Pregnancy with osteogenesis imperfecta: A scoping review

Study design

The study was conducted according to the PRISMA-Scr guidelines, which include research questions; identifying appropriate studies; selecting, extracting, and charting data; and collating, summarizing, the results.¹⁸ A study protocol was developed.

Definition of research question: The formulation of search string followed the PCC system

Population – Pregnancies with OI

Concepts – Feto-maternal outcome and delivery

Context – Studies in English language

The protocol was not registered anywhere before.

Search strategies

A systematic literature search was carried out in PubMed, Embase, and web of science database from January 1975 to January 2025. The MeSH words used were “Osteogenesis imperfecta”, “Brittle bone disease” or “dwarfism” and “pregnancy” or “cesarean deliveries” or “obstetrics”. Osteogenesis imperfecta related to humans was used. Two consultants approved the search strategy. The content of interest was antepartum, intrapartum, and postpartum outcomes. The topics of interest were antenatal complications, including preeclampsia, diabetes, hemorrhage, pregnancy loss, maternal fractures, mode of delivery, congenital anomalies, and Intrauterine growth restriction/small for gestational age.

Inclusion criteria

All original studies, surveys or case series of with a minimum of 25 pregnancies were included. Only quantitative studies were included. Only studies in the English language were included.

Exclusion criteria

Review articles, conference proceedings, original articles without pregnancies with OI, case series with fewer than 25 pregnancies with OI, expert comments, book chapters, guidelines and qualitative studies were excluded. Studies concerning only genetics, diagnostics, and prenatal diagnosis, other than English languages, were excluded.

Study selection, data extraction, and synthesis

Two reviewers (* and **) independently screened the titles and abstracts to identify potentially eligible articles. The full-text articles were selected and assessed for eligibility by two reviewers to obtain the final study articles. One reviewer (*) studied the inclusion and exclusion criteria, and one reviewer (**) extracted the data from eligible studies. The first reviewer verified the results to ensure the accuracy of the synthesis. A priori data extraction form was used. Any disagreement in the process of study selection and data extraction was resolved by discussion with the other reviewer. An assessment of the methodology quality and bias of the included studies was not performed. The articles included were presented in texts and tables. The data extracted included antepartum complications, medical and obstetrical complications, types of delivery, maternal and fetal outcomes, NICU admission, low APGAR scores, and maternal and fetal fractures.

Search results

The flow chart in Figure 1 depicts the research results and selection of eligible studies. The initial search generated a total of 1434 articles. After removing duplications and non-relevant studies, a total of 546 articles were identified for title and abstracts screening. 28 full-text articles were included for further analysis. Seven of them who met the eligibility criteria were included in the study. The main results of the excluded studies were case reports, series with fewer than twenty-five pregnancies, and original articles that included only OI children without maternal OI. All review articles and conference proceedings were excluded.

Figure 1. PRISMA flow diagram of the search strategy and selection process.

Primary studies

Table 1 presents the characteristics of the included studies. It depicts the characteristics of primary studies with information on the year of study, author, title of study, country of origin, study time, type of study, and sample size. The included studies were registry databases, original cohort studies, retrospective studies or case series. The diagnosis of osteogenesis imperfecta was made clinically and radiologically, as were the data from the registry of the OI group. All except one study comprised inclusion and exclusion criteria. Including studies stated the limitations of the study. Regarding the country of origin, most studies were from the USA or Europe. The included studies were published after 2000. Studies focused on the characteristics of fractures, musculoskeletal issues during pregnancy, and maternal and fetal outcomes.

Pregnancy characteristics

Table 2 displays the main information of the included studies. The study includes 1096 pregnant women with OI (1804 pregnancies). Table 3 displays the summary of all included studies.

Age at pregnancy: Five studies mentioned the age of the women at pregnancy. The age range mentioned was between 15-42 years.

BMI: BMI was mentioned in 4 studies. It was in the range of 23.4 kg/m² to 26.7 kg/m². The mean height mentioned was 153-164 cm.

Severity of OI: Four studies mentioned the severity of OI. A mild phenotype was frequently noted (75–86%), and a moderate and severe OI phenotype is observed in 14–25% of patients.^7,8,11,14

Maternal observations

OI pregnancies carry a greater risk of complications from the antenatal period to delivery. Yimgang et al. reported that 29% of maternal complications were associated with the severity of OI and not with the mode of delivery or number of children.¹⁴

However, observations vary across studies. Rao noted greater rates of diabetes during pregnancy, hemorrhage, cesarean section, and antepartum and postpartum fractures.¹¹ Similar observations were made by Ruiter-Ligeti et al.,⁶ who reported increased chances of antepartum hemorrhage, placental abruption, uterine rupture and hospital stay. Lykking revealed similar complications of miscarriage, preeclampsia, and antenatal and perinatal hemorrhage in both the case and control groups.¹² Ruiter-Ligeti et al. reported no changes in maternal mortality or stress fractures compared with those in the control group.⁶ Preeclampsia, premature rupture of membrane (PROM), excessive bleeding, breech presentation, other musculoskeletal issues, bone fractures, bone deformities, and joint dislocation are common complications.¹⁴ The Mentioned incidence of various observations is as below:

Antenatal observations

Pregnancy loss was studied in two studies. Termination of pregnancy in the OI cohort was reported to be approximately 18% before 12 weeks, which was similar to the non-OI cohort. 30% of pregnancies were aborted before 22 weeks of gestation, which was 5% greater than that of the reference population.¹² Elective abortions were less common in the OI group in comparison to the non-OI group (4% vs. 21%).¹¹ Antepartum hemorrhage was studied in Four studies.^6,11,12,14 In 5% of the OI population had early hemorrhage, and 3% had late hemorrhage, which was like the findings in the reference cohort.¹² The abruption of placenta was significantly associated with OI, with an odds ratio (OR) of 2 and an antepartum hemorrhage of 1.5 OR.⁶

Gestational diabetes was not widely studied however, two studies have evaluated GDM incidence. A greater proportion of OI had GDM but was not significantly associated with OI⁶; a higher GDM (13.3 vs. 7%) was noted in another study.¹¹ Four studies evaluated hypertension during pregnancy. Study by Ruiter-Ligeti et al. and Lykking EK et al. suggested no difference in the incidence of preeclampsia^6,12; However, another study reported a higher incidence 18%,¹⁴ while another reported 12.8%.¹¹

Intrapartum and post-partum observations

Period of gestation at delivery was studied by four studies. The prevalence of preterm delivery varies between 6-15%.^11,12,14 One study reported significant higher prevalence.⁶ Term delivery/past dates were observed in 84-92% of the patients in the OI group, whereas it was 94% among the reference population.^6,11,12 Postpartum hemorrhage (PPH) was reported in three studies. Mild PPH was observed which was not different than reference population.^6,12 However, the increase in the risk of hemorrhage and need of blood transfusion was 8.3% in OI population vs 1.5% in non-OI population.¹¹ The mode of delivery was well studied (six studies). Cesarian delivery was common, accounting for 25% to 75% of deliveries. A study revealed that the frequency of cesarians was comparable to that of the general population (26%),⁸ whereas the frequency of cesarians was high (55%) in another study.¹⁴ The rate of cesarean delivery was almost 2-fold greater than that of the reference population.¹² Elective LSCS was 3-fold greater, and emergency pre-labor and labor LSCSs were like those in the reference population.¹² Seventy-five percent of LSCS patients with a history of maternal pelvic fractures or pelvic deformity due to OI need delivery via LSCS.⁶

Other complications and observations: Blood transfusion and venous thromboembolism were significantly more common.⁶ Genetic counseling was provided in 45% of the patients.¹⁴ Sixteen to 21% of the population used bisphosphonate before pregnancy.⁷ Mal-presentation and preterm PROM were found to be more common in two studies.^6,11 No difference in the incidence of placenta previa or polyhydramnios was found.⁶ Two cases of uterine rupture were reported after a trial of labor for previous LSCS.⁶ The length of hospital stay of mothers was significantly greater than that of the reference population.⁶ One case of maternal mortality was reported in one study.⁸

Fetal complications

Rao reported a higher frequency of low birth weights (LBW) in neonates born to OI mothers than in the general population (LBW-26% vs. 6.8%) (very LBW-13% vs. 1.5%). A higher rate of neonatal intensive care unit admission of OI neonates (19% vs. 5.6%) and neonatal mortality at 28 days of life, regardless of neonatal OI status (4.8% vs. 0.4%), were noted.¹¹ Ruiter-Ligeti et al. reported a higher frequency of intrauterine growth restriction/small-for-gestational-age infants (2.44-fold increase) and congenital malformation.⁶ However, Lykking noted that the frequencies of low birth weight, low Apgar score, need for CPAP, and birth-related fracture are similar between OI pregnancies and the control population.¹²

The true incidence of OI in offspring could not be evaluated. Congenital abnormalities (excluding OI) were more common (12% vs. 6%) in the OI cohort.¹² However, a 7-fold increase in the incidence of congenital malformation was noted.⁶ Forty-eight percent of cases involve OI children, and 5% of cases involve other anomalies.¹¹ Rao evaluated the BF rate at 6 months, which was lower than that reported in the general population (34.8% vs. 54%), but the BF rates at 1 month were not similar.¹¹

Fractures during pregnancy

Five studies evaluated fractures during pregnancy. The frequency of fractures among pregnant OI patients was 10%-25%. The frequency of fracture among pregnant OIs significantly differed from that in the control population. Lykking et al. reported that the frequency of fractures was similar without an increase in the risk of fractures during and 12 months postpartum compared with 12 months prior to conception.¹² Koumakis et al. reported that one-quarter of patients experienced fractures during pregnancy (femur, pelvic, rib, ankle, or spine).⁷ One quarter experienced a fracture within 6 months of delivery (mainly in the proximal femur and spine).

A total of 10% of fractures during pregnancy and 12% of fractures after delivery have been reported.¹¹ The spine and other bones are common sites after delivery. The rate of fracture was significantly greater than that in the general population.¹¹ McAllion reported fractures of the limb and spine during pregnancy (vertebral crush fracture-9, tibia-4, radius-1, ankle-2, finger-1, and rib-1). One post-natal maternal fracture was noted.⁸ Only one stress fracture has been reported in a large cohort studied by Ruiter-Ligeti et al.⁶ Breastfeeding, increased age, and low bone mineral density were associated with the frequency of fractures. Breastfeeding was a risk factor for 85.7% of patients in the fractured group and 47.1% in the non-fractured group.⁷

Other musculoskeletal issues during pregnancy

Back pain during delivery was noted to be similar to that in the normal population.¹¹ Worsening pain during pregnancy and the need for limited activities were noted in 44% of the patients.¹¹ Fifty-eight percent of the OI population had back pain.⁸ Moderate to severe backache was noted in 13–35% of the patients. Backache was common with high gestational age and with cesarean delivery.

Recurrent sprain of the ankle, hyper extensible knee joint, frozen shoulder and symphysis pubis separation were other musculoskeletal problems.⁸ A height loss of 1 cm to 11 cm was noted. Spondylolisthesis with severe backache during subsequent pregnancy was observed.⁸

Publication trends

All but one included study was published in the last decade. Very few original articles addressing rare combinations of pregnancy with OI were published earlier. This might be due to the increased number of registries and databases of rare diseases such as OI in recent times.

In all included studies, Pre-pregnancy BMI was similar to BMI in the general population. The height of a woman is considered a pseudo marker of severity. The height indirectly predicts the severity of the disease; a milder form has a near-normal height, and severe OI results in more shortness. Most of the included studies mentioned milder cases of OI.

Antenatal issues

There are no uniform observations of increased antenatal and perinatal complications in OI pregnant women. This might be due to differences in demographic characteristics. A few studies compared OI groups with non-OI groups, and a few studies evaluated only the OI registry and databases. Many complications were not clearly studied or mentioned in the included cohort. For example, spontaneous miscarriage was not clearly mentioned in a study of late pregnancy registrations.⁶

Few etiological factors for abortions, such as the rates of exposure to teratogenic drugs, smoking and bisphosphonate, were similar between the OI group and the reference non-OI group. Hence, the rate of abortion might be related to OI pathogenicity. Similarly, higher frequency of preterm labor was also noted. The possible causes of higher frequencies of preterm labor are the abruption of the placenta, antepartum hemorrhage, growth restrictions and preterm prolabor rupture of membranes.

A higher marginal incidence of pre-eclampsia and gestational diabetes was associated with OI. The causes of these observations were unknown. OI-related cardio-respiratory problems were not mentioned in any of the studies.

Collagen is an important component of the extracellular matrix; hence, it plays a key role in the structural integrity and function of the uterus and cervix. Defective collagen can lead to improper wound healing following cesarean deliveries leading to higher chances of uterine rupture in subsequent deliveries. Collagen defects in OI can impair vascular integrity and intrinsic platelet defects resulting in greater incidence of antepartum hemorrhage and PPH.

Fetal growth restriction is also common. It is related to the severity of maternal and fetal OI.¹⁷ Multifactorial intrauterine fractures have also been shown to play a role in etiogenesis.⁶ None of the included studies evaluated the exact frequency of prenatal diagnosis.

Perinatal issues, including type of delivery

A greater rate of cesarean delivery in the OI population is a consistent finding in most studies. Pelvic deformities leading to CPD, abnormal fetal presentation, fear of maternal pelvic fracture during delivery, and fetal OI detection are contributing variables for higher LSCS in the OI population.^16,17 Most of the time, the decision of an obstetrician is to choose LSCS in fear of fetal trauma when an intrauterine diagnosis of OI is made. Anesthetic management (general and spinal) of these deliveries is challenging due to spine and pelvic deformities and intubation difficulties due to the short neck, prominent mandible and occipital projection.²²

Neonatal complications

Neonatal OI and other congenital anomalies are more common among OI pregnant women. The increased incidence of neonatal OI might be related to autosomal dominant and autosomal recessive inheritance. The reason for the higher risk of congenital anomalies other than those in reference populations is unknown.¹²

Neonates requiring NICU admission and CPAP therapy were more common in the OI cohort, which may be due to the greater number of affected children with OI. In children with OI, the birth fracture rate is similar irrespective of the type of delivery (vaginal/cesarean delivery).^16,17 Hence, it was recommended that cesareans be performed only for other fetal or maternal indications but not for the objectives of fracture prevention in OI neonates.^16,17

The milder form of OI might not affect neonatal outcomes; however, severe and lethal varieties of OI could increase the frequency of neonatal complications, including high neonatal mortality. Higher associated cardiac anomalies might affect hospital stay and neonatal complications.

Higher rates of cesarean delivery in the OI group may increase the number of respiratory complications requiring a longer hospital stay. Vertebra collapse and pneumonia in the neonatal period might also compromise respiratory function, leading to prolonged NICU admission.

Musculoskeletal issues

Low BMD is found in most patients with OI.⁷ The effect of low BMD increases the risk of fracture at any age. During pregnancy, due to calcium transfer to the fetus (mainly in third trimester), further depletion of BMD occurs. Preconception bisphosphonate is recommended to reduce the fracture rate among this population.⁶ However, there is no consensus regarding the use of bisphosphonate in reproductive-aged women due to possible adverse effects on the baby.²³ Bisphosphonate should be stopped soon after pregnancy is detected to avoid adverse effects on the fetus.²⁴ The third trimester of pregnancy and the 2-month postpartum period are the most crucial factors for the occurrence of fracture in this population.⁷

Breastfeeding reduces maternal calcium even more, leading to bone loss of nearly 10%. Hence, women with OI or osteoporosis during pregnancy are often advised to refrain from breastfeeding. Breastfeeding, increased age, and low bone mineral density are constant risk factors associated with a high frequency of fractures.⁷ However, the exact causal effect of these variables has not been studied until now.

Many reported high prevalence of backaches during pregnancy, whereas others reported no change in backache.¹¹ McAllion reported height loss during pregnancy (1–11 cm) indirectly.⁸

Strengths

This is the first scoping review of a unique combination of pregnancy and OI. This is the only study that combined a description of antenatal, perinatal, and postnatal musculoskeletal complications in pregnant women with OI. An attempt was made to extract all available data on pregnancy and related complications. This study could be useful for formulating obstetric and orthopedics specific recommendations to pregnant women with OI.

Limitations

Due to the rare combination of pregnancy and OI, very few articles are included in the scoping review. Only English language articles were included. All included studies were either from North America or Europe; hence, the global perspective might be missing from this scoping review. The frequency of complications and the conclusions of various studies contradict those of other studies. The characteristics of the complications are different. Hence, we cannot recommend any guidelines on the basis of this scoping review. Critical appraisal of the included articles was not done. This review includes articles published over 50 years, and the practice of obstetrics as well as advances in technology might affect the final maternal and fetal outcomes. Further research, including large-scale, prospective studies, is needed to provide a greater level of evidence.

Implications and future directions

This study provides baseline information on the types and occurrence of maternal, fetal and musculoskeletal complications among women with OI. Multicenter studies including registries of every woman with OI should be started to estimate the exact frequency of maternal and fetal complications. Data specific to obstacles and complications related to obstetrics should be collected to form formal guidelines specific to OI pregnancies.