Multiple Pregnancy: Boon or Bane – An Indian Perspective

Abstract

In the era of rising multiple pregnancy, it is important for us to analyse the recent trends. Assisted reproductive technology has brought hope to many childless couples. But it comes with a price. The prevalence of multiple gestation globally at present is 32 per 1000 deliveries. Recent studies from India report an incidence of 30.5 per 1000 deliveries. The most important complication associated with multiple gestation is prematurity. From the neonatology point of view, the increase in multiple gestation has opened an additional opportunity for the neonatologists to see and manage more preterm babies. Infants born after a multifetal pregnancy are associated with an increased risk of prematurity, cerebral palsy, learning disabilities, slow language development, behavioural difficulties, chronic lung disease, developmental delay, and death. The relative risk of cerebral palsy in twins and triplets compared to a singleton is 4.9 and 12.7, respectively. Foetal reduction as a routine should be discussed with all couples with multiple gestation including twins, to improve the pregnancy and neonatal outcome. Any multifetal gestation is a high-risk pregnancy should be managed efficiently by a multidisciplinary team involving Senior Obstetricians, neonatologists, intensivists, anaesthesiologists, physicians and nursing team in a well-equipped centre.

1. Introduction

In the era of rising multiple pregnancy, it is important for us to analyse the recent trends. This chapter will highlight the same and the recent updates in the management from an Indian perspective.

The prevalence of multiple gestation globally at present is 32 per 1000 deliveries [1]. Recent studies from India report an incidence of 30.5 per 1000 deliveries [2]. These again vary with respect to private and government sectors, with more spontaneous multiple pregnancies in the government and more ART (assisted reproductive technology)-associated multiple pregnancies seen in the private sector.

Due to the changes in lifestyle, delayed age of childbearing and stressful life, we see a lot of increase in infertility. At least one in five couples are known to have fertility issues these days. These ART techniques including ovulation induction with or without IUI are associated with a risk of multiple pregnancy of 8–10%. This increases up to 30% with IVF and two blastocyst transfer.

Assisted reproductive technology has brought hope to many childless couples. But it comes with a price. Each blastocyst of good quality can potentially give rise to four foetuses. There are many case reports of multiple pregnancy after a single-embryo transfer. With the routine trend of many ART specialists adopting two or more embryo transfer to achieve better pregnancy rates, the incidence of multiple gestation is known to increase.

From the neonatology point of view, the increase in multiple gestation has opened an additional challenge to the neonatologists to manage more preterm babies. Gone are those days, when extremely premature babies less than 28 weeks were not considered viable and were not resuscitated. Extremely premature babies with less as 24 weeks or 450 gm rate are being resuscitated and managed efficiently in NICU and successfully sent home. Perinatal outcomes may not be optimum with extremely premature babies, but over the last few decades, we have learnt a lot about extremely premature new-born care. This has helped us to analyse the data and improvise our protocols in the management.

2. Causes of multiple gestation

1. Higher maternal age

2. Family history of twinning

3. Prior OCPs use—the cycles immediately after stoppage of contraceptive pills will be associated with superovulation, higher fecundity and multiple pregnancy also

4. ART—ovulation induction carries a risk of multiple pregnancy of 8%. Incidence increases with IVF (in vitro fertilisation) and blastocyst transfer. Each blastocyst can potentially give rise to four foetuses in utero.

2.1 Types of multiple gestation

1. Dizygotic—resulting from fertilisation of two separate ova. They are fraternal twins and do not look alike. They are always dichorionic diamniotic.

2. Monozygotic—resulting from a single fertilised zygote. They look alike.

Depending on the timing of cell division after fertilisation, chorionicity and amnionicity develop in monozygotic twins. After fertilisation, when the division happens.

1. 0–4 days—dichorionic, diamniotic

2. 4–8 days—monochorionic, diamniotic

3. 8–12 days—monochorionic, monoamniotic

4. After 12 days—conjoined twins.

2.2 Multiple pregnancy boon or bane

It may be very nice to have twin babies, triplets might be fancy, and quadruplets would be a burden. But any multiple gestation is termed a high-risk pregnancy.

The most important complication associated with multiple gestation is prematurity (Kamlesh Kumari et al. [3]). 65.7% increased chances of preterm labour and 61.4% increased chances of having a caesarean section have been reported with multiple pregnancies – with most common reason being malpresentation of one of the fetuses.

2.3 Maternal complications

The maternal complications with multiple pregnancy include preterm labour, PPROM, anaemia, gestational hypertension, gestational diabetes, polyamnios, oligoamnios, haemorrhage including post-partum, and more incidence of caesarean delivery.

2.4 Foetal complications

Infants born after a multifetal pregnancy are associated with the increased risk of prematurity, cerebral palsy, learning disabilities, slow language development, behavioural difficulties, chronic lung disease, developmental delay, and death. The relative risk of cerebral palsy in twins and triplets compared to a singleton is 4.9 and 12.7, respectively.

Determination of chorionicity is very important in these pregnancies.

1. Dichorionic diamniotic pregnancies carry least complication rates. This is the most common variety.

2. Monochorionic twins are at higher risk of complications and among them monoamniotic are at the highest risk. The risk is due to placental vascular anastomoses and/or placental sharing. The complications include selective growth restriction, twin reverse arterial perfusion sequence (TRAP), twin-to-twin transfusion syndrome (TTTS), and twin anaemia-polycythemia sequence (TAPS).

The other complications include single foetal demise, congenital anomalies, discordant twins, conjoint twins, birth asphyxia, low birth weight, birth trauma, still birth, perinatal death and prolonged NICU stay. In India, 10% of the perinatal mortality can be attributed to twin pregnancies (Table 1).

Study	Anita et al. [2]	Kamlesh et al. [3]	Nutan Yadav et al. [4]	P Upreti et al. [5]
Number of patients	51	70	72	218
Mean age		27.6	26.08	25.4
Preterm labour	84.31%	25.4%	79.2%	58.3%
PPROM	23.53%	18.3%	22.29%	4.1%
Gestational diabetes	13.73%	5.6%	2.7%
Gestational HTN	15.68%	22.5%	37.5%	21.1%
Anaemia	62.74%	26.8%	91.67%	30.7%
APH	3.33	1.4%	2.7%	5.95
Malpresentation	47%	37.8	22.2%	36.9%
Caesarean	58.82%	64.3	50%	49%
Anomalies	0.97%	0
Foetal demise	1.94	0
Perinatal mortality	17.48%	12.9
IUGR	14.56%	11.4%	20.8%
Growth discordance		21.4%		25%
NICU admission	20.38%

Table 1.

Demographics of multiple gestation studies in India.

The above comparison reports various descriptive Indian studies done in recent years with respect to multiple pregnancy. The mean age of women in these studies was in the range of 25–27 yrs. So, they are all young women mostly conceptions with ART. Preterm labour was the most common complication with incidence going up to 84.31%, and in them, preterm premature rupture of membranes was noted in up to 23.52%. Among the medical complications, anaemia was the most common complication ranging from 30.7 to 91.67%. This is due to nutritional deficiency developed due to increased demand of twins or triplets or due to hyperemesis associated with these pregnancies. Incidence of gestational diabetes is up to 13.73%, and gestational hypertension is seen up to 37.5%, which can be explained by a larger placenta seen in these pregnancies. Antepartum haemorrhage was seen in up to 5.95% patients. Most of these patients present with low-lying placenta mainly due to a larger placental surface and develop intermittent spotting or bleeding creating panic in patients. Many of them also develop abruption associated with hypertension. There is an increased incidence of postpartum haemorrhage also in multiple gestation mainly due to overdistended uterus and post-partum atony. It would be wise to be prepared for it with active management of the third stage of labour and keeping blood and blood products cross-matched and ready.

Caesarean delivery is the most common of delivery in multiple pregnancy seen in up to 64.3% mainly due to malpresentation (in up to 47%). Normal delivery is an option only in twin deliveries and not on triplets or higher orders. In twins, cephalic-cephalic position is the most common presentation where vaginal delivery is feasible. The second most common is cephalic and second breech position where vaginal delivery also can be done. However, in these cases, there is a small risk of the requirement of Caesarean for second twin due to malpresentation or non-progress of labour. In cases of transverse lie or both breech or other presentations, Caesarean would be the option. In the breech and second cephalic presentation, there is risk of the first twin’s head getting locked against the second twin (interlocking twin) and hence vaginal deliveries should be thought about only when the first twin is in cephalic presentation.

3. Foetal reduction

It has been developed since the 1980s, as a method to reduce the multiple gestation to twin or singleton gestation to reduce the complications. It involves preliminary screening of foetuses at NT scan and reduction of foetuses that are abnormal or relatively abnormal. If there are no abnormal foetuses, then a decision is taken based on the most accessible foetus for the procedure. Gender selection is not allowed in India as per PCPNDT rules and hence shall not be a criterion to decide. It is done as a day-care procedure with some minimal local anaesthesia. It involves transabdominal ultrasound-guided injection of KCl into the foetal heart to stop its function. Some studies report doing chorionic villus sampling of foetuses and FISH before reduction. The procedure is ideally done between 12 and 14 weeks after the NT scan to allow for spontaneous reductions to happen till then and NT screening to be done. In up to 20 to 60%, spontaneous reduction to singleton pregnancy happens [6]. The demised twin disappears as a vanishing twin. There has been an increasing trend of reducing even twins to singleton to avoid the complications associated with multiple births.

Jung Ryeol Lee et al. [7] report early foetal reduction at 6–8 weeks by transvaginal ultrasound guidance using a 19G needle. Cardiac puncture and amniotic fluid aspiration is done to produce foetal reduction, which may be added on with KCl injection. However, this study reports better pregnancy and foetal outcomes with early foetal reduction at 6–8weeks without using KCl.

The foetal reduction procedure is therefore not limited to triplets or quadruplet gestations. Twin gestation reduced to singleton, do better according to studies. We do see patients refusing reduction on moral or religious grounds, thinking about foeticide or about the risk of miscarriage.

The procedure is associated with a small risk of miscarriage and infection, which should be explained to the couple against the risks involved in continuing with the multiple gestation.

Foetal reduction as a routine should be discussed with all couples with multiple gestation, including twins to improve the pregnancy and the neonatal outcome. This counselling should involve an explanation of the risks specifically with multiple pregnancy and the option to reduce the pregnancy. The moral and ethical background should be kept in mind before counselling the couple about the procedure.

4. Interventions to reduce multiple gestation

1. Routine single-embryo transfer—many European countries have adopted routine single-embryo transfer to avoid multiple gestation. In such countries, healthcare and IVF treatment are government funded and multiple IVF cycles are also funded by the government. So, the patient is not concerned about the reduced pregnancy rates with single-embryo transfer against double-embryo transfer. However, in India, where all infertility treatments are neither covered under insurance nor are government funded and when the patient has to spend out of his pocket, it becomes difficult for them to accept any method with slightly reduced pregnancy rates. Hence, it becomes difficult for Indian clinicians to convince patients for single-embryo transfer.

2. Cancelling ovulation induction when multiple follicles are developed—sometimes when we give ovulation-inducing agents to patients either letrozole, clomiphene citrate, or gonadotrophins, we do see some patients hyper-responding with the development of more than three mature follicles. It would be a wise decision to not give ovulation trigger or human chorionic gonadotropin injection in cases where more than three mature follicles have developed. In that way, multiple pregnancies can be avoided.

3. Efficient counselling of the couple to make an informed choice—we are in an era where patients are bombarded with information all over. It is essential for them to make to understand the risks and complications associated with multiple pregnancy and the future outcome and with that perspective, the concept of foetal reduction.

4. Offer foetal reduction to all multiple gestations including twins. Infants born after a multifetal pregnancy including twins are associated with the increased risk of prematurity, cerebral palsy, learning disabilities, slow language development, behavioural difficulties, chronic lung disease, developmental delay, and death. Considering the perinatal morbidity and NICU care requirement in these twin gestations, it would be prudent to give all couples an option to consider about foetal reduction of twins to the singleton.

5. Antenatal care

It is important to determine the chorionicity with a good transvaginal ultrasound at the time of the dating scan (7–10 weeks). According to the chorionicity, the pregnancy is categorised, and the antenatal visit schedule is planned. All women should be offered screening for trisomy 21 at 11–13 + 6 weeks of gestation. This ultrasound can be combined with first-trimester biochemistry (serum PAPP-A and beta-Hcg) to make it combined screening with the better detection rates. For triplets or higher-order pregnancies, only nuchal translucency screening should be done.

The next level of ultrasound screening is an anomaly scan, which is offered between 18 and 22 weeks. Monochorionic pregnancies should be scanned at 16–17, 19–20, and 21–22 weeks. Monoamniotic twins should be screened from 15 to 16 weeks and 18 to 20 weeks. A five-chamber view of the heart should be carried out at 18–19 weeks and 21–22 weeks. Further growth scan shall include complete documentation of full biometry, foetal weight, liquor, and bladder size. Scans should be performed at a frequency dictated by the chorionicity (Table 2) [8].

Type of pregnancy	Growth scans
Dichorionic gestation	24, 28, 32, 36
Monochorionic	24, 28, 32, 34
Mono amniotic	24,26, 28, 32, 34
Triplet/quadruplet	Individualised

Table 2.

Suggested ultrasound scans for multiple gestation pregnancies.

It is important for the obstetrician to be well versed with the complications associated with multiple gestation. Accordingly, the antenatal visits should be scheduled, and the pregnancy closely monitored. Where required, a multidisciplinary team involving foetal medicine consultants, neonatologists and physicians should be involved in the management. Routine antenatal visits should include screening for anaemia, hypertension, diabetes, and foetal heartbeat assessment.

5.1 Cervical length screening

It is done by transvaginal ultrasound at 12 weeks, 16 weeks, 20 weeks and 24 weeks. Cervical length less than 2.5 cm is considered short. Prophylactic cervical cerclage in multiple gestation is controversial. Evidence suggests that cervical length is a moderate predictor of spontaneous preterm labour in twin pregnancy. Vaginal progesterone may reduce this risk in women with a twin pregnancy. However, in patients with ART conception especially with polycystic ovaries that are known to be associated with cervical insufficiency, prophylactic cervical cerclage would be beneficial. It is ideally applied after NT scan between 13 and 14 weeks or if history indicated, at least 2 weeks before the previous miscarriage.

5.2 Antenatal corticosteroids

If elective delivery or Caesarean is planned before 38 weeks, antenatal corticosteroids are warranted to be given, either betamethasone or dexamethasone. This is according to the present data available. A lot of newer studies are ongoing with respect to the assessment of newborn adverse effects due to antenatal steroids. The present protocols suggest two doses of betamethasone, 12 mg given intramuscular, 24 hrs apart. Similarly, dexamethasone can be given 6 mg, 12th hourly four doses 6 hrs apart.

5.3 Antenatal magnesium sulphate

BEAM trial [9] in 2002 first proposed the beneficial effects of antenatal magnesium sulphate in women at imminent preterm delivery. All pregnancies that are at risk of premature delivery shall be given an intravenous infusion of magnesium sulphate over 24 hrs. It is given as a loading dose of 4 g slow IV over 5 minutes followed by 1 g/hour infusion for 24 hrs. Magnesium sulphate is a weak tocolytic. It is very efficient in preventing cerebral palsy in preterm newborns (RR 0.70, 95% CI 0.55–0.89). It also has a neuroprotective role in preventing intra-ventricular haemorrhage.

5.4 Tocolysis

Preterm labour being the most common complication with multiple pregnancy, it is essential to provide tocolysis to the patient at least to have antenatal steroid cover for 48 hrs. This would improve neonatal neurological and respiratory outcomes. The most effective tocolysis available is Atosiban, which is an oxytocin antagonist and should be the first choice of drug. It is started as a 0.9 ml (6.75MG) loading dose intravenous and followed by a high-dose infusion of 300 mcg per minute for 3 hrs. This is followed by a low-dose maintenance infusion of 100 mcg per minute for the next 45 hrs. The total dose infused shall not exceed 330.75 mg. The second-best drug for tocolysis is nifedipine given as a loading dose of 30–40 mg followed by 10 mg sixth hourly. Nifedipine being a calcium channel blocker relaxes the smooth muscle of the uterus and induces tocolysis. The main aim of tocolysis is to safely transfer the mother to a tertiary care centre well equipped for multiple gestation and preterm newborn care and also to allow for the antenatal steroid prophylaxis to act. Hence, it should not be prolonged for more than 48 hrs. Tocolysis should be weighed against the maternal risks of sepsis and pulmonary oedema before continuing the therapy.

6. Delivery plan

It is essential to have institutional deliveries for all multiple pregnancies. The centre should be well equipped for emergency Caesarean facilities, blood bank, tertiary NICU care, and a multidisciplinary team involving intensivists, physicians, endocrinologists, and foetal medicine consultants. The timing of delivery is crucial to optimise the neonatal outcomes. The mode of delivery again should be individualised, and the main deciding factor is the foetal presentation (Table 3).

Type of multiple pregnancies	Planned birth to be offered at	Increased risk of foetal death beyond	Mode of delivery
Dichorionic diamniotic	37 weeks	37 + 6weeks	Individualised
Monochorionic diamniotic	36 weeks	36 + 6	Individualised
Monochorionic monoamniotic	32 to 33 + 6 weeks	33 + 6	Caesarean
Trichorionic triamniotic	35 weeks	35 + 6	Caesarean
Dichorionic triamniotic	35 weeks	35 + 6	Caesarean

Table 3.

Recommended time table for delivery of multiple pregnancies.

Table reference [8].

6.1 Intrapartum monitoring

Monitoring twin foetuses in labour can be difficult at times. They should be monitored with twin foetal heart probes to avoid the same foetal heart being traced twice on cardiotocography. Always perform a portable ultrasound bedside to ascertain the presentation at the start of labour.

6.2 Post-partum period

There is more incidence of post-partum haemorrhage in these women, mainly due to an overdistended uterus in pregnancy. The obstetric team should be prepared with oxytocics, blood and blood products at the time of delivery to efficiently manage it. Active management of the third stage of labour should be routinely done in all women to reduce the incidence of haemorrhage.

6.3 Breastfeeding

It can be a challenge with respect to demand in twin and triplets gestation. Most of these babies are born prematurely with poor suckling or latching, and hence, there can be difficult establishing the feeding. More so many of these babies stay in the NICU in the initial few days or weeks when rooming in and breastfeeding could be difficult to establish. As suckling is the most important stimulus for further breast milk production, when the baby is away from the mother breastfeeding establishment becomes a challenge. Feeding both babies simultaneously is another technique to increase the milk output in the mother.

7. Conclusion

Multiple pregnancy is a high-risk pregnancy to be always managed by an efficient and experienced multidisciplinary team. Foetal reduction is an option to be explained to all couples with multiple pregnancy to reduce the neonatal and childhood morbidity. Foetal reduction is more common in LMIC countries than in developed world because of the higher morbidity and cost of healthcare associated with multiple pregnancies.