morbidity of the secondborns. In two large series, mean latency was 18 to 19 days [7] and 36 days [2]; in two other large series, median latency was 6 days [5] and 16 days [8]. However, at the individual level, patients need to understand the duration of latency reported in the literature is extremely wide, from 1 to 154 days [2,4,5,7,8,41,42] and an individual's latency duration is unpredictable [2,5,43].
DELAYED-INTERVAL DELIVERY — The most common reasons for delivery are preterm labor (with or without ruptured membranes) and clinical chorioamnionitis [2], but delivery at >37 weeks of gestation has been reported [44]. Cerclage is removed when delivery is imminent or indicated (preterm prelabor rupture of membranes [PPROM], labor, or chorioamnionitis), or at 36 to 37 weeks. Cesarean birth is performed for standard indications.
OUTCOME
Perinatal mortality — In a 2020 meta-analysis of the effect of delayed-interval delivery on survival of the remaining fetuses (16 observational studies including 492 pregnancies [432 twins, 56 triplets, 3 quadruplets, and 1 quintuplet]), delayed-interval delivery was associated with improved perinatal survival of the secondborn(s) compared with the firstborn (55.8 versus 31.8 percent; odds ratio [OR] 5.22, 95% CI 2.95-9.25), particularly when the firstborn delivered before 20+0 weeks (29 versus 0 percent; OR 6.32, 95% CI 1.99-20.13) versus between 20+0 and 23+6 weeks (41.8 versus 16.2 percent; OR 3.31, 95% CI 1.95-5.63) or after 24+0 weeks (72.9 versus 59.6 percent; OR 1.92, 95% CI 1.21-3.05) [32].
Neonatal morbidity — Neonatal morbidity depends primarily on gestational age at birth. In the meta-analysis described above, among the survivors, there were no significant differences in short-term and long-term neonatal morbidities between the firstborn and the remaining fetus(es) [32].
Maternal morbidity — In the meta-analysis described above, serious maternal morbidity was reported in 39 percent of pregnancies after delayed-interval delivery (71 of 183 cases in 12 studies), but there were no maternal deaths [32]. Maternal morbidity included one or more of the following: local infection and/or sepsis (56 cases), postpartum hemorrhage (12 cases), placental abruption (8 cases), and hysterectomy (2 cases, one because of sepsis and one because of hemorrhage). The authors did not distinguish between local infection and sepsis but others have reported maternal sepsis in 4 in 19 (21 percent) and 4 in 81 (4.9 percent) delayed-interval deliveries [8].
Amniocentesis to evaluate for infection before attempting delayed-interval delivery was not always successful in preventing future maternal morbidity. This highlights the small, but potentially life-threatening, risk of delaying delivery after the birth of one fetus.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple gestation".)
SUMMARY AND RECOMMENDATIONS
●Candidates
•Delayed-interval delivery (>24 hours between the firstborn and secondborn) may be an option when one or more fetuses of a multiple gestation deliver because of obstetric factors and concurrent delivery of fetuses unaffected by these factors would likely result in their death or severe morbidity. The potential benefit of delaying delivery depends on both the gestational age of the firstborn and latency duration. (See 'Selecting candidates' above and 'Outcome' above.)
•For otherwise uncomplicated multiple gestations, we suggest delayed-interval delivery rather than contemporaneous delivery of the entire pregnancy if all of the following conditions are met (Grade 2C) (see 'Selecting candidates' above):
-The pregnancy is at an early gestational age (usually <24 weeks)
-The firstborn delivers vaginally due to cervical insufficiency, preterm prelabor rupture of membranes (PPROM), preterm labor, or intrauterine demise
-Infection has been excluded in the remaining gestational sacs
Delayed-interval delivery carries a substantial risk for maternal morbidity (including sepsis), and a risk of subsequent birth of a very preterm infant with high risk for long-term morbidity. Thus, individual patients' values and preferences play an important role in decision making. (See 'Outcome' above and 'Informed consent' above.)
●Contraindications (See 'Contraindications' above.)
•We do not offer delayed-interval delivery to patients with pregnancy complications associated with a high risk of serious maternal or fetal injury (eg, preeclampsia with severe features, abruption, intraamniotic infection of the undelivered fetus(es)), or gestational age ≥28 weeks.
•We consider either monochorionicity of the firstborn with another fetus or the need for cesarean delivery of the firstborn relative contraindications to delayed-interval delivery.
•We do not consider intraamniotic infection limited to the firstborn an absolute contraindication.
●Management – The optimal strategy to achieve a successful delayed-interval delivery has not been validated by randomized studies, nor have there been adequate sample sizes in observational studies to draw statistically meaningful conclusions. There is no consensus as to optimum management of potential candidates for delayed-interval delivery. (See 'Introduction' above.)
•Informed consent – The counseling and consent process should address the risks and benefits of delayed-interval delivery, including the possibility and consequences of extending the pregnancy from a previable to a periviable gestational age at birth; the risk of maternal, fetal, and/or neonatal infection, as well as potential sequelae of infection; and the option of not attempting delayed-interval delivery. (See 'Informed consent' above.)
•Evaluation for infection – Prior to an attempt at delayed-interval delivery, we perform amniocentesis to exclude subclinical microbial infection of the amniotic fluid of the fetus(es) in whom pregnancy prolongation is planned. (See 'Evaluation for infection' above.)
•Management of the first delivery – After expulsion of the firstborn:
-Umbilical cord/placenta – We perform high ligation of the umbilical cord with absorbable suture and leave the placenta in situ. (See 'Deliver the presenting fetus' above.)
-Uterine quiescence – If the uterus is contracting, we administer nitroglycerin to promptly initiate uterine quiescence. We then begin a tocolytic (eg, indomethacin) and continue it for 24 to 48 hours postoperatively, depending on uterine activity. (See 'Induce uterine quiescence' above.)
-Prophylactic antibiotics – We suggest administering local and systemic antibiotics (Grade 2C). (See 'Administer local and systemic antibiotic prophylaxis' above.)
-Cerclage – We suggest placing a cerclage (Grade 2C) because it is usually impossible to exclude the possibility that cervical insufficiency was causing or contributing to early delivery of the firstborn. Cerclage may forestall the birth of the secondborn in this setting. (See 'Place a cerclage' above.)
•Antenatal corticosteroids – We administer antenatal corticosteroids (ACS) at the gestational age at which parents who have been counseled by the neonatology service desire aggressive support of the newborn if delivered. This is typically between 22 and 24 weeks. Rescue steroids are offered two weeks later. Evidence regarding risks and benefits of ACS are reviewed separately. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)
•Postdelivery maternal and fetal monitoring – Ongoing maternal and fetal surveillance during latency involves assessment for signs of infection, preterm labor, PPROM, cervical change, fetal heart rate abnormalities, and other complications. (See 'Postdelivery inpatient monitoring' above and 'Outpatient care and monitoring' above.)
•Latency – Length of latency is important since achieving an extended time interval between births of fetuses at critical gestational ages is the basis for improved neonatal survival and reduced morbidity in undelivered fetuses. In two large series, mean latency was 18 to 19 days and 36 days and in two other large series, median latency was 6 days and 16 days. However, at the individual level, the duration of latency reported in the literature is extremely wide, from 1 to 154 days, and an individual's latency duration is unpredictable. (See 'Latency duration' above.)
•Management of the second delivery – The cerclage is removed at 36 to 37 weeks or earlier if delivery is likely (eg, preterm labor, PPROM, chorioamnionitis). Cesarean delivery is performed for standard indications. (See 'Delayed-interval delivery' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Richard P Porreco, MD, who contributed to earlier versions of this topic review.
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