Key words embryonic period - malformation - infertility - pregnancy - reproductive medicine
- sonography
Schlüsselwörter Embryonalstadium - Fehlbildung - Unfruchtbarkeit - Schwangerschaft - Reproduktionsmedizin
- Ultraschall
Introduction
We report on a 38-year-old female with secondary infertility and multiple fibroids
who underwent diagnostic hysteroscopy and laparoscopic myomectomy involving opening
of the uterine cavity during the implantation stage of an undetected pregnancy. To
our knowledge, only three other cases have been published on invasive procedures (hysteroscopy,
laparoscopy and chromopertubation) involving the uterine cavity during the implantation
stage. None of these other cases involved myomectomy or opening of the uterine cavity
[1 ], [2 ], [3 ].
Our patient underwent a scheduled cesarean section in week 37 and delivered a child
with congenital cerebellar vermis hypoplasia, a rare complex malformation of the brain
with multiple causes, as described in the Discussion section below.
Case Presentation
A 38-year-old patient and her husband of African origin presented with secondary infertility.
They had been trying to have children for six years. Three years ago, they achieved
a spontaneous pregnancy, which ended at around 20 weeks of gestation at the coupleʼs
home in Africa. The patient could not provide any information or documentation that
would have given a clue about the potential etiopathology of this miscarriage. The
patient had multiple uterine fibroids. On presentation to our infertility clinic,
she reported regular menstrual periods of 3–5 days every 27–28 days with severe dysmenorrhea.
We found no indication of hyperandrogenism, and the patient did not report hypermenorrhea.
In addition to her infertility, she complained of recurrent mild back pain and pelvic
pain which did not require medication. She reported no significant diseases or prior
operations and no use of drugs or medications. Endocrine work-up in the early follicular
phase including androgens was not significant apart from an elevated FSH of 15.7 U/l
and a low AMH of 0.3 ng/ml. Transvaginal and abdominal ultrasound showed four fibroids:
the first was located intramurally at the fundus and measured 60 × 66 × 52 mm; the
second was located close to the cervix subserosally and measured 47 × 47 × 45 mm;
the third was located subserosally in the anterior wall and measured 47 × 38 × 40 mm;
and the fourth was located intramurally in the anterior wall and measured 30 × 30 × 40 mm.
The endometrial lining was irregular and intracavitary fibroids could not be excluded.
Semen analysis of the husband showed a volume of 0.9 ml and a total sperm count of
24 million. Sperm motility grade A and B was 35 %, and normal sperm morphology was
20 %. According to the WHO criteria (2010) this represents hypospermia. The 57-year-old
male patient had fathered three children aged 31, 21 and 19 with a previous wife.
Because of her fibroids and her infertility combined with chronic back and pelvic
pain, the patient was offered laparoscopic chromopertubation, hysteroscopy and myomectomy.
Routine preoperative blood work-up carried out 5 days prior to surgery on cycle day
15 was normal, and serum hCG was undetectable (< 0.1 IU/l). Hysteroscopy showed an
unremarkable cavity and no evidence of transmural or intracavitary fibroids. Both
proximal tubal ostiums could be visualized and were unremarkable. Five fibroids were
seen on laparoscopy ([Fig. 1 ]): 1. intramural fibroid at the fundus (6 cm); 2. subserosal fibroid close to the
entrance of the right fallopian tube (4 cm); 3. subserosal fibroid close to the cervix
(4 cm); and two further small subserosal fibroids (each 2 cm). Both fallopian tubes
and ovaries appeared normal. On chromopertubation, no dye could be passed through
the tubes, even with increasing pressure. The large fibroid at the fundus and the
fibroid close to the fallopian tube were removed. During myomectomy, the uterine cavity
was opened with a transverse incision measuring 3 cm and was subsequently closed with
4 deep simple interrupted stitches. The operation took a total of 120 minutes and
there were no complications or significant blood loss. The patient recovered well
and was discharged home on the third postoperative day. Because of the tubal findings,
we recommended IVF at 6 months after the operation.
Fig. 1 Laparoscopic surgery: myomectomy of the large fibroid at the fundus.
After 4 weeks the patient presented with nausea and pelvic pain. Ultrasound examination
showed an intact intrauterine pregnancy with an embryonic heartbeat and a CRL of 18 mm,
corresponding to the 8 + 1 week of gestation p. m. According to this biometry, the
patient had conceived one day prior to her preoperative blood hCG test, and she was
in the 2 + 6 week of gestation on the day of the operation. The couple was given detailed
information about the situation and all potential maternal and fetal risks involved,
including preterm labor, preterm delivery, uterine rupture and abnormal placental
implantation. In addition, a thorough evaluation of the potentially teratogenic effects
of the operation and related compounds was done ([Table 1 ]). The Pharmacovigilance and Counseling Center for Embryonic Toxicology at the Charité
in Berlin did not report any teratogenic or toxicological hazards. Findings at consecutive
ultrasound examinations performed in weeks 10 and 13 were limited due to the remaining
fibroids but showed normal biometry, fetal growth, and placental implantation. For
religious reasons, the patient preferred not to undergo nuchal translucency screening.
In week 18, sonography showed an enlarged cisterna magna and an echogenic intracardiac
focus. At this point, amniocentesis and karyotyping of the fetus were recommended,
but the couple decided against it, again for religious considerations. Ultrasound
in week 20 confirmed the enlarged cisterna magna and mild ventriculomegaly as well
as potential hypoplasia of the cerebellar vermis ([Fig. 2 ]). An MRI, recommended for further evaluation, also confirmed these findings. The
couple was informed in detail about this particular syndrome, its prognosis and the
consequences for infantʼs later life and clearly stated their decision not to intervene
with the pregnancy. Fetal growth and general development remained within normal limits,
but in week 37 sonography indicated progressive thinning of the myomectomy scar. An
elective cesarean section was scheduled to avoid the risk of uterine rupture. At 36 + 6
weeks of gestation, a female infant of normal weight and size (length 48 cm; 38th
percentile), weighing 2810 g was delivered with Apgar scores of 9/10/10. Her immediate
postnatal adaptation was normal. Initially the little girl presented with hypoglycemia
of 43 mg/dl and hyperbilirubinemia. From day 3, both values were normal. Findings
of postnatal neurological examination and developmental neurological examinations
were within normal ranges. The child drank normally and had a normal weight gain.
An MRI on day 5 showed a complex brain malformation with congenital cerebellar vermis
hypoplasia, moderate microcephaly, and multiple heterotopias ([Fig. 3 ]). In addition, ultrasound examination showed left renal dysplasia. Both kidneys
were small and the left kidney showed hyperechogenic parenchyma at the lower pole.
Ophthalmologic examination was within normal ranges except for an abnormal configuration
of the papillae. After 10 days the little girl was discharged with her mother with
the recommendation that she should have an ultrasound examination of her kidney together
with a check-up by the nephrology outpatient clinic after 3–4 months, she should be
followed up by the department for developmental neurology and should receive regular
physiotherapy.
Fig. 2 Fetal ultrasound imaging at 25 weeks of gestation shows hypoplasia of the cerebellar
vermis with an enlarged cisterna magna.
Fig. 3 Neonatal MRI: sagittal T2-weighted image shows hypoplasia of the vermis with malrotation.
Table 1 Potential teratogenic effects of the operation and related compounds; Source: Pharmacovigilance
and Counseling Center for Embryonic Toxicology at the Charité in Berlin, Germany.
Medication
Potential teratogenic effect
Midazolam
none
Sufentanil
none
Cefuroxime
none
Propofol
none
Mivacurium
none
Dexamethasone
none
Ranitidine
none
Dexketoprofen
none
Indigo carmine dye
none
Developmental neurological examination at three months showed normal somatic development,
good communication behavior and eye contact. But the movement patterns of the girl
were suspicious, with erratic, isolated movements of the arms and legs and a rigid
posture of the left arm, as well as limited control of the head when lifting it up.
In addition, the girl had a discrete intermittent nystagmus and propulsive movements
of the tongue. This amounts to a central motor disorder which can be only classified
further when the girl is older.
Discussion
We report on a case of a woman who had hysteroscopy, laparoscopy with myomectomy involving
hysterotomy and chromopertubation during the implantation stage of an unknown pregnancy.
To the best of our knowledge this is the first case that describes a term pregnancy
after myomectomy with opening of the uterine cavity during the early implantation
stage.
Uterine fibroids are common in women of reproductive age and prevalence rates range
from 20–50 % [4 ]. Depending on their location fibroids are associated with impaired fertility, abnormal
sites for placental implantation as well as an increased risk of spontaneous abortion
or preterm labor and delivery [5 ]. Fertility outcomes are decreased in women with submucosal fibroids, and removal
of such fibroids seems to confer benefit. The effect of intramural fibroids remains
unclear. If they have an impact on fertility it appears to be small, depending on
the size and if the endometrium is involved.
According to the patientʼs menstrual history and consecutive sonographies, the gestational
age on the day of the operation was probably around 2 + 6 weeks of gestation p. m.
This is consistent with a negative hCG serum concentration (< 2 IU/l) 5 days prior
to this date. Neither the hysteroscopic examination, which used saline to distend
the uterine cavity, nor the chromopertubation or the myomectomy with opening of the
uterine cavity disrupted the pregnancy. This could be explained by the stable adhesion
between blastocyst and early decidua that has been reported for the adhesion phase,
even prior to invasion phase of the implantation process. The implantation process
involves three key phases: apposition, stable adhesion, and invasion of the blastocyst.
The apposition phase is characterized by the start of interaction and attachment between
the blastocyst and the apical surfaces of the endometrium. This process is strongly
influenced by the adhesion molecule L-selectin [6 ], [7 ]. More stable attachments are formed during the adhesion phase involving interaction
of integrins. Finally, the blastocyst invades between luminal epithelial cells and
embeds itself between the stromal cells of the endometrium on the 6th – 7th day after
fertilization [8 ]. It is only at this stage when the embryo connects to the maternal circulation that
hCG can be detected in maternal blood.
This timing of the gestation is consistent with the fact that no signs of an early
pregnancy were detected on hysteroscopy. The early implantation site is thought to
be significantly smaller than 1 mm2 [9 ], and a site of this size could not be identified hysteroscopically. During the further
course of this pregnancy, the placental implantation site was monitored closely by
high resolution sonography but did not show any pathologies. All medications, anesthetics
and dyes which were used were evaluated in cooperation with the Pharmacovigilance
and Counseling Center for Embryonic Toxicology at the Charité in Berlin, which did
not find any hint of toxic or teratogenic effects.
Fetal biometry and growth remained within normal limits during the entire course of
the pregnancy. However, the uterine wall at the site of the myomectomy showed progressive
thinning so that an elective cesarean section was performed at 36 + 6 weeks of gestation.
To date, only a few successful pregnancy outcomes have been reported after an inadvertent
invasive procedure such as hysterosalpingography, laparoscopy, or chromopertubation
during early pregnancy [1 ], [2 ], [3 ]. It should be noted that none of the previously described cases reported a myomectomy
with opening of the uterine cavity.
The female newborn was of normal size and weight and had a complex brain malformation
with congenital cerebellar vermis hypoplasia, moderate microcephaly, and multiple
heterotopias. In addition, ultrasound revealed dysplasia of the left kidney. The right
kidney was normal and BUN (blood urea nitrogen) was within normal ranges. These anomalies
may be due to a wide range of causes, such as ionizing radiation in the second half
of the pregnancy [10 ], drugs such as phenytoin [11 ], viral causes such as cytomegalovirus infection during pregnancy [12 ], [13 ], and chromosomal syndromes such as trisomy 18 [14 ] and trisomy 21 [15 ], all of which have been associated with congenital cerebellar vermis hypoplasia.
These anomalies can also be part of complex malformations such as Marsden-Walker syndrome
[16 ]. It should be noted that neural development starts at week 5, which was more than
2 weeks after surgery was performed in our case. It is difficult to estimate the influence
that the invasive surgical procedure performed during very early pregnancy may have
had on the complex disorder documented in the female neonate born to our patient,
as no other cases of comparable operations have been reported to date.
A large Swedish study covering 2 million deliveries in Sweden examined fetal outcomes
after laparoscopy and laparotomy performed between the fourth and the twentieth week
of gestation. A total of 2181 patients with laparoscopy and 1522 with laparotomy were
evaluated but none of the cases involved opening of the uterine cavity. Pregnancies
where the mother underwent surgery were compared with the total population for birth
weight, duration of gestation, growth restriction, infant survival, and fetal malformations.
The study revealed a significantly increased risk for infants in both the laparoscopy
and the laparotomy groups of weighing < 2500 gm and being delivered before 37 weeks
of gestation, as well as a higher incidence of infants with growth restriction compared
to the total population. There were no differences in the rate of fetal malformations
or the cumulative infant survival rates up to 1 year compared to the total population
[17 ].
Conclusion
Laparoscopies and hysteroscopies are usually scheduled in the follicular phase of
the cycle. However, patients with an oligomenorrhea/amenorrhea or irregular cycles
may be difficult to schedule. In addition, patients may alter the timing of the procedure
for personal reasons. We always perform hCG tests prior to any surgery. However, this
case documents the limitations of our approach in excluding very early pregnancy.
A hysteroscopy or laparoscopy should preferably always be done in the follicular phase,
but the risks of luteal phase surgery for an unrecognized pregnancy may be lower than
expected.
