Journal of Genital System & DisordersISSN: 2325-9728

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Case Report, J Genit Syst Disor Vol: 5 Issue: 3

Maternal Congenital Central Hypoventilation Syndrome in Pregnancy: A Case Report

Keller NA*, Hall J, Sack V and Rijhsinghani A
Department of Obstetrics and Gynecology, Albany Medical Center, 391 Myrtle Avenue, Second Floor, Albany, New York, 12208, USA
Corresponding author : Nathan A Keller, MD
Department of Obstetrics and Gynecology, Albany Medical Center, 391 Myrtle Avenue, Second Floor, Albany, New York, 12208, USA
Tel: 1-717-679-5629
Received: March 25, 2016 Accepted: May 02, 2016 Published: May 09, 2016
Citation: Keller NA, Hall J, Sack V, Rijhsinghani A (2016) Maternal Congenital Central Hypoventilation Syndrome in Pregnancy: A Case Report. J Genit Syst Disor 5:3. doi:10.4172/2325-9728.1000155


Background: Congenital Central Hypoventilation Syndrome is an exceedingly rare condition which may predispose to compromised placental function and intrauterine growth restriction. Labor is best managed in an intensive care unit. Congenital Central Hypoventilation Syndrome (CCHS) is an exceedingly rare autosomal dominant condition with about 160-180 cases diagnosed worldwide. It is characterized by adequate ventilation while awake and alveolar hypoventilation during sleep and if untreated the affected individual may survive only one to two months of age. Given the extreme rarity of the condition ideal antepartum and intrapartum management is largely undefined.

Case: A 28 year-old primigravida with CCHS was followed from 16 weeks gestational age through delivery and post partum course. Amniocentesis confirmed that the fetus was not affected. During the antepartum course there was a progressive lag in fetal growth and placental weight was found to be much less than the third percentile. At night mechanical ventilation was utilized and a normal spontaneous vaginal delivery was achieved in the intensive care unit.

Conclusion: CCHS is an exceedingly rare diagnosis. During pregnancy multispecialty interaction is critical for both maternal and fetal wellbeing. Fetal and placental growth is likely impacted by a hypoxic environment even with nightly mechanical ventilation. Amniocentesis and PHOX2B gene testing should be highly considered even if termination is not an option as it allows critical preparation for the newborn caregiver and other hospital personnel.

Keywords: Congenital Central Hypoventilation Syndrome(CCHS); Intensive Care Unit (ICU); Rapid Eye Movement (REM) Sleep; Non-Rapid Eye Movement (Non-REM) Sleep; PHOX2B gene


Congenital Central Hypoventilation Syndrome (CCHS); Intensive Care Unit (ICU); Rapid Eye Movement (REM) Sleep; Non-Rapid Eye Movement (Non-REM) Sleep; PHOX2B gene


Congenital Central Hypoventilation Syndrome (CCHS) is an exceedingly rare diagnosis made in infancy. There are approximately 160-180 cases diagnosed worldwide [1]. Due to the variability in symptomatology and potential failure to correctly diagnose, the prevalence is likely much higher [2]. In CCHS, the ventilation is typically adequate during wakefulness, however during sleep the patient experiences alveolar hypoventilation due to compromised ventilation sensitivities [1,2]. The hypoventilation during sleep leads to progressive hypercapnia and hypoxemia but respiratory centers are unable to respond to these changes [1]. Infants with this condition will experience cyanosis when falling asleep with no increase in the rate of breathing [1]. An infant may survive one to two months with considerable organ damage from both the hypoxemia and hypercarbia if the condition is left untreated [1]. CCHS is likely a small part of a more diffuse alteration in autonomic nervous system functioning in some patients [1]. For instance, other possible autonomic nervous system dysfunctions include, but are not limited to, Hirschsprung disease, altered pain sensitivity, syncope, excessive sweating, and altered lacrimation [1,2]. Mutations in the PHOX2B gene, which is responsible for a transcription factor linked to normal autonomic nervous system generation has been identified in 93-100% of cases [2,3]. Such mutations predominantly occur during gametogenesis although the mutations can also be inherited in an autosomal dominant method [2].
Diagnosis of CCHS is established by pediatric respiratory physiology laboratory evaluation during Rapid Eye Movement (REM) sleep, non-Rapid Eye Movement (non-REM) sleep, and wakefulness [1]. Additionally, blood is sent for PHOX2B gene evaluation. The diagnosis is considered exclusive, and is made when there is no cardiac, neuromuscular, or other lung disease that could account for the symptoms [2]. Chest x-ray and computed tomography, head magnetic resonance imaging, echocardiogram, muscle biopsy, and testing for inborn errors of metabolism should all be considered to rule out other causes of the symptomatology [2]. When diagnosed, a tracheostomy is required for lifelong ventilatory support during sleep with a primary mechanical ventilator [4]. There is no known effective pharmacologic treatment [2]. Given the extreme rarity of this condition, information regarding antepartum and intrapartum management in the setting of CCHS is lacking. We present a case describing antepartum and intrapartum management of a 28 year old primagravida with CCHS.

Case Report

A 28 year-old primigravida at 16+1 weeks gestational age (WGA) weighing 52.2 kilograms presented as a transfer of care to our Maternal Fetal Medicine service for pregnancy complicated by known maternal CCHS. Her CCHS was diagnosed in the neonatal period due to difficulty breathing during sleep. She required a tracheostomy and was placed on a mechanical ventilator during sleep. Throughout her adolescent and young adult life she had been maintained on a mechanical ventilator at night. At the time of presentation to our clinic, the patient had no specific complaints. She reported no breathing difficulties while awake and was able to carry out her daily activities without limitations. At night her reported ventilator settings were as follows:
Tidal Volume 650 ml, Respiratory Rate 20/min, FIO2 21%, and Inspiratory Time 1.2 seconds. She also reported using fluticasone/ salmeterol 250/50 mcg one puff twice daily. The patient’s past medical, surgical, family, and social histories, as well as review of systems, were otherwise noncontributory.
The patient presented to our office with a clinical diagnosis of CCHS. She was subsequently referred to the institution’s pulmonary service where Pulmonary Function Tests (PFTs) and an Arterial Blood Gas (ABG) were performed to establish baseline lung function. She had never undergone genetic evaluation to determine the specific cause of her CCHS. She was counseled and subsequently opted for sequence analysis of the PHOX2B gene for molecular confirmation of her diagnosis. Her subsequent genetic workup revealed that she had the autosomal dominant condition. She was heterozygous for 33 Polyalanine Repeats in the PHOX2B gene, specifically 20 repeats at one allele and 33 repeats at the other (Table 1). Approximately 92% of people with CCHS have a polyalanine repeat expansion mutation (PARM) within coding exon 3 of the PHOX2B gene [5]. There are typically ≤20 alanine repeats in this exon, however, individuals with CCHS can have 25-33 repeats [5]. The remaining ~8% of patients have non-polyalanine repeat expansion mutations (NPARMs), including sequence variants and frameshift mutations [5]. The patient and her partner were counseled on the autosomal dominant inheritance pattern of this mutation. She desired prenatal diagnosis by amniocentesis to prepare for care of her newborn. The amniocentesis revealed that the fetus was 46 XY and homozygous for 20 Polyalanine Repeats in the PHOX2B gene, indicating that the fetus did not have CCHS (Table 1).
Table 1: Results of Serum Testing and Amniocentesis for Number of Polyalanine Repeats in PHOX2B gene for Patient and Fetus.
Due to the possibility of maternal nocturnal hypoxia impacting fetal growth, monthly ultrasound examinations were performed. As demonstrated in Table 2 the fetal growth was adequate, but with advancing gestational age the growth percentile was documented to decrease.
Table 2: Estimated Fetal Weight and Growth Percentiles with Increasing Gestation (Percentiles Calculated by Hadlock Formula).
A multidisciplinary team including Maternal Fetal Medicine specialists, primary obstetricians, pulmonologists, ENT specialists, anesthesiologists, and Intensive Care Unit (ICU) physicians followed her care closely throughout the pregnancy. Despite her rare respiratory condition, her antenatal course was uneventful. Due to her stable condition during wake hours a vaginal delivery was favored with cesarean delivery reserved for routine obstetrical indications. Due to the need for ventilator support, the labor and delivery was planned in the ICU.
At 38+0 WGA the patient presented in active labor. An epidural catheter was placed following which the patient was transferred to the ICU. Labor was augmented by artificial rupture of membranes and oxytocin. After seven hours in labor, the patient had a spontaneous vaginal delivery of a live male infant weighing 2795 grams and APGARs of 9 and 9 at 1 and 5 minutes respectively. The placenta delivered intact with a normal three vessel cord. Total length of labor in the hospital was 7 hours 40 minutes, with second stage of labor lasting only 6 minutes. The patient did not require oxygen supplementation during the labor process. The post-partum course was uncomplicated except that the patient continued mechanical ventilation during sleep. She was discharged on post partum day number two without complication.


Congenital Central Hypoventilation Syndrome is an exceedingly rare diagnosis made in infancy with approximately 160-180 total reported cases worldwide [1]. It results in adequate ventilation during wakefulness with consequent alveolar hypoventilation during sleep [1]. While there are a few reports of offspring born to women with CCHS [6], the pregnancy course is not the focus of these reports. Thus, guidelines on management of this condition during the antepartum and intrapartum course are lacking due to the rarity of the condition.
In our case, despite an uncomplicated antenatal course the fetus progressively began to fall off the growth curve with a delivery weight at the 14% by Hadlock calculations (Table 2). The placenta was very small and weighed 394 grams. A study performed at McGill University in Montreal, Canada, in which 20,635 singleton deliveries were examined for placental weight at various gestational ages had previously been used to generate percentiles for placental weight [7]. Based on the Canadian study, the placental weight percentile in our case was below the third. While difficult to say definitively, the very small placental size is possibly related to a chronic hypoxic environment even in the setting of night time mechanical ventilation.
In pregnancies where a parent is affected by CCHS, invasive testing to determine the mutation in the PHOX2B gene in the fetus should be strongly encouraged. Knowledge of an affected fetus can help prepare for care of the neonate. NICU teams, respiratory physicians, and anesthesia teams can all be immediately available to assess the infant and establish a tracheostomy if needed. This anticipation will undoubtedly result in a more structured process and likely decreased infant morbidity. Fortunately in our case, the amniocentesis provided us with results predicting the fetus was unlikely to be affected.
A multidisciplinary team approach with advanced planning helped streamline the hospital course. Genetic counseling provided the patient information on the disease based on which the patient was able to make decisions regarding her pregnancy. This advanced planning undoubtedly improved patient care.


In conclusion, CCHS is an exceedingly rare condition with minimal information on pregnancy course in affected individuals. Our case seems to suggest that the hypoxic environment present in CCHS has growth restrictive effects on both the placenta and the fetus even when nightly mechanical ventilation occurs. The authors would recommend regular ultrasound examinations to evaluate for fetal growth in pregnant women with CCHS. Additionally, in patients desiring optimal care for an affected fetus, prenatal diagnosis should be strongly encouraged so a multidisciplinary team including NICU, anesthesia, and respiratory physicians can be assembled in advance to streamline the hospital course.




Written informed consent was obtained from the patient for publication of this case report and accompanying images.


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