High-Order Multiple Gestations John P. Elliott, MD Infertility treatments have produced an increase in multiple gestations with twins accounting for 3.3% of births in the United States in 2002. Over that same time period, premature deliveries increased from 10.7% in 1992 to 12.1% in 2002. High-order multiple gestations have also increased, and virtually all of those deliver prematurely. Clinicians are facing the challenge of managing these complicated pregnancies. Neonatal outcome will primarily depend on the gestational age at delivery and the birth weight of the babies. Care is directed at aggressively and proactively preventing preterm delivery. Ultrasound assessments are made frequently to assess fetal anatomical abnormalities, nuchal translucency, fetal growth, cervical length, amniotic fluid, and biophysical profile. Stress reduction and activity reduction will decrease uterine activity, and tocolytic drugs are employed to decrease background contractions to reduce preterm labor (PTL). Fetal fibronectin testing helps predict risk of PTL, and magnesium sulfate tocolysis is used in aggressive dosing to arrest PTL if it occurs. Outcomes are presented and discussed. Successful outcomes are not only possible, but probable. Semin Perinatol 29:305-311 © 2005 Elsevier Inc. All rights reserved. KEYWORDS multiple gestation, high order multiple gestation, twins, triplets, quadruplets T he incidence of multiple gestation has increased dramatically in the last 25 years. The reasons for this increase include the choice of many women to delay childbearing while advancing their careers and, more importantly, new technologies and advances in reproductive medicine that overcome infertility.1 The incidence of multiple births increased from 2.4% of all births in 1992 to 3.3% (38% increase) in 2002 in the United States.2 Over that same time period, the preterm birth rate in the US increased from 10.7% of live births to 12.1%.1 Approximately 94% of multiple gestations are twins, which deliver preterm about 55% of the time. Thus, the majority of the increase in premature delivery noted from 1992 to 2002 is due to the increase in multiple gestations. Preterm delivery (PTD) places the babies at risk for short- and long-term morbidity and mortality. Intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), cerebral palsy, necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), and respiratory distress syndrome (RDS) are complications of prematurity that can result in permanent injuries, including cerebral palsy, mental retardation, chronic lung disease, and loss of vision and hearing. Department of Obstetrics and Gynecology, Banner Good Samaritan Medical Center, Phoenix, AZ. Address reprint requests to John P. Elliott, MD, Department of Obstetrics and Gynecology, Banner Good Samaritan Medical Center, 1111 E. McDowell Road, Phoenix, AZ 85006. E-mail: Barbara.standage@ bannerhealth.com 0146-0005/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2005.08.001 Multiple gestation contributes disproportionally to the PTD rate. The National Vital and Health Statistics report1 documents that in 2002 there were 6898 triplet deliveries (0.2% of all liveborn deliveries), 434 quadruplets (0.01%), and 69 quintuplets (0.001%). These pregnancies are considered high-order multiple (HOM) gestations. Garite and coworkers3 demonstrated in a large database of newborns (51,388) from Pediatrix Medical Group that gestational age-specific mortality and survival without significant morbidity are similar for singleton, twins, and triplets, establishing that the determining factor affecting neonatal outcome is prematurity. Outcome was determined by the gestational age at delivery, with twins or triplets having a greater chance of delivering prematurely. This chapter will present information about HOM pregnancies and recommendations for management, which must address issues of fetal growth and prematurity prevention. There are four factors that will affect outcome in HOM gestations. The height of the mother influences the weight of the babies as reported by Blickstein and coworkers,4 who documented heavier birth weight and a lower risk of delivering very low birth weight triplets if maternal height was taller than 165 cm. In unpublished data from our practice, there is a greater gestational age at delivery if the maternal height is 5 feet, 3 inches or greater. Parity is an important influence on gestational age at delivery. Patients with a history of one or more term deliveries 305 J.P. Elliott 306 Table 1 Effect of Parity on Gestational Age at Delivery in High Order Multiple Gestations Author Gest. Age Difference Parous > Nulliparous Ron-El, et al (1981)5 Gonen, et al (1990)6 McKeown, et al (1952)7 Elliott, et al (1992)8 Aina-Mumuny, et al (2004)9 2 week 2 week 1 week 1.4 week 3 week have an advantage in carrying a HOM gestation. Table 1 summarizes data from five publications5-9 that reported outcome data based on parity. One to three weeks extra time was achieved by the parous women. Unfortunately, in our practice, 92% of our HOM gestations were nulliparous, negating that advantage. The most important factor that affects gestational age at delivery is the number of live fetuses (Table 2). This fact is illustrated by a report by Collins and Bleyl10 that reported outcome data on 71 quadruplet pregnancies. The mean gestational age at delivery was reported to be 31.4 weeks, but if all pregnancies that did not deliver 4 live babies were excluded from the analysis, the mean gestational age at delivery dropped to 29.7 weeks. The excluded pregnancies delivered at a gestational age that corresponded to the expected age for the number of live babies. The final influence on outcome is placentation. The safest type of placentation has 1 placenta for each sac and baby (dichorionic/diamniotic). Blastocyst transfer can result in twinning of 1 or more embryos that will be beyond day 3 of embryonic life when the twinning occurs, which will result in monochorionic/diamniotic placentation. Anytime there are 1 or more monochorionic placentas, the risk of twin--twin transfusion syndrome (TTTS) is added to the risks of the HOM gestation. Acute, severe TTTS develops in about 15% of monochorionic diamniotic twins. Heyborne and colleagues11 reported a diagnosis of TTTS in 3 of 96 (3.1%) of monochorionic/monoamniotic twin pregnancies. In our experience, TTTS occurs in HOM pregnancies slightly later (22-27 weeks) than in monochorionic/diamniotic twin gestations (16-24 weeks), and responded better to intervention with therapeutic amniocentesis. Management of HOM Gestation Prenatal care of a patient carrying a HOM pregnancy will differ in many respects from a low-risk singleton woman. Once a HOM gestation has been diagnosed by ultrasound, the couple is vulnerable. They did not expect to have so many embryos successfully growing, and they are certainly overwhelmed by this reality. Frequently, the reproductive endocrinologist will suggest multi-fetal pregnancy reduction of one or more embryos to leave twins. Although multi-fetal pregnancy reduction is certainly an option, there also needs to be a balanced discussion about carrying the HOM gestation, including outcome data for mortality and morbidity. Prompt consultation with a perinatologist who has experi- ence in caring for HOM pregnancies is important. The couple needs to get as much information as possible to make an informed decision for their circumstances. After considering the medical/obstetric/neonatal risks and the psychosocial/ economic impact on their family, each couple must decide on multi-fetal pregnancy reduction or carrying their HOM gestation. A perinatologist should be managing these very challenging pregnancies. At the first prenatal visit, there are a number of important assessments and management interventions that are initiated. Ultrasound assessment is important to determine placentation because obstetric complications and management will differ based on the nature of the placentas and sacs. Signs of dichorionicity include separate placentas, fetuses of different gender, ”thick“ membrane, and ”twin peak“ or lambda sign.12 The twin peak sign is an ultrasound finding of a triangular projection of placental tissue between the layers of dividing membrane at the junction of the two placentas. Early ultrasound evaluation correctly identifies placentation in over 90% of multiple gestations. If placentation cannot be clearly established, the assumption should be made that it is monochorionic and the pregnancy managed by default as being at risk for TTTS. The rare occurrence of monochorionic/monoamniotic placentation adds increased risk of fetal death from cord entanglement to the risks of HOM gestation. Assessment of the uterus for the location of the lowest placenta is important. Despite the presence of three, four, or five placentas, Francois and coworkers13 demonstrated no statistical difference in the incidence of placenta previa in singleton (55/ 29,268; 0.19%), twins (3/766; 0.46%), or triplets and quadruplets (1/140; 0.71%). Other assessments and interventions would include cigarette smoking, alcohol or recreational drug usage, and prescription medications that should be avoided in pregnancy (eg, ACE inhibitors). Other areas of inquiry include questions regarding domestic violence, which may involve up to 8% of pregnant women and age-related risk of chromosomal abnormalities. Biochemical assessment of genetic risk is not available for triplets or quads. First trimester nuchal translucency measurements will not differ from singleton assessment and prenatal invasive testing offered for fetuses with abnormal measurements. Second trimester genetic ultrasound assessment for “minor markers” associated with aneuploidy may also allow selective sampling of individual fetuses if invasive procedures [chorionic villus sampling (CVS) or amniocentesis] are to be avoided. The risk of three or four amniocenteses is not currently known, but twin amniocenTable 2 Approximate Gestational Age at Delivery No. of Live Born Babies Mean Gest. Age at Delivery Singleton Twins (Spontaneous) Twins (Reduced) Triplet Quadruplets Quintuplets 40 weeks 36-1/2 weeks 35-1/2 weeks 33 weeks 29-1/2 weeks 29 weeks High-order multiple gestations tesis may be associated with a greater than 1% risk of miscarriage. HOM gestations need to be assessed for stress factors in the patient’s life, including heavy work, prolonged standing, high emotional or intellectual stress, heavy lifting or straining, or perhaps caring for one or two young children in the home. As these activities often precede preterm labor, it is important to reduce or eliminate the majority of them wherever possible. In addition, the mother should eliminate activities that cause fatigue, minimize standing, lifting, and bending, and plan increased periods of rest. Because the commute to/from work may be stressful, working at home may help if that is possible. Sexual activity is permissible up to 20 weeks, and beyond, if the couple desires to continue. However, the male ejaculate contains prostaglandin compounds that may initiate contractions, so it is wise to use a condom after 20 weeks to reduce any possible stimulation of contractions. The next aspect of information-sharing involves a discussion of the physiologic and psychologic stresses of a HOM pregnancy. Every organ system in the mother’s body will be affected by the physiologic changes of her special pregnancy. She may already be experiencing nausea and vomiting (frequently encountered in multiple gestations). Uterine distention occurs early and becomes extreme beyond 30 weeks. Backache, pressure, heartburn, constipation, hemorrhoids, headaches, leg cramps, constant fetal movement, pelvic pressure, and urinary frequency often make the mother miserable. Psychologic stresses will also take their toll on the mother, as well as her partner and children, if any are in the home. Anxiety about the risk to her babies, guilt about not carrying her share of the household chores (other children, cleaning, cooking, washing, working), depression, sleep deprivation, and physical stresses are all extreme in HOM gestations. These eventualities must be discussed with the patient early on so that preparation can be made to minimize their effects. The ability to discuss their feelings with others who have experienced a HOM pregnancy is extremely important. There are two large support groups for multiple gestations. Mothers of Supertwins (MOST) can be reached at Info@mostonline.org, phone (631) 859-1110; and The Triplet Connection can be contacted at www.tripletconnection. org, phone (435) 851-1105. The next part of the first prenatal visit should shift to describing the proactive approach that the physician will take to give the patient the best possible chance for a good outcome. It is not appropriate to be passive in caring for a triplet or quadruplet gestation. The most important and frequent risks include: preterm labor which occurs in 76% to 90% of HOM gestations,14,15 pregnancy-induced hypertension (PIH) in 35% of triplets15 and 72% of quadruplets,15 preterm premature rupture of the membranes (PPROM) in 20%,14,15 anemia in 25%,14,15 gestational diabetes (7% in triplets, 19% in quads),14,15 and incompetent cervix in 14%.15 Small for gestational age (birth weight ⬍10th centile for a singleton gestation) and intrauterine growth restriction (IUGR) (birth weight ⬍3rd centile for a singleton gestation) occur, respectively, in about 20% and 9% of triplets14 and 10% and 1% of quads.15 Our proactive approach includes aggressive weight 307 gain, modified bed-rest at 20 weeks (which usually means stopping work), cervical length assessment every 1 to 2 weeks from 18 to 24 weeks, fetal fibronectin testing (fFN) starting at 24 weeks, home uterine activity monitoring (HUAM) at 20 weeks, office visits every 1 to 2 weeks, monitoring for PIH, ultrasound follow-up of fetal growth, and biophysical profile (BPP) assessment of fetal acid-base status. The purpose of each of these interventions is explained to the patient initially and then re-explained in detail when they are instituted. Certain medications are prescribed routinely in our practice. Prenatal vitamins once a day and folic acid 1 mg/d are continued from preconception. Ferrous sulfate 325 mg/d is started after the first trimester. Baby aspirin 81 mg/d and calcium supplementation 2000 mg/d (four Tums® have 2000 mg of calcium) are started at about week 15, as they may lessen the risk of PIH developing. Colace is started at 100 mg (once or twice a day) for stool softening. We also recommend magnesium supplementation at 1.2 g/d and zinc supplementation at 45 mg/d, as preterm labor is associated with a low serum magnesium level and zinc levels may be related to PPROM. At 18 weeks, the patient should have a targeted ultrasound examination to assess carefully the anatomy of each fetus to determine whether any identifiable malformations exist that may present special needs for intervention, either in utero or in the NICU. Careful attention should also be paid to the cervix. A vaginal ultrasound examination should be performed to assess cervical length and any evidence of funneling. Even nulliparous patients with a HOM gestation are at risk of a functionally incompetent cervix. This is probably due to increased levels of relaxin, a hormone that causes softening and dilation of the cervix,16 as well as downward pressure from the expanding uterine contents. The two circumstances producing the highest levels of relaxin in pregnancy are multifetal pregnancy and ovarian stimulation to cause multiple follicles to mature. Such infertility manipulations are frequent in HOM gestations. Follow-up cervical length ultrasound examinations should be done every 2 weeks (between 18 and 24 weeks) if cervical length is greater than 3 cm, or more frequently if it is less than 3 cm. Cervical shortening should prompt careful assessment for uterine contractions. If contractions are documented, treatment should be initiated with tocolytic drugs, preferably with a terbutaline pump for continuous parenteral administration of the drug.17 If uterine activity is not occurring, strong consideration should be given to cervical cerclage. Further ultrasound assessments are routinely indicated for fetal growth every 3 to 4 weeks. Routine assessment of fetal well-being in all HOM pregnancies is indicated beginning at the 32nd week. It is difficult at best and often impossible to use electronic FHR monitoring to assess fetal status, so BPP testing is equally appropriate. Elliott and Finberg reported on the utility of BPP testing in HOM pregnancies, and recommended routine testing twice a week starting at 32 weeks for normally progressing pregnancies.18 BPP should be started earlier if there is a small-for-gestational age fetus or if PIH is diagnosed. 308 It is important to note that abnormal placentation affects the need for ultrasound assessment in multiple gestation, including HOM pregnancies. In particular, monochorionic twins, or less commonly, monochorionic triplets, are at risk of developing acute, severe TTTS.19 This complication occurs most frequently in the second trimester when discordant fetal size and extremes of amniotic fluid volume (polyhydramnios in the recipient sac and oligohydramnios in the donor sac) can develop very quickly (10 days to 2 weeks).20 Making the diagnosis in a timely manner allows appropriate intervention to be initiated. Two treatments that have improved outcome in TTTS include aggressive therapeutic amniocentesis20 and laser ablation of anastomotic vessels on the chorionic plate.21 It is important that fetal size and amniotic fluid volume be assessed every 2 weeks from 16 to 26 weeks in pregnancies containing one or more monochorionic placentas. Office visits should be every 2 weeks after 18 weeks. At ⱖ20 weeks, a digital cervical examination is added at each visit to assess for cervical dilation, which is sometimes difficult to assess with ultrasound. The patient is also asked about signs/symptoms of preterm labor. These would include: cramping, pelvic pressure, backache, contractions, change in vaginal discharge, pressure sensation in the inner thighs, or a feeling that things are just not right. The benefit of bed-rest is very difficult to establish. Goldenberg and colleagues reviewed the literature and concluded that bed-rest is of no benefit in any obstetric circumstance.22 It is my belief that, whereas bed-rest alone will not prevent preterm delivery, it may decrease the frequency of uterine contractions. It is widely appreciated that the more contractions that are occurring the greater the possibility that preterm labor (PTL) will occur. Garite and coworkers demonstrated an increase in contractions 48 hours before PTL to a mean of 3.5/h, and further to 5.5/h in the 24 hours before the onset of PTL.23 In our patients with HOM gestations, administration of betamethasone caused PTL in those patients whose background uterine activity was ⱖ3.5 contractions/ hour, although it did not initiate PTL if the contractions were less than 3.5/hour when the steroids were given.24 We believe that 3.5 contractions/hour represents a threshold value that increases the likelihood of PTL. In our practice, modified bed-rest is prescribed to lower the background contraction frequency to reduce the likelihood of PTL. Modified bed-rest includes time spent recumbent in bed, on a couch, on a recliner chair, or outdoors in a chaise-lounge. The patient can go to the bathroom ad libitum and shower once a day. Mild ambulation for 15 to 30 minutes can be added for individual patients. Tocolysis may also be needed to keep the background contractions fewer than 3.5/hour.17 The role of contraction monitoring in the management of patients at risk of PTL remains controversial. In theory, detection of uterine contractions is important in attempting to detect PTL early. If a patient calls her physician with a complaint of cramping or contractions, the initial evaluation includes placing the patient on a contraction monitor in the hospital. However, the use of a more sensitive tocodynamometer in the outpatient setting evokes intense feelings in practitioners about the clinical utility of the same technology J.P. Elliott that is used in the hospital. In either event, the monitor will not prevent PTD, whereas it might allow detection of PTL at an earlier stage to allow appropriate intervention possibly to prevent PTD.25 The vast majority of articles evaluating home uterine activity monitoring (HUAM) support the concept that daily interaction with the patient by a specially trained nurse with or without a tocodynamometer affords better outcomes than typical standard management with weekly office evaluations.26 Dyson and coworkers27 later reported no difference in twins followed by weekly nursing contact, daily nursing contact, or HUAM. In HOM gestations, it is important to keep background uterine contractions to ⱕ3.5/h. The HUAM can be utilized to assess this background activity, in addition to picking up active PTL in a more timely manner. Outpatient management of HOM gestations is not only appropriate but is psychologically beneficial for the patient and her family.28-30 Fetal fibronectin testing is a useful laboratory test to predict risk of PTD in patients at risk. In singleton pregnancies at risk of PTD, Peaceman and colleagues demonstrated a PTD rate of ⬍1% within 2 weeks of a negative fFN test.31 This is very reassuring. A positive fFN is associated with approximately a 17% risk of PTD in the next 2 weeks. The significance of fFN in HOM gestations is less well understood. In unpublished data for our practice, a negative fFN in a HOM gestation is associated with a 6% risk of PTD in the next 2 weeks, whereas a positive test has almost a 50% risk of delivery over the same period. A positive fFN should prompt closer monitoring of contractions, steroid administration if that has not yet been given, and weekly office visits. Aggressive tocolysis should be initiated when labor occurs. Another routine recommendation in our practice is the use of hydrotherapy. The patient is encouraged to stand in a swimming pool (if available) for 20 to 30 minutes a day. A spa or Jacuzzi is also appropriate, with the legs as deep as possible. The water is very soothing both physically and psychologically, especially as the mother gets into the third trimester. The physiologic benefits of hydrotherapy include a beneficial effect on peripheral edema, which occurs in almost all HOM gestations. Head-out immersion is useful in increasing the intravascular volume, which in turn increases blood flow to the placentas. Strong32 reported an increase in amniotic fluid volume in placental insufficiency in five patients utilizing this therapy. Although I believe that prevention of PTL should be the goal of management, there will be patients who develop PTL. PTL in a multiple gestation is very difficult to control with tocolytic drugs once it has started. The increased renal clearance of drugs in multiple gestations due to increased blood flow to the kidneys necessitates increased dose of tocolytic drugs in acute PTL. Elliott and Radin33 published data showing that higher doses of MgSO4 had to be administered to achieve therapeutic serum levels in HOM gestations compared with singleton pregnancy. It is important to remember that therapeutic serum levels are necessary for the tocolytic drug to be successful. Frequently, too little drug is administered to achieve a therapeutic effect, and when contractions do not stop, the drug is declared a failure and discontinued High-order multiple gestations 309 when really the dosage only needed to be increased to treat the patient successfully. A prospective study by Cox and coworkers34 illustrates the danger of giving too little drug and then declaring that the drug is ineffective at preventing PTD. In our experience acute tocolysis in multiple gestations frequently requires not only higher dosages but also multiple drugs (MgSO4, terbutaline, and indomethacin). I limit intravenous fluids to reduce the risk of pulmonary edema, but am aggressive with all these drugs. The initial bolus of MgSO4 is 6 g and then 3 g/h infusion. I occasionally increase it to as much as 6 g/h infusion, if necessary, monitoring magnesium levels to maintain a serum level of 8.5 mg/dL in resistant cases.33 Serum Mg levels can be checked if tocolysis is not achieved to determine whether an increase in the dosage being administered is warranted or if the patient is excessively symptomatic to determine whether the MgSO4 infusion can be reduced. Routine serum Mg determinations are seldom necessary but can be obtained every 6 hours. Subcutaneous terbutaline can be used as intermittent injection dosing (0.25 mg) or with continuous infusion of a basal rate and programmed periodic boluses by infusion pump. Indomethacin (100-mg suppositories, every 6 hours ⫻ 6 to 8 doses) can be added, or alternatively, ibuprofen 600 mg every 6 hours may be used. After 48 to 72 hours with the contractions spaced out to three to five per hour, the patient can be converted to a terbutaline pump. Oral maintenance tocolysis is generally ineffective, especially in multiple gestations because of the enhanced renal clearance of the drug. Extended tocolysis with continuous intravenous MgSO4 or terbutaline pump17 is more effective in maintaining the pregnancy than oral agents, especially when the cervix is dilated greater than or equal to 2 cm or the station is ⫺1 or lower. Both MgSO4 and terbutaline pumps can be used for months with minimal side effects, but the former is used inpatient, whereas the latter may be used in the home. The side effects of MgSO4 Table 3 Maternal Morbidity and Obstetrical Complications of Quadruplet Pregnancy Variable Incidence (%) Antepartum hospitalization Hyperemesis gravidarum Hyperemesis gravidarum, TPN required Gestational diabetes mellitus A1 Gestational diabetes mellitus A2 Anemia (Hct <30%), no antepartum transfusion required Anemia (Hct <30%), antepartum transfusion required Antepartum bleeding Placenta previa Pre-eclampsia HELLP syndrome Preterm premature rupture of the membranes Preterm labor Twin-to-twin transfusion syndrome Chorioamnionitis 100 9.4 3.1 18.8 3.1 Data from Francois and colleagues.40 25 15.6 3.1 0 71.9 12.5 18.8 90.6 3.1 6.3 Table 4 Neonatal Outcomes of Quadruplet Pregnancy Variable Incidence (%) Intrauterine growth restriction Small for gestational age Chromosomal abnormalities Congenital malformations Respiratory distress syndrome Transient tachypnea of the newborn Apnea Suspected or culture-proven sepsis Necrotizing enterocolitis Intraventricular hemorrhage, grades III/IV Periventricular leukomalacia Gastroesophageal reflux Retinopathy of prematurity Neonatal seizures Pulmonary hypertension Neonatal death 0.8 10 0 1.7 32.5 12.5 1.7 7.5 1.7 0 0.8 12.5 6.6 0.8 1.6 0.8 Data from Francois and colleagues.40 include headache, chest pressure, warm flushed feeling, nausea, double vision, and muscle weakness. These all disappear at 72 to 96 hours of therapy. Extended home management on terbutaline pump therapy is appropriate in many circumstances.17 There is absolutely no evidence that tocolytic drugs lose their efficacy at 48 hours. Physicians have a tendency to decrease drug therapy too soon when the PTL has not resolved, when one should use the drugs aggressively and appropriately to achieve the desired effect. The most feared complication of tocolytic therapy is pulmonary edema. Pulmonary edema is not caused by the MgSO4, but is related instead to associated cardiovascular stresses. In unpublished data from our practice, every patient who developed pulmonary edema had one or more of the following cardiovascular stressors: fluid overload, hypertension, infection, multiple gestation, or anemia. If pulmonary edema develops, one should decrease the dose of MgSO4 and treat with oxygen and furosemide for diuresis. The drug does not need to be discontinued. The incidence of pulmonary edema is 3% to 5% in multiple gestations on MgSO4. Complications of terbutaline pump therapy are very rare. Elliott and coworkers35 documented mild transient side effects (tremors, SOB, or chest discomfort) in 15.5% and serious cardiovascular complications in 12 (0.1%) of 9359 patients treated with terbutaline pump therapy, with 9 of the 12 being pulmonary edema. Tocolytics are safe and effective when used by experienced physicians and nurses. PIH is frequent in HOM gestations, and often HELLP syndrome is present. We will aggressively use dexamethasone to treat HELLP syndrome when it develops in our HOM pregnancies. We use a dosage regimen of 2 mg of dexamethasone IV q6 hours ⫻ 2 days; 2 mg IV q8 hours ⫻ 2 days, and then 2 mg q12 hours until delivery. Heller and Elliott36 reported the successful use of steroids to treat HELLP syndrome in these circumstances. Although the therapy is not 100% successful, days to many weeks can be gained using this treat- J.P. Elliott 310 ment, and any gestational gain affects three or four babies, emphasizing the importance of any lengthening of gestation. Delivery represents the final obstetrical report card for an HOM gestation. We deliver our HOM pregnancies by way of cesarean section, as has been documented to occur in over 90% of patients with triplets.37 Although vaginal delivery is not inherently a more risky alternative, cord prolapse and placental abruption may complicate attempted vaginal delivery. Our goal is an elective delivery. We choose 35-0/7 weeks for delivery of triplets and 34-0/7 weeks for quadruplets and quintuplets. The reason for this is respect for the physical and psychologic well-being of the mother and the excellent neonatal outcome of babies born at that gestational age, although we do not advocate elective earlier delivery of HOM gestations or other pregnancies solely because of overall excellent neonatal outcome. In general, it is not appropriate to deliver a patient unless the dangers of leaving the patient pregnant exceed the risk to the fetus in the nursery. A delivery at 36 weeks is better for a baby than a delivery at 35 or 34 or 33 weeks.36 In our quadruplets, elective delivery occurred in 22.7% of our patients, which was second to PIH (40.3%) as the reason for delivery.38 In the last 20 years, we have cared for over 500 triplet pregnancies, over 75 quadruplets, and 6 quintuplets. Francois and colleagues15,38-40 reported our outcome with 32 nonconsecutive quadruplet pregnancies. These were chosen because they were the patients that we were able to get the medical records of mother and all 4 babies in time to submit an abstract to the Society of Maternal Fetal Medicine meeting. Maternal morbidity is given in Table 3, and neonatal outcome is presented in Table 4. The mean gestation age at delivery was 32.1 weeks (⫾2.1 weeks) with a range of 26.7 to 34.1 weeks. Six pregnancies (20%) were delivered between 30 and 32 weeks, and 18 (60%) were delivered between 33 and 34 weeks. There was 1 death in these 120 babies, for a perinatal mortality rate of 8.3/1000. Major neonatal morbidity was rare, with necrotizing enterocolitis in 1.7%, intraventricular hemorrhage (grade III or IV) in 0%, periventricular leukomalacia in 0.8%, and retinopathy of prematurity (grade II to III) in 6.6%. This low rate of morbidity certainly reflects the large number of babies born after 32 weeks. Garite and colleagues3 have provided data that document that the outcome of babies in a multiple gestation is similar to singletons born prematurely at each week after viability. Thus, it is clear that delivery at a more advanced gestational age is the key to successful pregnancy outcome in multiple gestation. Poor outcome in HOM gestation is a possible result, but it is not even a common result with our approach to management. Conclusion This article provides an overview of HOM gestation and our suggestions for management. Based on our outcomes, we advocate an aggressive approach to HOM pregnancy management. Adequate weight gain will help reduce the incidence of low birth weight and IUGR fetuses. Aggressive manipulation of background uterine contractions with bed rest, psychologic reassurance, and tocolysis with a terbutaline pump will decrease the incidence of true PTL, and aggressive tocolysis with MgSo4 and other drugs will decrease PTD. Treatment of HELLP syndrome with dexamethasone will prolong pregnancy in those patients developing PIH/HELLP. Management is directed at delaying delivery until 34 to 35 weeks if at all possible. References 1. Jewell SE, Yip R: Increasing trends in pleural births in the United States. Obstet Gynecol 85:229-232, 1995 2. National Vital Statistics Reports. Vol 52 No 10. Hyattsville, MD, National Center for Health Statistics, 2003 3. Garite TS, Clara RH, Elliott JP, et al: Twins and triplets: the effect of plurality and growth on neonatal outcome compared with singleton infants. Am J Obstet Gynecol 191:700-707, 2004 4. Blickstein I, Jacques DL, Kieth LG: Effect of maternal height on gestational age and birth weight in nulliparous mothers of triplets with a normal pregravid body mass index. J Reprod Med 48:335-338, 2003 5. Ron-El R, Caspi E, Schreyer P, et al: Triplet and quadruplet pregnancies and management. Obstet Gynecol 57:458-463, 1981 6. Gonen R, Heyman E, Asztalos EV, et al: The outcome of triplet, quadruplet, and quintuplet pregnancies managed in a perinatal unit: obstetric neonatal, and follow-up data. Am J Obstet Gynecol 162:454459, 1990 7. McKeown T, Record RG: Observations on foetal growth in multiple pregnancy in man. J Endocrinol 8:360-400, 1952 8. Elliott JP, Radin TG: Quadruplet pregnancy: contemporary management and outcome. Obstet Gynecol 80:421-424, 1992 9. Aina-Mumuney AJ, Rai KK, Taylor MY, et al: Nulliparity and duration of pregnancy in multiple gestation. Obstet Gynecol 104:110-113, 2004 10. Collins MS, Bleyl JA: Seventy-one quadruplet pregnancies: management and outcome. Am J Obstet Gynecol 162:1384-1392, 1990 11. Heyborne KD, Porreco RP, Garite TJ, et al: Improved perinatal survival of monoamniotic twins with intensive inpatient monitoring. Am J Obstet Gynecol 192:96-101, 2005 12. Sepulveda W, Sebive NJ, Hughes K, et al: Evaluation of the lambda or twin-chorionic peak sign in dichorionic twin pregnancies. Obstet Gynecol 89:439-441, 1997 13. Francois K, Johnson JM, Harris C: Is placenta previa more common in multiple gestations? Am J Obstet Gynecol 188:1226-1227, 2003 14. Malone FD, Kaufman GE, Ghelmow D, et al: Maternal morbidity associate with triplet pregnancy. Am J Perinatol 15:73-77, 1998 15. Francois K, Sears C, Wilson R, et al: Maternal morbidity and obstetrical complication of quadruplet pregnancy: twelve year experience at a single institution. Am J Obstet Gynecol 184:S174, 2001 16. Vogel I, Salvig JD, Secher NJ, et al: Association between raised serum relaxin levels during the eighteenth gestational week and very preterm delivery. Am J Obstet Gynecol 184:390-393, 2001 17. Elliott JP, Flynn MJ, Kaemmerer EL, et al: Terbutaline pump tocolysis in high-order multiple gestation. J Reprod Med 42:687-694, 1997 18. Elliott JP, Finberg HJ: Biophysical profile testing as an indicator of fetal well being in high order multiple gestations. Am J Obstet Gynecol 172:508-512, 1995 19. Gaziano EP, De Lia JE, Kuhlmann RS: Diamnionic monochorionic twin gestations: an overview. J Matern-Fetal Med 9:89-96, 2000 20. Elliott JP, Urig MA, Clewell WH: Aggressive therapeutic amniocentesis in the treatment of acute twin-twin transfusion syndrome. Obstet Gynecol 77:537-540, 1991 21. Quintero R, Morales W, Mendoza G, et al: Selective photocoagulation of placental vessels in twin-twin transfusion syndrome: evolution of a surgical technique. Obstet Gynecol Surv 53:S97-S103, 1998 (suppl) 22. Goldenberg RL, Cliver SP, Bronstein J, et al: Bed rest in pregnancy. Obstet Gynecol 84:131-136, 1994 23. Garite TJ, Bentley DL, Hamer CA, et al: Uterine activity characteristics in multiple gestations. Obstet Gynecol 76:565-595, 1990 High-order multiple gestations 24. Elliott JP, Radin TG: The effect of corticosteroid administration on uterine activity and preterm labor in high order multiple gestations. Obstet Gynecol 85:250-254, 1995 25. Mou S, Sunderji SG, Gall S, et al: Multicenter randomized clinical trial of home uterine activity monitoring for detection of preterm labor. Am J Obstet Gynecol 165:858-866, 1991 26. Elliott JP, Istwan N, Jacques D, et al: Expectant management of the quadruplet pregnancy: inpatient or outpatient? Am J Obstet Gynecol 185:5110, 2002 27. Adams DM, Sholl JS, Haney EI, et al: Perinatal outcome associated with outpatient management of triplet pregnancy. Am J Obstet Gynecol 178:843-847, 1998 28. Newman RB, Hamer C, Miller MC: Outpatient triplet management: a contemporary review. Am J Obstet Gynecol 161:547-555, 1989 29. Peaceman AM, Andrews WW, Thorp JM, et al: Fetal fibronectin as a predictor of preterm birth in patients with symptoms: a multicenter trial. Am J Obstet Gynecol 177:13-18, 1997 30. Strong TH: Reversal of oligohydramnios with subtotal immersion: a report of five cases. Am J Obstet Gynecol 169:1595-1598, 1993 31. Elliott JP, Radin TG: Serum magnesium levels during magnesium sulfate tocolysis in high order multiple gestations. J Reprod Med 40:450, 1995 32. Cox SM, Sherman LM, Leveno KJ: Randomized investigation of mag- 311 33. 34. 35. 36. 37. 38. 39. 40. nesium sulfate for prevention of preterm birth. Am J Obstet Gynecol 163:767, 1990 Elliott JP, Istwan NB, Rhea D, et al: The occurrence of adverse events in women receiving continuous subcutaneous terbutaline therapy. Am J Obstet Gynecol 191:1277-1282, 2004 Heller CS, Elliott JP: The use of corticosteroids to prolong gestation to high order multiple pregnancies complicated by HELLP syndrome. J Reprod Med 42:743-746, 1997 Dommergues M, Mahieu-Caputo D, Dumez Y: Is the route of delivery a meaningful issue in triplets and higher order multiples? Clin Obstet Gynecol 41:25-29, 1998 Elliott JP, Istwan NB, Rhea D, et al: Indicated and non-indicated preterm delivery in twin gestations: impact on neonatal outcome and cost. J Perinatol 25:4-7, 2005 Francois K, Sears C, Wilson R, et al: Twelve-year experience of quadruplets at a single institution. Am J Obstet Gynecol 184:S174, 2001 Francois K, Sears C, Wilson R, et al: Twelve-year experience of quadruplets at a single institution. Am J Obstet Gynecol 184:S174, 2001 Francois K, Sears C, Wilson R, et al: Neonatal outcomes of quadruplet pregnancies: twelve-year experiences at a single institution. Am J Obstet Gynecol 184:S174, 2001 Francois K, Sears C, Wilson R, et al: Neonatal outcomes of quadruplet pregnancies: twelve-year experiences at a single institution. Am J Obstet Gynecol 184:S174, 2001