Arch Gynecol Obstet
DOI 10.1007/s00404-016-4012-2
REVIEW
Management of osteogenesis imperfecta type I in pregnancy;
a review of literature applied to clinical practice
Mauro Cozzolino1 • Federica Perelli1 • Luana Maggio1 • Maria Elisabetta Coccia1
Michela Quaranta2 • Salvatore Gizzo3 • Federico Mecacci1
Received: 25 July 2015 / Accepted: 5 January 2016
Ó Springer-Verlag Berlin Heidelberg 2016
Abstract
Purpose Osteogenesis imperfecta (OI) is a rare herita-
ble heterogenous disorder characterized by bone fragility
and susceptibility to fractures with a wide spectrum of
clinical expression due to defects in collagen type I
biosynthesis. The purpose of the review is to highlight the
practical norms in pregnancies with osteogenesis
imperfecta.
Methods We carried out a literature review in MEDLINE
on OI during pregnancy, focusing on diagnosis, therapy
and delivery. We reviewed 28 articles (case reports, orig-
inal articles and reviews).
Results Pregnant women affected by type I OI should be
closely monitored to assess fetal well-being and detect
pregnancy-related complications associated with an
increased risk for osteoporosis, restrictive pulmonary dis-
ease, cephalopelvic disproportion and other problems
related to connective tissue disorders. Mode of delivery
remains controversial and should be determined on an
individual basis.
Conclusion In conclusion, women affected by type I OI
represent a subset of patients whose pregnancies should be
considered high risk and warrant a multidisciplinary
approach in a referral center.
& Mauro Cozzolino
maurocoz@yahoo.it
1
Department of Biomedical, Experimental and Clinical
Sciences - Division of Obstetrics and Gynecology, University
of Florence, Largo Brambilla 3, 50134 Florence, Italy
2
Department of Obstetrics and Gynecology, NHS Trust,
Northampton General Hospital, Northampton, UK
3
Department of Woman and Child Health, University of
Padua, 35128 Padua, Italy
•
Keywords Osteogeneis imperfecta
Pregnancy

Biphosphonates
Anesthesiologic technique
Introduction
Osteogenesis imperfecta (OI), first described in the sev-
enteenth century, is a heterogeneous group of inherited
connective-tissue disorders characterized by bone fragility
and low bone mass and susceptibility to bone fractures with
variable severity [1]. OI is most frequently caused by
mutations in the genes that code for certain proteins that
constitute the chains of type I collagen [2] or proteins
involved in post-translational modification of collagen type
I. Type I collagen fibers are polymers of molecules
tropocollagene, each of which is a triple propeller. The
most frequently occurring mutations are autosomal domi-
nant mutations in COL1A1 (located 17q21.31-q22) or
COL1A2 (located 7q22.1) that alters the structure of one of
the two alphachains in collagen type I. The diagnosis is
relatively easy in patients with bone fragility and a positive
family history or in the presence of extraskeletal events [3].
However, in the absence of overt clinical manifestations,
diagnosis can be difficult. The various phenotypes have
been classified by Sillence and colleagues into four groups
according to clinical, radiological and genetic criteria. In
cases of OI type I, bone fragility is less severe than other
forms with a variable fracture rate ranging from very few
or no fracture before puberty to several throughout life [4].
Deformity is minimal and stature is usually normal.
Individuals with type I OI occasionally present in the
perinatal period with intrauterine femoral bowing or frac-
tures, but rarely present with fractures until they begin
toddling or walking [5]. Treatment of OI requires a mul-
tidisciplinary approach. Physiotherapy, rehabilitation, and
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orthopedic surgery are the mainstays of treatment. In recent
years there have been interesting developments in the
medical management of OI. Biphosphonates have been
shown to increase bone turnover, decrease fracture rates,
and relieve symptoms in patients with OI [6].
Few data-based guidelines exist for the obstetric man-
agement of OI during pregnancy. Recommendations in the
literature have been based on the experience of case reports
or small case series. Our case brings into focus a series of
internistic, obstetric and anesthesiological investigations
we believe should be performed in this patient subgroup.
We commented on the optimal management during preg-
nancy in patients affected by OI type I, based on our
experience and review of current literature.
Methods
Data sources
A literature analysis was performed on the electronic data-
bases Medline, Embase, and Science Direct considering
papers published in English in the time interval from 1952 to
2014. We searched for case reports, observational and ret-
rospective studies, original works, and review articles on the
topic of management of maternal osteogenesis during
pregnancy. We performed using key-terms ‘‘osteogenesis
imperfecta and pregnancy’’, ‘‘maternal osteogenesis imper-
fecta’’ and ‘‘management osteogenesis imperfecta’’.
A total of 375 articles were identified through this
search. We selected 28 articles focusing on the pregnancy
outcome in patients affected by OI. Among these were 25
case reports, 1 original article and 2 reviews, no clinical
trials about OI management in pregnancy were found.
Only one large survey investigating type of delivery in
women affected by osteogenesis imperfecta has been pub-
lished but, to our knowledge, no systematic review of preg-
nancies has been published. We report a case of pregnancy in
an affected woman and reviewed the currently available
literature regarding pregnancy in patients with OI.
We evaluated the clinical significance of the diagnosis
of OI before pregnancy and possible complications of
gestation, and the role of medical therapy during preg-
nancy. We analyzed the optimal mode of delivery and the
choice of anesthesia. We discussed ideal medical surveil-
lance during pregnancy and especially the importance of
the multidisciplinary approach in the event of pregnancy in
women with OI.
Case presentation
A 29-year-old woman affected by type I osteogenesis
imperfecta, with a height of 116 cm and a weight of 51 kg
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Arch Gynecol Obstet
(BMI 37.9), was referred to our hospital at 7 weeks of
gestation. She was diagnosed with OI during the seventh
month of her intrauterine life due to the presence of fetal
fractures. The diagnosis was subsequently confirmed clin-
ically following the occurrence of multiple fractures and
consequent surgical procedures; however, she never
underwent any genetic testing prior to conception. There
was no family history of OI, and no congenital defects or
genetic syndromes were seen up to three generations.
Due to the presence of kyphoscoliosis with chest volume
reduction and a family history of cardiomyopathy, we
performed additional cardiologic evaluations during preg-
nancy: two transthoracic cardiac ultrasounds showed nor-
mal heart function, and blood pressure was strictly
monitored. Before conceiving, our patient was treated with
infusions of quarterly Sodium neridronate, an aminobis-
phosphonate, with the last administration carried out in
July 2013 and on such occasion performed a dual-energy
X-ray absorptiometry (DXA) scan. Her bone mineral
density (BMD) was compatible with stable mild osteo-
porosis, a satisfying result for a patient with OI, and
therefore discontinued neridronate therapy at the beginning
of pregnancy. During the entire pregnancy, only vitamin D,
vitamin supplements, and calcium were prescribed and
laboratory tests, including several metabolic parameters,
remained in the normal range. Furthermore, chromosomal
mapping was performed on peripheral blood cells, showing
a heterozygous missense mutation in the COL1A1 gene.
Our patient then declined the option of invasive prenatal
diagnosis, and an intense ultrasound monitoring began.
Level II ultrasound follow-ups in the third trimester
showed a normal fetus with no bone abnormalities.
An elective cesarean section was performed under spinal
anesthesia at 36 ? 6 weeks. Intraoperatively, the patient
remained hemodynamically stable and blood values (CBC,
renal function, blood glucose levels, and coagulation) were
normal. The patient was monitored by continuous cardio-
graphy, pulse oximetry, and non-invasive blood pressure
monitoring. The newborn weighed 2780 g, his Apgar score
at birth was 7–8, and venous pH 7.22.
After childbirth, our patient developed uterine atony
treated by intravenous oxytocin (20 UI) and misoprostol
suppository (600 lg).
The post-partum was uneventful and the patient was
discharged three days after delivery.
Literature review
Analysis of cases of OI present in the literature show a
predominance of OI of type I from 28 articles cited, 13
articles concern type I (Table 2), likely due to the better
prognosis in this group. The average age at the time of
pregnancy was 25.2 years. Almost all the articles cited did
Arch Gynecol Obstet
not report data about the use of medical therapy for the
control of OI in pregnancy Chen et al. discontinued therapy
with Pamidronate in the first month of pregnancy, while
Anderer et al. had suggested the association of calcium and
vitamin D. As shown in Table 2, in the majority of cases
delivery was by cesarean section. Regarding the type of
anesthesia, in most cases it is not clear what technique was
used, we report five cases with epidural anesthesia, three
under general anesthesia, one spinal anesthesia, one com-
bined anesthesia. Table 2 shows the various complications
during pregnancy, for the most part, these complications
involve the skeletal system, one case of malignant hyper-
thermia, two cases of severe pain, one case of uterine
rupture. A total of four cases of the disease transmitted to
the fetus genetically.
Discussion
Osteogenesis imperfecta (OI) is the collective term for a
heterogeneous group of connective-tissue syndromes
characterized by mutations in collagen genes with clinical
manifestation depending on genetic involvement. Its inci-
dence varies between 1 in 20,000 and 1 in 60,000 in the
literature [7]. Based on the pattern of inheritance and nat-
ural history, OI is classically divided into four subtypes,
with the most common and benign form being type I and
the most severe type IV; recently, thanks to radiographic,
bone morphology studies, and molecular genetic analyses,
seven categories of OI are now identified [8]. The diag-
nosis, which can be suspected beginning in fetal life, is
usually based on typical clinical and radiological features,
and then confirmed by biochemical and genetic tests. Type
I collagen is the major protein component of bone and
many other connective tissues, so its alteration can cause a
wide range of clinical manifestations.
The main clinical features of OI are: recurrent fractures
and other skeletal issues, very short stature, thoracic scol-
iosis with spine deformity, blue sclerae, hyperhidrosis,
conduction deafness, hyper-metabolism and hyperthermia,
odontological deformities, platelet dysfunction, congenital
cardiopathy, and fragility of many tissues including bone,
joints, blood vessels and skin. Many of these manifesta-
tions can cause pregnancy-related complications as repor-
ted in Table 1 [7, 9]. It is of the utmost importance to seek
anesthesiological evaluation in early pregnancy, due to the
possible challenges these patients may present [10]. In fact,
general anesthesia could be complicated by intubation
difficulties due to short neck, temporal and occipital pro-
jections, and prominent mandible, while spinal anesthesia
could be more challenging due to spinal deformities.
To date, most patients discontinue bisphosphonates
infusions from the start of pregnancy due to the relative
stability of disease revealed by DEXA scans possibly
linked to the beneficial effects of different hormones levels
achieved early in the first trimester of pregnancy [11].
Bisphosphonates inhibit osteoclast bone reabsorption
by interfering with the mevalonate pathway of cholesterol
biosynthesis, and exposure to these drugs during
intrauterine life could cause skeletal abnormalities or
congenital malformations. The use of bisphosphonates in
women of child-bearing age raises the concern that the
fetus may potentially be exposed to drug released from
the maternal bone if the mother received bisphosphonates
before conception, or directly transmitted from the pla-
centa if the mother receives them during pregnancy [12].
Therefore, it has been recommended that all bisphos-
phonates be relatively contraindicated in females of
reproductive age [13]. There is no global consensus
regarding the use of bisphosphonates prior to conception,
and the cases summarized in Table 2 give scarce infor-
mation about the effect of therapy during pregnancy;
however, many studies recommend discontinuation of
therapy after conception, due to possible adverse fetal
outcomes, even though an absence of fetal risks after
exposure to bisphosphonates in the first trimester has also
been reported [14].
During pregnancy, laboratory tests should be obtained
every 3 months and biochemical findings such as calcium,
phosphate, vitamin D, urea, creatinine, parathyroid hor-
mone, LDH, CK, CRP and liver enzymes should lead
proper therapeutic changes [15]. In 95 % of cases, OI is
caused by mutations in the COL1A1 and COL1A2 genes
that encode the alpha1 and alpha2 chains of collagen type 1
and in the most cases the transmission is autosomal dom-
inant. We believe that the patient should be aware that the
presence of a variant in a single copy of the gene results in
the clinical manifestations of the disease and that the
recurrence risk in the offspring is 50 % (Table 2). The first
step in risk estimation should be to obtain a detailed family
history including information about previous cases and
severity of clinical manifestations, revisiting the family
tree for at least three generations. Identifying the specific
variant of the COL1A1 responsible for the clinical disease
does not change the approach to pregnancy, childbirth, or
the future management of the patient. Mutation detection is
used to confirm the clinical diagnosis and confirm the risk
of recurrence by 50 %, and it allows the search for the
same variant on fetal DNA by means of invasive prenatal
diagnosis for any future pregnancy. Sampling methods
used are the chorionic villus sampling, (possible starting
from week 11) or amniocentesis (from week 16). Invasive
prenatal diagnosis has an increased risk of miscarriage
related to the sampling estimated at around 1 %, even if
this risk varies for different centers. We must also reiterate
that for all pregnancies the empirical risk of congenital
123

Table 1 Problems linked to collagen deficiency, sorted by organ involved [7, 9]
Vascular problems Inadequate vasoconstriction
Uterine problems Atony and post-partum hemorrhage
Scoliosis and spinal Difficult spinal anesthesia
deformities
Short neck Difficult intubation
Increased metabolic Risk of malignant hyperthermia under
rate general anesthesia
Demineralization Osteoporosis
Bone fragility Risk of vertebral and hip fractures
malformations or intellectual disability is estimated at
about 3 %.
Fetal wellbeing was assessed with non-invasive exams,
including fetal echocardiography, Doppler velocimetry of
the main vessels, and fetal biometry to measure feto-pla-
cental hemodynamic state. Sonographic markers of OI are
reported in several studies and the most characteristic
features seem to be increased nuchal translucency, reduced
acoustic shadowing of long bones, and marked bowing and
shortening of long bones [16].
Fertility is preserved, especially in patients with OI type
I, and pregnancy can be carried to term. The incidence of
fractures is not increased during pregnancy, but due to
pelvic deformities, an increased incidence of cephalopelvic
disproportion and common abnormalities in fetal presen-
tation are more likely to present and delivery more typi-
cally occurs by cesarean section. [17, 18].
Literature reports both successful vaginal and cesarean
births in these patients and the optimal mode of delivery
should be decided on an individual basis (Table 2).
Cesarean section is adopted mainly to avoid respiratory
comorbidities, because the impact of a gravid uterus on a
reduced chest volume may worsen the restrictive pneu-
mopathy, and to reduce the risk of cephalopelvic dispro-
portion [19]. We do not advocate induction of labor due to
the impossibility to predict the evolution of induced uterine
contractions in a context of distorted collagen. The choice
to perform a C-section at 36 ? 6 weeks, was mainly due to
the risk of onset of spontaneous labor and cephalopelvic
disproportion. Delivery by cesarean section is not free of
risks, though largely comparable to those of the general
population such as thrombosis, pain, uterine atony and
post-partum hemorrhage [20–23]. Moreover, we would like
to assure the less traumatic mode of delivery so as to avoid
both the occurrence of pelvic or vertebral fractures and the
risk of uterine rupture, as described in two reports [19, 20].
Problems linked to the pregnancy in patients affected by OI
are firstly musculo-skeletal: back pain, spinal deformity,
non-vertebral fractures, disc and ligament problems [26].
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Arch Gynecol Obstet
Impaired platelet activity (low platelet count and Capillary fragility
impaired platelet aggregation)
Spontaneous uterine rupture
Reduced chest volume with restrictive lung disease Risk of cephalopelvic
disproportion
The incidence of maternal fractures is not increased in
pregnancy but may rarely occur during delivery. Various
anesthesiology approaches (general, epidural and spinal)
have been described: in spinal anesthesia, besides the
technical difficulties, spinal deformities make the level of
the blockade unpredictable. Continuous spinal anesthesia
with epidural or subarachnoid catheter is a safer option. On
the other hand, general anesthesia may represent problems
related to intubation and the development of malignant
hyperthermia. These patients, as reported in Table 1, have
an increased risk of developing pulmonary and cardiovas-
cular disease which is likely further increased by preg-
nancy status and delivery could have the potential to
represent a maternal life-threatening event, independently
from fetal well-being monitoring [27]. We hereby suggest
the main investigations that should be performed on these
patients to minimize the risk of harm to both mother and
child.
Pre-conceptional counseling and medical and genetic
evaluation should be offered to all affected women and,
where not possible, laboratory and instrumental tests
should be planned as soon as possible.
At the first visit, a detailed family history should be
taken and the woman must be assessed for disease severity
through clinical examination, laboratory testing and
imaging, and current therapy should be discussed. The next
step is adequate therapy adjustment for fetal safety (i.e.
discontinuation of bisphosphonates therapy). Women must
be monitored closely through daily home blood pressure
measurements also, echocardiography and an anesthetic
opinion should be sought as soon as possible and every
2–3 months to correctly evaluate risk evolution.
In cases of a known maternal mutation in it is possible to
search for the same mutation in the fetal DNA; if mutations
are not known surveillance is carried out with repeated
second level obstetric ultrasound scans, and genetic coun-
seling should be offered.
Last but not least in importance is the potential specu-
lation regarding the increased risk for preeclampsia and
Arch Gynecol Obstet

Table 2 Conditions associated with OI, type of delivery, type of anesthesia, complication, therapy
Authors Type Age Therapy Mode of Type of Gest Baby Complications
of OI delivery anaesthesia Age weight
(g)

Staples 1954 [30] – 18 – Vaginal – – 3147 Maternal fracture

– 23 – Vaginal – 3147 None
Johnson 1957 [31] – 28 – Vaginal – 38 3320 None
Cohn 1962 [32] – 27 – Vaginal – 38 – None
White 1963 [33] – 23 – Vaginal – 41 3820 None
Dunham 1967 [34] – 27 – Vaginal – 39 2690 Affected fetus
– 31 – CS – 39 3540 None
Geyman 1967 [35] – 19 – Vaginal – – 3459 None
Roberts 1975 [36] – 21 – CS Epidural 39 2892 None
Key 1977 [37] I 22 – CS Epidural 39 3200 None
Sauer 1981 [38] – 13 – CS General 39 3147 Low grade fever of unknown
etiology
Cunningham 1984 – 27 – CS Epidural,General – 1900 None
[39]
Cho 1992 [40] I 20 – CS General 38 1900 Maternal hyperthermia
Carlson 1993 [41] I 27 – Vaginal Epidural 38 3000 –
Zolezzi 1997 [42] IV – CS 39 2240 Affected fetus
Sharma 2001 [24] I 21 – Vaginal – 38 2720 Ankle fracture
I 17 – CS – 38 2430 None
Krishnamoorthy I 24 – CS – 39 2300 None
2002 [25]
Vogel 2002 [17] IV 30 – Surgical – 24 – Contracted pelvis, severe
III 35 – termination – 32 – kyphoscoliosisand significant
for trisomy restrictive respiratory disease
18 Marked limb deformity, severe
CS kyphoscoliosis
Chan 2006 [43] IV 28 – Vaginal – 34 2270 Severe back and pelvic pain
Chen 2006 [44] I 28 – CS – 37 2358 Affected fetus
Christodoulou I 23 – CS – 39 2300 Uterine rupture
2007 [45]
Parasumaran 2007 III 20 – CS – 34 1708 Severe
[46] kyphoscoliosis
Anderer 2008 [47] I 35 Metamizole ? CS – 33 – Pain of the lumbar spine and
calcium ? vitamin arthralgia of the hip
D during joints
pregnancy
Murray 2009 [48] III 24 – CS Sequential 35 2418 Marked scoliosis
combined
spinal epidural
Benbara 2010 [49] I 34 – Abortion – 13 – Severe kyphoscoliosis and
restrictive pulmonary
syndrome
Lyra 2010 [9] I 23 None CS Spinal 38 – –
Fiegel 2011 [50] III 27 CS General 31 – Rectosigmoid resection during
CS for
a presumed colonic pseudo-
obstruction

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 Arch Gynecol Obstet

Table 2 continued
Authors Type Age Therapy Mode of Type of Gest Baby Complications
of OI delivery anaesthesia Age weight
(g)

Rebelo 2011 [51] I 25 None Vaginal – – – Severe low back pain

Chen 2012 [52] I 26 Pamidronate Vaginal – 37 2840 None
discontinued 1
moth before
pregnancy
Feng 2012 [53] IV 31 – CS – 27 650 –
Papinger 2012 I 32 Transient osteoporosis
[15]

intrauterine fetal growth restriction that may present this
pregnancy, since emerging evidences strongly suggest the
calcium metabolism as potential mechanism involved in
pathogenesis of preeclampsia [28, 29].
In conclusion, women affected by type I OI represent a
subset of patients whose pregnancies should be considered
high risk and warrant a multidisciplinary approach in a
referral center.
Compliance with ethical standards
Conflict of interest The authors did not report any potential con-
flicts of interest.
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