Repeated biochemical pregnancy
loss – definition, potential loss – definition, potential
causes, prognosis and treatment
Ole B. Christiansen
Fertility Clinic 4071 Rigshospitalet, Copenhagen
and Dept. of Obstetrics and Gynaecology, Aalborg
Hospital, Denmark
Questions to be addressed
• What is the cause of repeated biochemical
pregnancy losses?
• How do biocehmical pregnancy losses
affect the future pregnancy prognosis?
In theory biochemical pregnancy
losses can be
• Death of embryos after implantation in the
uterus before visibility by ultrasound
or
• Spontaneously resorbed ectopic pregnancies
Inclusion criteria
• Patients with at least 3 involuntary
pregnancy losses before GA 22 weeks
confirmed by pregnancy test, plasma hCG, confirmed by pregnancy test, plasma hCG,
ultrasound or histology after D&C
• Referred to the Danish recurrent
miscarriage clinic after January 2000
Exclusion criteria• Previous birth or stillbirth
• Incomplete pregnancy records
• Age > 42 years at referral
• Lupus anticoagulant, significant uterine abnormality or parental chromosome abnormality
• Irregular mestruations with intervals < 21 or > 35 days
• Pregnancy after IVF/ICSI/FET
Definition 1
• Miscarriage: intrauterine pregnancy
documented by ultrasound and/or histology
of tissue from the uterusof tissue from the uterus
• Biochemical pregnancy: loss in the first
trimester without documentation of
intrauterine pregnancy as above
Definition 2
• Miscarriage: 1) loss after 6th completed GW irrespective of findings by ultrasound/histology or 2) loss prior to 6th week with documentation of intrauterine pregnancy by ultrasound/histology.
• Biochemical pregnancy: loss prior to 6th completed GW with no ultrasound or histology being undertaken or ultrasound showing an empty uterus
Example: 1st pregnancy
Positive
pregnancy test Vaginal bleeding Ultrasound:
empty uterus, endometrium 4 mm
Missed
period
According to definition 1 this is classified as a biochemical
pregnancy, according to definition 2 as a miscarriage
GW5 GW6 GW7 GW8
Types of intrauterine pregnancies in 204 RM patients
• Definition 1
• 340 biochemical pregnancies
• 469 miscarriages
• Biochemical pregnancy rate = 42.0%• Biochemical pregnancy rate = 42.0%
• Definition 2
• 264 biochemical pregnancies
• 545 miscarriages
• Biochemical pregnancy rate = 32.6%
• A possible association between repeated
biochemical pregnancies and biomarkers
linked to recurrent miscarriage emphazises
the belief that repeated biochemical
pregnancies are indeed very early deaths of
intrauterine pregnanciesintrauterine pregnancies
Not addressed in this presentation
Questions to be addressed
• What is the cause of repeated
biochemical pregnancy losses?
• How do biocehmical pregnancy losses affect the future
pregnancy prognosis?
• A possible association between repeated
biochemical pregnancies and clinical
ectopic pregnancies emphazises the belief
that repeated biochemical pregnancies are
indeed spontaneously resorbed ectopic
pregnanciespregnancies
Addressed in this presentation
Confirmed ectopics in groups of recurrent miscarriage patients
according to no. of prior biochemical pregnancies and
confirmed miscarriages (definition 1)
2000%
2500%
3000% N = 22
P = 0.00002 comparing % patients with ectopics
0%
500%
1000%
1500%
2000%
0 misc 1 misc 2 misc 3 misc 4+ misc
ectopics
N = 29 N = 67 N = 69 N = 22
Birth
year
Prior
PID
1st 2nd 3rd 4th 5th 6th 7th
1970 Yes Ex* Term Bio Bio Bio
1974 No Bio Bio Bio Bio Ex* Bio
History of the 6 patients with only biochemical pregnancies and ectopics
1974 No Bio Bio Bio Bio Ex* Bio
1969 No Bio Ex* Bio Bio
1968 No Bio Bio Bio Bio Ex* Bio
1978 No Bio Bio Bio Ex** Bio Bio Bio
1973 No Bio Ex* Bio Bio Bio
* = unilat. salpingectomy; ** tubotomia
Mean
age
No. Remark Subsequent
treatment
Outcome of first
subsequent
pregnancy
Final outcome
32 7 1 Mb. Crohn None/IUI 7 Live births
34 2 None/IUI 2 Mis/bio 2 Live births
35 6 None No pregnancy
Subsequent pregnancy outcome in 22 patients with only biochemical
pregnancies and ectopics
35 6 None No pregnancy
32 2 1 Mb Crohn IVF 2 Live births
34 4 IVF 4 Mis/bio 2 Live births
33 1 Severe
hyperhomocyste-
aemia
High dose
folate
Live birth
Cumulative live birth rate in all patients: 14/22 = 63.6%
Born in 1979, reg. cycle 30 days, BMI: 20.4, never clinical
salpingitis, normal hysteroscopy, karyotypes 46XX, 46XY
Normal trombophilia screening. No autoantibodies, AMH 33 pmol/l
Pos preg.
testS-hCG
Max 604
S-hCG
Max 431
S-hCG
Max 534
S-hCG
Max 2269
2 IVF +
2 FER,
no preg.
Spontaneous
conception
Spontaneous conception
Bleeding
GW 6
2006 2007 2008
Bleeding
GW 6
Bleeding
GW 68 mm GS + 4 mm
yolk sac in right
uterine corner
Emergency
laparoscopic
bilateral
salpingectomia
Bleeding
GW 7Bleeding
GW 7
A very relevant clinical question: does the
presence of biochemical pregnancies in the
reproductive history affect the chance ofreproductive history affect the chance of
a subsequent live birth?
Frequency of miscarriage/biochemicals/ectopics in the next pregnancy
among women with RM according to no. of previously confirmed
miscarriages (definition 1)
40
50
60
No
. p
reg
na
ncie
s
28% 37%
0
10
20
30
40
No
. p
reg
na
ncie
s
0 mis +
3+ bio
1 mis +
2+ bio
2 mis +
1+ bio
3 mis +
0+ bio
4+ mis +
0+ bio
Losses
Births27%
37% 63%
No significant differences between loss rates in different groups
Frequency of miscarriage/biochemicals/ectopics in the next pregnancy
among women with RM according to no. of previously confirmed
miscarriages (definition 2)
40
50
60
No
. p
reg
na
ncie
s
24%
38%
55%
0
10
20
30
40
No
. p
reg
na
ncie
s
0 mis +
3+ bio
1 mis +
2+ bio
2 mis +
1+ bio
3 mis +
0+ bio
4+ mis +
0+ bio
Losses
Births25%
47%
55%
No significant differences between loss rates in different groups
60
70
80
90
100
Loss rates in first pregnancies after referral of patients with < 2 prior
miscarriages according to previous number of miscarriages (m) and
biochemics (b)
7 6
3 1
13 5
2 5
0
10
20
30
40
50
0+3 0+4 0+5 1+2 1+3 1+4 2+1 2+2 2+3
Def 1
Def 2
m + b
Numbers in subgroups too small for valid comparisons
5 4
5 4
33 3415 12 6 5
Frequency of miscarriage/biochemicals/ectopics in the next pregnancy
among women with 3 confirmed miscarriages according to no. of previous
biochemicals (definition 1)
20
25
30
No
. p
reg
na
ncie
s
32% NS
0
5
10
15
20
No
. p
reg
na
ncie
s
3 mis 3 mis + 1
bio
3 mis +
1bio
Losses
Births
39%
No significant differences between future loss rates in different groups
43%
Frequency of miscarriage/biochemicals/ectopics in the next pregnancy
among women with RM according to no. of previous miscarriages and
biochemicals (definition 1)
20
25
30
No
. p
reg
na
ncie
s
32%
40%
NS
0
5
10
15
No
. p
reg
na
ncie
s
3 mis 3 mis +
1bio
4 mis 4 mis +
bio
5 mis 4 mis +
bio
Losses
Births
40%
No significant difference between future loss rates in different groups
50%71%
50% 100%
Frequency of miscarriage/biochemicals/ectopics in the next pregnancy
among women with 3 confirmed miscarriages according to no. of previous
biochemicals (definition 2)
25
30
35
40
No
. p
reg
na
ncie
s
27% P = 0.05
0
5
10
15
20
25
No
. p
reg
na
ncie
s
3 mis 3 mis + 1
bio
3 mis +
1bio
Losses
Births
50%
P = 0.05 for the difference between future loss rates in different groups
57%
Frequency of miscarriage/biochemicals/ectopics in the next pregnancy
among women with RM according to no. of previous miscarriages and
biochemicals (definition 2)
25
30
35
40
No
. p
reg
na
ncie
s
27%
52%
P = 0.05
0
5
10
15
20
25
No
. p
reg
na
ncie
s
3 mis 3 mis +
1bio
4 mis 4 mis +
bio
5 mis 4 mis +
bio
Losses
Births
52%
P = 0.05 for the difference between future loss rates in different groups
40%
57%67%
100%
Conclusion 1
• Biochemical pregnancies comprise a
significant proportion (33-42%) of
pregnancy losses among Danish patients pregnancy losses among Danish patients
diagnosed with recurrent miscarriage
Conclusion 2
• Among patients with exclusively biochemical
pregnancies the risk of a clinical ectopic
pregnancy is considerable (27%)
• Among other patients with a diagnosis of recurrent
miscarriage the risk of a clinical ectopic pregnancy
is much lower and at the same level as in the
background population
Conclusion 3
• The risk of a new miscarriage/biochemical
loss seems to be independent of the number
of biochemical pregnancies included in the of biochemical pregnancies included in the
patient’s reproductive history in patients
with less than 3 confirmed miscarriages
Conclusion 4
• In patients with 3 or more confirmed
miscarriages each additional biochemical
loss significantly increases the risk of new loss significantly increases the risk of new
pregnancy loss
Conclusion 5
• In patients dignosed with recurrent
miscarriage but with exclusively repeated
biochemical pregnancies, IVF may be the biochemical pregnancies, IVF may be the
best treatment option
Thank you for
your attention
