Asia-Oceania J . Obstet. Gynaecol. Vol. 18, No. 4; 299-307 1992
Outcome of 143 Pregnancies Conceived by Assisted Reproductive Techniques
Mary H.M. Yang, Soon-Chye Ng, Shan S. Ratnam, Sharath Devendra, Barry Marshall, C. Anandakumar, Yee-Chee Wong, and Ariff Bongso Department of Obstetrics and Gynaecology, National University of Singapore, National University HoQitaI, Singapore
Abstract One hundred and forty-three pregnancies conceived by assisted reproductive techniques (ART) from October 1985 to June 1989 in the National University Hospital, Singapore, resulted in 66 deliveries and 89 babies. There were 27 (18.7%) biochemical pregnancies, 44 (30.7%) clinical miscarriages and 6 (4.2%) ectopic pregnancies when total pregnancies were considered. Of those who continued pregnancy to second trimester multiple births occurred in 20 (13.3%) patients. A high incidence of vaginal bleeding and hypertension in pregnancy was noted in 32 (48.5%) patients and 18 (27.3%) patients, respectively. Caesarean section was the method of delivery in 48.5% of patients. Twenty-six (29.2%) babies required admission to the neonatal intensive care unit. All babies except one set of twins delivered at 24 weeks of amenorrhoea survived. Fetal abnormality was noted in 2 cases. Key words: pregnancy outcome, assisted reproductive techniques, in vitro fertilization, gamete-intra-fallopian transfer, tubal embryo transfer
Introduction Steptoe and Edwards reported the world’s first birth after in witro fertilization (IVF). Since then, IVF has brought new hope to childless couples who have no prospect of natural pregnancy. Much work and research have been done in the area of assisted reproduction. Many new techniques have evolved including gamete intrafallopian transfer (GIFT) and tubal embryo transfer (TET). There are not many detailed analysis of the
obstetric experience of pregnancy conceived in a single clinic using assisted reproductive techniques (ART). This paper analysed 143 pregnancies (including 27 biochemical pregnancies) to assess if they are of higher risk when compared with the general patient pool.
Materials and Methods Pregnancies conceived in the National University Hospital, Singapore, using assisted reproductive techniques from October 1985 till
Received: Jan.13,1992 Reprint request to: Dr. Soon-Chye Ng, Department of Obstetrics and Gynaecology, National University of Singapore, National University Hospital, Lower Kent Ridge Road, Singapore 0511
M.H.M. YANG ET AL.
June 1989 were analysed. These included pregnancies from GIFT, TET, IVF and those from subsequent thaw cycles with embryos from any of the above techniques. Three stimulation regimes were used. Group A received clomiphene citrate 50 mg twice a day on days 2-6 with the addition of human menopausal gonadotrophin, hMG (Pergonal, Serono) on an individualized dose from day 7. Group B received pure follicular stimulating hormone, FSH (Metrodin, Serono) 2 or 3 ampoules plus hMG (Pergonal, Serono) 1 ampoule on days 2-6 followed by an individualised dose of hMG subsequently from day 7. Group C received intranasal GnRH analogues (Buserelin, Hoechst) 300 pg thrice daily from day 22 onwards of the preceeding cycle till the day human chorionic gonadotrophin, hCG (Pregnyl, Organon) was given with the addition of hMG (Pergonal, Serono) after 15 days of GnRH agonist (Buserelin, Hoechst). Luteal phase support for groups B and C included intramuscular progesterone 25 mg given daily from 5th day post G I F T or T E T procedures or embryo replacement. Intramuscular hCG is given to those in group C on 5, 8, and 11 days. The maximum number of oocyte or embryo replaced was 4 in all cases. Beta-hCG and oestradiol levels were measured on the 14th and 16th day post GIFT, T E T or embryo replacement. Two positive and rising hCG levels above 25 IU/l were required to confirm a pregnancy. It is later confirmed with an ultrasound scan 6 weeks post procedure. If no gestational sac was seen despite 2 positive hCG values, the pregnancy was considered a biochemical one. A clinical pregnancy is said to have occurred when a gestational sac and fetal heart are demonstrated by either abdominal or vaginal scan. Miscarriage included all the pregnancies that ended before 28 completed weeks of amenorrhoea. Antenatal complications in singleton, twin and triplet pregnancies were studied. The number of patients requiring surgical induction and caesarean section were analysed. The need for neonatal intensive care and perinatal outcome were also studied. All ba-
300
bies born were screened by a paediatrician and any fetal abnormalities was noted.
Results Among 148 pregnancies the outcome of 5 clinical pregnancies were not known as the patients returned to a foreign country during the antenatal period after confirmation of the pregnancy by ultrasound scan. Of the 116 clinical pregnancies with known outcome there were 66 (46.2%) deliveries which produced 89 babies, 44 (30.7%) miscarriages and 6 (4.2%) ectopic pregnancies (Table 1). Characteristics of the patients and their pregnancy outcome in the different ethnic group and nationality were not different. Chinese and Singaporean made up at least 50% of the total patient pool. The mean maternal age for the various pregnancy outcome were similar and was 34.3 years (range of mean 32-35.4 years).
A. Biochemical Pregnancy Twenty-seven patients (18.9%) with 2 positive pregnancy tests did not proceed on to clinical pregnancies. Testing the difference between 2 proportions, those conceived by IVF have a higher percentage of biochemical pregnancy significant at the 10% level when compared to T E T (Table 2). This was not statistically significantly different at the 10% level when IVF and G I F T was compared. Unfortunately 10 of the ART format kept separately from the patient’s case record could Table 1. Outcome of 143 pregnancies conceived by ART techniques
Deliveries Singleton Twins (set) Triplets (set)
Biochemical pregnancy Miscarriage Ectopic pregnancy
No.
%
47 4
32.9 10.5 2.8
66
46.2
27 44 6
18.9 30.7 4.2
143
100.0
15
ART PREGNANCY OUTCOME
Table 2. The pregnancy outcome among 143 pregnancies conceived according to ART methods TET
GIFT
Biochemical pregnancy Miscarriage Ectopic pregnancy Singleton birth Multiple births
IVF
STC*
No.
%
No.
%
No.
%
No.
%
14 23 1 30 9
18.2 29.9 1.3 38.9 11.7
3 16 2 5 1
11.1 59.3 7.4 18.5 3.7
10 5 3 11 8
27.0 13.5 8.1 29.8 21.6
0 0 0 1 1
50 50
Total
77
27
37
2
* STC=Spontaneous thaw cycle Table 3. The pregnancy outcome of 143 pregnancies conceived according to stimulation regimes Clomid/HMG
FSH/HMG
GnRH analogue/HMG
No.
%
No.
%
No.
%
Biochemical pregnancy Miscarriage Ectopic pregnancy Singleton births Multiple births
4 5 2 11 3
16 20 8 44 12
13 26 4 20 13
17.1 34.2 5.3 26.3 17.1
10 13 0 8 1
31.3 40.6 0 25.0 3.1
Total
25
not be found and the stimulation regimes were not available. Pregnancy loss (both biochemical and clinical pregnancies) were highest in stimulation regime using GnRH analogues and hMG (Table 3). The difference is only statistically significant at 10% level when compared with clomid hMG regimes in terms of miscarriage.
B. Miscarriage The overall miscarriage rate in this series was 30.7% (44 cases). After conception the total pregnancy loss (including biochemical pregnancy and clinical miscarriage) was 39.8%. T E T pregnancies seem to have a much higher miscarriage rate. Table 3 indicates the distribution according to stimulation regime. Two cases of second trimester abortion occurred. The first occurred in a GIFT pregnancy of a 40 years old patient. She complained of no fetal movement for 5 days and a macerated still birth was terminated by intramuscular prostaglandin. The second was a twin pregnancy conceived by GIFT which occurred at 20 weeks. The mother had raised
76
32
No. record 0 0 0 8 2
10
blood pressure and started regular painful contraction. Inhibition with intravenous salbutomal failed. Retroplacental clot was noted at delivery of the placenta.
C. Ectopic Pregnancy The overall ectopic pregnancy rate was 4.2% if all pregnancies were considered. After excluding biochemical pregnancies, it occurred in 6 of the 116 clinical pregnanciesa rate of 5.2%. The incidence was higher in the IVF group (Table 2). I n 2 patients, an abdominal pregnancy co-existed with an intra-uterine pregnancy (hetero-trophic). The 2 intraabdominal pregnancies were removed at laparotomy at 8 weeks and 12 weeks respectively. Both cases had an uneventful antenatal period subsequently. One mother had a forceps delivery at 36 weeks of amenorrhoea for prolonged second stage. The other delivered in Malaysia also by the normal vaginal route.
D . Multiple Pregnancy There were 20 pregnancies with 2 viable fetuses during the ultrasound scan at 6 weeks 301
M.H.M. YANG ET AL.
Table 4. Antepartum complications among the 66 pregnancies conceived by ART Singleton (n=47)
Bleeding in Pregnancy Threatened abortion APH (placenta praevia) Others Hypertension Non Proteinuric Proteinuric Preterm deliver IUGR
Twins (n=15 sets)
Triplets (n=4 sets)
No.
%
No.
%
No.
%
19 1 2
40.4 2.1 4.3
6 0 1
40.0
2 0 1
50.0
1 8 5 0
2.1 17.0 10.6
0 9 10
2
6.7
60.0 66.7 13.3
25.0
0 0
4 2
100 50.0
APH : Antepartum haemorrhage, IUGR : intrauterine growth retardation
Table 5. The distribution of the timing of delivery among 66 pregnancies conceived by ART Completed weeks of amenorrhoea
Singleton (n=47) No.
%
Twins (n=15 sets) No.
%
Triplets (n=4 sets) No.
%
4
100
~~~
Outcome of 143 Pregnancies Conceived by Assisted Reproductive Techniques
Mary H.M. Yang, Soon-Chye Ng, Shan S. Ratnam, Sharath Devendra, Barry Marshall, C. Anandakumar, Yee-Chee Wong, and Ariff Bongso Department of Obstetrics and Gynaecology, National University of Singapore, National University HoQitaI, Singapore
Abstract One hundred and forty-three pregnancies conceived by assisted reproductive techniques (ART) from October 1985 to June 1989 in the National University Hospital, Singapore, resulted in 66 deliveries and 89 babies. There were 27 (18.7%) biochemical pregnancies, 44 (30.7%) clinical miscarriages and 6 (4.2%) ectopic pregnancies when total pregnancies were considered. Of those who continued pregnancy to second trimester multiple births occurred in 20 (13.3%) patients. A high incidence of vaginal bleeding and hypertension in pregnancy was noted in 32 (48.5%) patients and 18 (27.3%) patients, respectively. Caesarean section was the method of delivery in 48.5% of patients. Twenty-six (29.2%) babies required admission to the neonatal intensive care unit. All babies except one set of twins delivered at 24 weeks of amenorrhoea survived. Fetal abnormality was noted in 2 cases. Key words: pregnancy outcome, assisted reproductive techniques, in vitro fertilization, gamete-intra-fallopian transfer, tubal embryo transfer
Introduction Steptoe and Edwards reported the world’s first birth after in witro fertilization (IVF). Since then, IVF has brought new hope to childless couples who have no prospect of natural pregnancy. Much work and research have been done in the area of assisted reproduction. Many new techniques have evolved including gamete intrafallopian transfer (GIFT) and tubal embryo transfer (TET). There are not many detailed analysis of the
obstetric experience of pregnancy conceived in a single clinic using assisted reproductive techniques (ART). This paper analysed 143 pregnancies (including 27 biochemical pregnancies) to assess if they are of higher risk when compared with the general patient pool.
Materials and Methods Pregnancies conceived in the National University Hospital, Singapore, using assisted reproductive techniques from October 1985 till
Received: Jan.13,1992 Reprint request to: Dr. Soon-Chye Ng, Department of Obstetrics and Gynaecology, National University of Singapore, National University Hospital, Lower Kent Ridge Road, Singapore 0511
M.H.M. YANG ET AL.
June 1989 were analysed. These included pregnancies from GIFT, TET, IVF and those from subsequent thaw cycles with embryos from any of the above techniques. Three stimulation regimes were used. Group A received clomiphene citrate 50 mg twice a day on days 2-6 with the addition of human menopausal gonadotrophin, hMG (Pergonal, Serono) on an individualized dose from day 7. Group B received pure follicular stimulating hormone, FSH (Metrodin, Serono) 2 or 3 ampoules plus hMG (Pergonal, Serono) 1 ampoule on days 2-6 followed by an individualised dose of hMG subsequently from day 7. Group C received intranasal GnRH analogues (Buserelin, Hoechst) 300 pg thrice daily from day 22 onwards of the preceeding cycle till the day human chorionic gonadotrophin, hCG (Pregnyl, Organon) was given with the addition of hMG (Pergonal, Serono) after 15 days of GnRH agonist (Buserelin, Hoechst). Luteal phase support for groups B and C included intramuscular progesterone 25 mg given daily from 5th day post G I F T or T E T procedures or embryo replacement. Intramuscular hCG is given to those in group C on 5, 8, and 11 days. The maximum number of oocyte or embryo replaced was 4 in all cases. Beta-hCG and oestradiol levels were measured on the 14th and 16th day post GIFT, T E T or embryo replacement. Two positive and rising hCG levels above 25 IU/l were required to confirm a pregnancy. It is later confirmed with an ultrasound scan 6 weeks post procedure. If no gestational sac was seen despite 2 positive hCG values, the pregnancy was considered a biochemical one. A clinical pregnancy is said to have occurred when a gestational sac and fetal heart are demonstrated by either abdominal or vaginal scan. Miscarriage included all the pregnancies that ended before 28 completed weeks of amenorrhoea. Antenatal complications in singleton, twin and triplet pregnancies were studied. The number of patients requiring surgical induction and caesarean section were analysed. The need for neonatal intensive care and perinatal outcome were also studied. All ba-
300
bies born were screened by a paediatrician and any fetal abnormalities was noted.
Results Among 148 pregnancies the outcome of 5 clinical pregnancies were not known as the patients returned to a foreign country during the antenatal period after confirmation of the pregnancy by ultrasound scan. Of the 116 clinical pregnancies with known outcome there were 66 (46.2%) deliveries which produced 89 babies, 44 (30.7%) miscarriages and 6 (4.2%) ectopic pregnancies (Table 1). Characteristics of the patients and their pregnancy outcome in the different ethnic group and nationality were not different. Chinese and Singaporean made up at least 50% of the total patient pool. The mean maternal age for the various pregnancy outcome were similar and was 34.3 years (range of mean 32-35.4 years).
A. Biochemical Pregnancy Twenty-seven patients (18.9%) with 2 positive pregnancy tests did not proceed on to clinical pregnancies. Testing the difference between 2 proportions, those conceived by IVF have a higher percentage of biochemical pregnancy significant at the 10% level when compared to T E T (Table 2). This was not statistically significantly different at the 10% level when IVF and G I F T was compared. Unfortunately 10 of the ART format kept separately from the patient’s case record could Table 1. Outcome of 143 pregnancies conceived by ART techniques
Deliveries Singleton Twins (set) Triplets (set)
Biochemical pregnancy Miscarriage Ectopic pregnancy
No.
%
47 4
32.9 10.5 2.8
66
46.2
27 44 6
18.9 30.7 4.2
143
100.0
15
ART PREGNANCY OUTCOME
Table 2. The pregnancy outcome among 143 pregnancies conceived according to ART methods TET
GIFT
Biochemical pregnancy Miscarriage Ectopic pregnancy Singleton birth Multiple births
IVF
STC*
No.
%
No.
%
No.
%
No.
%
14 23 1 30 9
18.2 29.9 1.3 38.9 11.7
3 16 2 5 1
11.1 59.3 7.4 18.5 3.7
10 5 3 11 8
27.0 13.5 8.1 29.8 21.6
0 0 0 1 1
50 50
Total
77
27
37
2
* STC=Spontaneous thaw cycle Table 3. The pregnancy outcome of 143 pregnancies conceived according to stimulation regimes Clomid/HMG
FSH/HMG
GnRH analogue/HMG
No.
%
No.
%
No.
%
Biochemical pregnancy Miscarriage Ectopic pregnancy Singleton births Multiple births
4 5 2 11 3
16 20 8 44 12
13 26 4 20 13
17.1 34.2 5.3 26.3 17.1
10 13 0 8 1
31.3 40.6 0 25.0 3.1
Total
25
not be found and the stimulation regimes were not available. Pregnancy loss (both biochemical and clinical pregnancies) were highest in stimulation regime using GnRH analogues and hMG (Table 3). The difference is only statistically significant at 10% level when compared with clomid hMG regimes in terms of miscarriage.
B. Miscarriage The overall miscarriage rate in this series was 30.7% (44 cases). After conception the total pregnancy loss (including biochemical pregnancy and clinical miscarriage) was 39.8%. T E T pregnancies seem to have a much higher miscarriage rate. Table 3 indicates the distribution according to stimulation regime. Two cases of second trimester abortion occurred. The first occurred in a GIFT pregnancy of a 40 years old patient. She complained of no fetal movement for 5 days and a macerated still birth was terminated by intramuscular prostaglandin. The second was a twin pregnancy conceived by GIFT which occurred at 20 weeks. The mother had raised
76
32
No. record 0 0 0 8 2
10
blood pressure and started regular painful contraction. Inhibition with intravenous salbutomal failed. Retroplacental clot was noted at delivery of the placenta.
C. Ectopic Pregnancy The overall ectopic pregnancy rate was 4.2% if all pregnancies were considered. After excluding biochemical pregnancies, it occurred in 6 of the 116 clinical pregnanciesa rate of 5.2%. The incidence was higher in the IVF group (Table 2). I n 2 patients, an abdominal pregnancy co-existed with an intra-uterine pregnancy (hetero-trophic). The 2 intraabdominal pregnancies were removed at laparotomy at 8 weeks and 12 weeks respectively. Both cases had an uneventful antenatal period subsequently. One mother had a forceps delivery at 36 weeks of amenorrhoea for prolonged second stage. The other delivered in Malaysia also by the normal vaginal route.
D . Multiple Pregnancy There were 20 pregnancies with 2 viable fetuses during the ultrasound scan at 6 weeks 301
M.H.M. YANG ET AL.
Table 4. Antepartum complications among the 66 pregnancies conceived by ART Singleton (n=47)
Bleeding in Pregnancy Threatened abortion APH (placenta praevia) Others Hypertension Non Proteinuric Proteinuric Preterm deliver IUGR
Twins (n=15 sets)
Triplets (n=4 sets)
No.
%
No.
%
No.
%
19 1 2
40.4 2.1 4.3
6 0 1
40.0
2 0 1
50.0
1 8 5 0
2.1 17.0 10.6
0 9 10
2
6.7
60.0 66.7 13.3
25.0
0 0
4 2
100 50.0
APH : Antepartum haemorrhage, IUGR : intrauterine growth retardation
Table 5. The distribution of the timing of delivery among 66 pregnancies conceived by ART Completed weeks of amenorrhoea
Singleton (n=47) No.
%
Twins (n=15 sets) No.
%
Triplets (n=4 sets) No.
%
4
100
~~~
