Arch Gynecol Obstet DOI 10.1007/s00404-015-3893-9
MATERNAL-FETAL MEDICINE
Pregnancy outcomes in patients with Alport syndrome Enav Yefet1 • David Tovbin2,3 • Zohar Nachum1,3
Received: 25 March 2015 / Accepted: 14 September 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose To analyze the maternal and obstetric outcomes of patients with Alport syndrome. Methods We describe the pregnancy course of 8 pregnancies of three family members with the autosomal dominant (the rarest) form of Alport syndrome. We also analyzed 10 previously reported pregnancies with other Alport mutations in order to explore risk factors for unfavorable obstetric outcomes and maternal renal deterioration. Results In 13 pregnancies (72 %), renal function did not deteriorate permanently. All of these women had prepregnancy mild chronic kidney disease (CKD stage G1). In all of them, only a transient increase in proteinuria was recorded and in one case there was a transient decrease in the estimated glomerular filtration rate. In four other pregnancies (22 %), renal function deteriorated following pregnancy. All of them were complicated with preeclampsia. One woman had pre-pregnancy CKD-G2A3 and chronic hypertension. Two women had CKD-G1A3 of whom one had pre-pregnancy proteinuria near the nephrotic range. In the fourth case, renal function deterioration was reported without information on the exact prepregnancy renal function. In the last case, CKD-G2 was reported after pregnancy without information on CKD stage prior to pregnancy. Severe proteinuria did not imply a & Enav Yefet [email protected] 1
Department of Obstetrics and Gynecology, Emek Medical Center, Afula, Israel
2
Department of Nephrology, Emek Medical Center, Afula, Israel
3
Rappaport Faculty of Medicine, Technion, Haifa, Israel
permanent renal function deterioration if it developed during pregnancy. Ten pregnancies ended with preterm birth (56 %). Two stillbirths were reported (11 %); however, only one was attributed to maternal health deterioration. Conclusion Data regarding pregnancy outcomes in Alport syndrome is limited. The outcome seems favorable when pre-pregnancy kidney function is normal or near normal and when chronic hypertension/pre-eclampsia is absent. Keywords Alport syndrome Kidney disease Nephritis Pregnancy Renal failure
Introduction Alport syndrome is a genetically heterogeneous disease that results from mutations in genes encoding the alpha-3, alpha-4, and alpha-5 chains of type IV collagen, which comprises the basement membrane of the glomeruli, the inner ear, and the eye. X-linked (80 %), autosomal recessive (15 %), and autosomal dominant (5 %) forms have been identified. The classical presentation (X-linked) includes glomerular disease that progresses to end-stage renal disease (ESRD), sensorineural hearing loss, and ocular abnormalities. The autosomal forms are clinically similar to the X-linked forms; however, the deterioration of renal function is slower. The initial renal manifestation of Alport syndrome is asymptomatic microscopic hematuria. The blood pressure and serum creatinine are normal in early childhood, but progressive renal insufficiency, hypertension, and increasing proteinuria develop. ESRD usually occurs between the ages of 16 and 35, but the course might be slow in some families. Diagnosis is made
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by either renal or skin biopsy and confirmed genetically [1– 4]. Since the majority of the cases involve males (Xlinked), the data in the literature regarding the pregnancy course of patients with Alport syndrome are scant and even the little we know comes from a few anecdotal incidents documented in case reports [5–12]. The objective of the present manuscript was to characterize the effect of Alport syndrome on pregnancy course and vice versa. This manuscript comprises two parts: in the first part, we describe, in detail, the course of 8 pregnancies of 3 family members with the autosomal dominant form of Alport syndrome. To our knowledge, this is the first report in the literature of pregnancies of patients with this mutation and the largest series of pregnancies with Alport syndrome in general. In the second part, we conducted a literature search for additional pregnancies of patients with Alport syndrome (X-linked and autosomal recessive forms) and analyzed their pregnancies together with our cases in an effort to elucidate possible courses and prognostic factors in such cases.
Patients and methods Data collection of a family with the autosomal dominant form of Alport syndrome Family tree The family tree (pedigree) of the described family (Fig. 1) was built based on the clinically affected individuals. For purposes of description, the third daughter (patient II-4), who was treated in our institution, is referred to as the patient in the text, and the other affected individuals are
referred to as the mother (patient I-1) and oldest sister (patient II-2). Patient III-1 is healthy without microhematuria or proteinuria. The clinical and genetic status of the others in the third generation (III) is not known. Alport syndrome diagnosis and family characteristics The family origin was Kazakhstan. The family tree is described in Fig. 1. As can be seen, the mother and two daughters were clinically affected. The presenting symptom of the mother was non-progressive microhematuria. The oldest sister was affected more severely and presented with microhematuria that later progressed to kidney damage manifested by proteinuria. At the age of 14, she underwent kidney biopsy, which disclosed thin basement membrane consistent with Alport syndrome. The second daughter was healthy and was not tested for Alport syndrome. The third daughter (our patient) has suffered from persistent microhematuria since childhood. Altogether, by the evaluation of the genealogical tree, the modes of inheritance match the autosomal dominant mode with an incomplete penetrance. Alport syndrome was also identified by genetic analysis in the cases of the mother and oldest sister. Genetic analysis was done by the Department of Human Genetics of the University Medical Center Go¨ttingen, Germany. Blood samples were taken from the mother and oldest sister; both were found to be heterozygous for the autosomal dominant mutation in c2135G[T (Pg712V) in exon 29 of COL4A3 gene. The mutation in the COL4A5 gene (X-linked) was negative. Pregnancy documentation and management The third sister (patient II-4 in Fig. 1) was a patient in the Maternal-Fetal Medicine Department in our hospital (Emek Medical Center, Afula, Israel). Clinical assessments as well as laboratory investigations were acceptable and described thoroughly. Information regarding the other family members was collected by meticulous interviews as well as official documentations. Literature search for other reports of pregnancies with Alport syndrome
Fig. 1 The family tree (pedigree) of Alport syndrome-affected individuals with the autosomal dominant mutation c2135G[T (Pg712V) in exon 29 of COL4A3 gene. Circles represent females, squares represent males. Filled symbols indicate clinically affected individuals with Alport syndrome. Asterisks represent genetically confirmed Alport syndrome
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We searched PubMed, Medline, and Google Scholar for additional reports using the phrases ‘‘Alport or hereditary nephritis and Pregnancy’’ without limitations except for English language. We added, as appropriate, articles found through the references of included articles. We found 10 additional pregnancies of women with Alport syndrome and their details are described together with our series.
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Renal functions are presented as serum creatinine, proteinuria in 24-h urine collection, and estimated glomerular filtration rate (eGFR). The latter was calculated according to the chronic kidney disease Epidemiology Collaboration group (CKD-EPI) equation [13]. Please note that during pregnancy, eGFR calculated by the CKD-EPI equation underestimates the actual GFR, which returns to prepregnancy levels during the puerperium in healthy individuals [14, 15]. Creatinine clearance during the 2nd and 3rd trimesters is presented if available.
Results Pregnancy courses of family members with the autosomal dominant form of Alport syndrome Tables 1, 2, and 3 summarize the main clinical features and pregnancy outcomes of the mother (patient I-1), oldest sister (patient II-2), and our patient (patient II-4). Patients’ renal function following pregnancies is also described. Mother (patient I-1) The mother was healthy and suffered only from non-progressive persistent microhematuria. The mother’s first pregnancy was terminated in the third trimester due to fetal death of unknown cause. Afterward, she delivered three girls without complications. Laboratory assessment during pregnancies was normal. Oldest sister (patient II-2) The oldest sister had suffered from microhematuria since early childhood, and proteinuria developed a few years later. She had two spontaneous miscarriages. In the third pregnancy, she underwent labor induction at 35 weeks of gestation due to increasing blood pressure (pre-eclampsia). She delivered a healthy baby boy. During pregnancy her kidney function progressively deteriorated and 6 years later she began peritoneal dialysis. The third sister (patient II-4) Our patient had suffered from persistent microhematuria since childhood. Blood pressure and urea levels were normal. Figure 2 summarizes her kidney function profile according to the serum creatinine and proteinuria. Overall, renal function profile is compatible with CKD stage 1A3 according to the KDIGO 2012 criteria [13]. Her first pregnancy was unremarkable except for protein ?2 in urine dipstick throughout the pregnancy. Blood
pressure and creatinine were normal. A 24-h urine collection for protein was not performed. She delivered vaginally a 3500 g baby boy at 40 weeks of gestation without complications. Her second pregnancy was 5 years later. During that pregnancy, proteinuria progressively increased until it reached the nephrotic range of 3.6 g/24 h. Blood pressure and creatinine levels were normal. Due to proteinuria and deterioration of renal function, labor induction was performed at 39 weeks of gestation and proteinuria returned to pre-pregnancy levels. Her third pregnancy 4 years later was unremarkable until the third trimester except for progressively increasing proteinuria, which reached 3.9 g/24 h at 36 weeks of gestation (Fig. 2). Ultrasound directed to the kidney and urinary system was unremarkable. At 35.4 gestational weeks, she was admitted to the Maternal-Fetal Medicine Department due to headache and blurred vision. Physical examination disclosed pitting edema ?2 confined to the lower extremities. Blood pressure as well as creatinine, urea, uric acid, liver function, and CBC were normal. Fundoscopy was unremarkable. Ultrasonography assessment disclosed an appropriate for gestational age fetus with normal amniotic fluid volume and biophysical profile. Due to the worsening proteinuria and patient’s request, fetal lung maturity was confirmed with amniocentesis for lamellar bodies and labor induction was performed at 36.2 weeks without complications. After several weeks, proteinuria returned to pre-pregnancy levels (Fig. 2). Additional cases from the literature and data analysis The literature describes 10 pregnancies with Alport syndrome with variable pregnancy courses and post-pregnancy sequelae. Patient and pregnancy characteristics are summarized in Tables 1, 2, and 3. It should be noted that some of the cases were not genetically confirmed. None of the cases was reported to be of the autosomal dominant form of Alport syndrome. Only one case describes two consecutive pregnancies for a single patient. Together with our own series, 18 pregnancies are available for analysis. Renal outcomes Twelve pregnancies (67 %) began with CKD stage G1 and did not deteriorate (except for transient increase of the proteinuria). In one additional case (case 9), eGFR decreased but returned to pre-pregnancy level later on. Altogether, renal function did not deteriorate from stage G1 in 13 cases (72 %).
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Arch Gynecol Obstet Table 1 Patients’ characteristics and baseline renal functions in pregnancies with Alport syndrome Patient (references)
Mutation
Age (years)
Pregnancy no.
1 [6]
X-linkedc
35
2 [7]
X-linkedc
N/A
3 [5]
X-linkedc
Baseline renal functiona BP
Cr (mg/dl)
CCT (mL/ min)
Proteinuria (g/24 h)
eGFR CKD-EPI (mL/min/1.73 m2)b
CKD staging
1
N/A
0.7
85.1
0.2
113
G1A2
1
N/A
0.8
N/A
N/A
123
G1
29
1
140/90
1.0–1.2
57.8
1.0–2.0
68
G2A3
4 [9] (1st pregnancy)
X-linked
c
19
1
110/60
0.59
122
1.0–2.0
133
G1A3
4 [11] (2nd pregnancy)
X-linkedc
21
2
118/62
0.67
N/A
1
126
G1A3
5 [8]
Autosomal recessive
19
1
Normal
0.7–1.0
173
2.0–2.3
100
G1A3
6 [8]
Autosomal recessive
16
1
Normal
0.5–0.8
143
0.7–0.9
132d
G1A3
7 [10]
X-linked
38
1
N/A
N/A
N/A
N/A
N/A
N/A
8 [10]
X-linked
26
1
Normal
Normal
N/A
3.26
9 [12]
X-linked
20
1
116/78
0.7
NA
1.04
I-1
Autosomal dominant
N/A
1
Normal
20
2
27 28
3 4
II-2
Autosomal dominant
27
3 (after 2 spontaneous early miscarriages)
N/A
II-4
Autosomal dominantc
20
1
Normal
25 29
G1A3 125
G1A3 G1
At least 0.5
N/A
N/A
Normal
150 mg/dl in urinalysis
N/A
G1A3
2
N/A
Normal
At least 0.5
N/A
G1A3
3
0.58
162
0.63
126
G1A3
BP blood pressure (mmHg), CKD chronic kidney disease, CCT creatinine clearance test, Cr serum creatinine, eGFR CKD-EPI estimated glomerular filtration rate calculated with the chronic kidney disease Epidemiology Collaboration group equation, min minute, N/A not available, P proteinuria a
Renal function was evaluated before pregnancy or at the 1st trimester
b
CKD-EPI was calculated according to the serum creatinine value
c
Diagnosis was not genetically confirmed
d
According to pediatric formulas, the eGFR is 98.48 mL/min/1.73 m using the Bedside Schwartz equation, and 102.54 mL/min/1.73 m using the Counahan–Barratt equation
In 4 cases (22 %), renal function deteriorated following pregnancy (cases 2, 3, and 8, and patient II-2). All of those cases were complicated with pre-eclampsia. In cases 3 and 8, the baseline kidney disease was impaired according to the CKD staging (case 3) and baseline proteinuria was close to the nephrotic range (case 8). Baseline renal functions are not available for patient II-2. Only case 2 (6 %) demonstrated deterioration in renal function from CKD stage G1. In case 7, CKD stage G2 was reported after pregnancy without information on CKD stage prior to pregnancy. Notably, this woman was older than the others (38 years).
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The degree of proteinuria near delivery was not associated with permanent renal deterioration. Obstetric outcomes Eleven cases (61 %) were delivered preterm. Seven cases (39 %) had cesarean delivery, none due to fetal distress. Five cases (28 %) were complicated with pre-eclampsia. Stillbirth occurred in two cases (11 %); however, it was related to the renal disease in only one case. Only one case of intrauterine growth restriction (6 %) was reported. All the live born were reported to be in good health immediately after delivery.
G1A2
G1
G2A3 ? HTN
G1A3
G1A3
G1A3
G1A3
N/A
G1A3
1 [6]
2 [7]
3 [5]
4 [9]
4 [11]
5 [8]
6 [8]
7 [10]
8 [10]
CKD staging
Patient (references)
32
33
30
36
32
Through all trimesters
31–39
25
33
N/A
Hypertension (preeclampsia)
Normal
Normal
Normal
102–123/ 58–78
100–110/ 70–74
242/109
136/92
0.7
N/A
N/A
0.53 (28 weeks), reported normal at delivery
0.51
0.67–0.70
0.54–0.7
6.6
1.4–1.7
N/A
86.3
168 (28 weeks), reported normal at delivery
185 (28 weeks), reported normal at delivery
N/A
97–137
N/A
N/A
50
CCT (mL/min)
Proteinuria (g/24 h) 6
N/A
22 months
22 months
[7
6 months
6 months
2 months
6 months
6 months
N/A
3.4-7
10.6
9
0.8–2.0
1.42–2.22
15
N/A
22 months post-partum serum creatinine concentration was 1.48 mg/dl, eGFR CKDEPI—49 mL/min/1.73 m2 and proteinuria returned to 3.21 g/24 h
Proteinuria gradually improved (0.99 g/24 h), eGFR CKD-EPI 81 mL/ min/1.73 m2
Proteinuria reverted to prepregnancy values (1.4 g/ 24 h) when examined 6 months after delivery
Proteinuria first increased to 12.2 g/24 h and then reverted to prepregnancy values (1.8 g/ 24 h) when examined 6 months after delivery
Proteinuria, creatinine level, and blood pressure remained stable in a 2-month follow-up
Six months after delivery proteinuria remained (1.5 g/24 h), eGFR CKD-EPI—133 mL/min/ 1.73 m2 consisted with CKD G1A3
Hemodialysis was needed 48 h post-partum until the end of the reported time of follow-up
Improved
Improved
Post-partum renal function
Duration of follow-up after delivery
Cr (mg/dl)
Gestational week at examination BP
Renal function in follow-up after delivery
Renal function during pregnancy (2nd or 3rd trimester)
Table 2 Renal effects during and after pregnancies in women with Alport syndrome
G3aA3
G2A3
81
49
G1A3
G1A3
G1A3
G1A3
G5
CKD staging
N/A
N/A
N/A
133
N/A
N/A
N/A
eGFR CKDEPI (mL/min/ 1.73 m2)a
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123
G1A3
G1
N/A
G1A3
9 [12]
I-1
II-2
II-4
Normal
Normal 111/71
N/A
35
Hypertension
Normal
162/111
40
35
N/A
29
0.7
0.68
0.9
Elevated
1.53
146
171
N/A
Decreased
N/A
CCT (mL/min)
Proteinuria (g/24 h)
3.905
See Fig. 1
See Fig. 1
See Fig. 1
*0.5 to 1.5 (?2 in dipstick) 3.6
6 years
24 h
Deteriorated
15
Proteinuria reverted to prepregnancy values
Proteinuria reverted to prepregnancy values
Kidney function continued to deteriorate until peritoneal dialysis 6 years later Proteinuria reverted to prepregnancy values as well as creatinine and eGFREPI
Blood pressure became normal. Proteinuria decreased to 0.75 g/day and the serum creatinine decreased to 1.1 mg/dl on the day after delivery (eGFR CKD-EPI — 49 mL/min/1.73 m2). Serum creatinine was reported to return to baseline levels
Post-partum renal function
Duration of follow-up after delivery
Cr (mg/dl)
Gestational week at examination
BP
Renal function in follow-up after delivery
Renal function during pregnancy (2nd or 3rd trimester)
90
103
106
N/A
N/A
N/A
eGFR CKDEPI (mL/min/ 1.73 m2)a
G1A3
G1A3
G1A3
G5
G1
G1A3
CKD staging
a
CKD-EPI was calculated according to the serum creatinine value
BP blood pressure (mmHg), CKD chronic kidney disease, CCT creatinine clearance test, Cr serum creatinine, eGFR CKD-EPI estimated glomerular filtration rate calculated with the chronic kidney disease Epidemiology Collaboration group equation, HTN hypertension, min minute, N/A not available, P proteinuria
CKD staging
Patient (references)
Table 2 continued
Arch Gynecol Obstet
Arch Gynecol Obstet Table 3 Pregnancy and obstetric outcomes in women with Alport syndrome Patient [ref]
CKD staging
Gestational week at delivery
Mode of delivery
Birth weight (g)
gender
Apgar score at 1/5 min
Labor induction
Indication for deliverya
1 [6]
G1A2
32.2
CS
1820, AGA
Male
N/A
No
Renal function deterioration (mainly proteinuria)
2 [7]
G1
35.3
VD
1888, AGA
Female
N/A
Yes
3 [5]
G2A3 ? HTN
25.5
VD
400, SGA
Female
0
Yes
Renal function deterioration and preeclampsia Renal function deterioration and preeclampsia
4 [9]
G1A3
39.2
CS
2868, AGA
Male
8 after 5 min
No
Labor began spontaneously. CS was performed due to labor dystocia
4 [11]
G1A3
37.1
CS
2458, AGA
Female
N/A, reported as a healthy infant
No
Labor began spontaneously. CS was performed due to previous CS
5 [8]
G1A3
32
CS
1830, AGA
Female
5/8
No
CS due to renal function deterioration (severe proteinuria)
6 [8]
G1A3
36
CS
2335, AGA
Female
7/9
Yes
CS was performed due to labor dystocia
7 [10]
N/A
34
CS
2165, AGA
Male
9 after 5 min
No
Renal function deterioration (mainly proteinuria)
8 [10]
G1A3
33
VD
2400, AGA
Male
9 after 5 min
Yes
Renal function deterioration and pre-eclampsia
9 [12]
G1A3
29
CS
N/A
N/A
Healthy neonate
Yes
Acute renal failure and preeclampsia. Cesarean section was performed due to failed induction
I-1
G1
*28
VD
N/A
N/A
0/0 stillborn
Yes
stillborn
Term
VD
N/A
Female
N/A
No
Not applicable
Term
VD
N/A
Female
N/A
No
Not applicable
Term
VD
N/A
Female
N/A
No
Not applicable
35
VD
N/A
Male
Healthy
Yes
Labor induction due to aggravating hypertension (pre-eclampsia)
II-2
N/A
II-4
G1A3
40
VD
3500, AGA
Male
Healthy
No
Not applicable
39
VD
3100, AGA
Female
Healthy
Yes
Labor induction due to aggravating proteinuria
36.2
VD
2686, AGA
Female
9/10
Yes
Labor induction due to aggravating proteinuria
AGA appropriate for gestational age, CS cesarean section, CKD chronic kidney disease, HTN hypertension, N/A not available, SGA small for gestational age, VD vaginal delivery a
In cases of delivery due to renal deterioration see Table 2; Fig. 2 for specific details
Discussion Presented here are three patients with the autosomal dominant type of Alport syndrome. Genetic confirmation was available for the mother and the oldest sister. The third sister refused to undergo either biopsy or genetic diagnosis;
however, her family history and clinical signs were highly suggestive of Alport syndrome. Interestingly, though these patients share an identical mutation, the prognosis ante-partum and post-partum differed. Moreover, in the case of the third daughter, the course of pregnancies differed as the first one ended
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Fig. 2 Kidney function profile of patient II-4. Solid line represents serum creatinine (mg/dl) levels. Dashed line represents protein (in mg) in a 24-h urine collection. Gray rectangle represents the periods during which the woman was pregnant
uneventfully at term with mild proteinuria, the second required induction of labor at term due to aggravation of the proteinuria, and the third prompted preterm delivery due to early marked proteinuria. Since kidney function is known to deteriorate with age, this might serve as an explanation for this observation. In a 4-year follow-up, renal function according to eGFR by CKD-EPI deteriorated to 90 mL/min/1.73 m2, which is the lower limit of CKD stage G1 [13]. This indolent course is probably related to the natural course of the disease and not related directly to her last pregnancy. In addition, while in the mother and younger sister (our patient) renal function did not deteriorate substantially following pregnancy, in the oldest sister renal function deteriorated markedly to ESRD. Pre-pregnancy basal renal function and different genetic penetrance might play a role in this observation. Ten pregnancies of 9 patients from the literature are also described. Analysis of all the pregnancies with Alport syndrome suggests that older age, pre-pregnancy renal function impairment, chronic hypertension, and the development of pre-eclampsia are risk factors for renal function deterioration following pregnancy. Those factors were shown to be risk factors for unfavorable pregnancy outcomes in other renal diseases as well [16]. Moreover, patients with Alport syndrome are at increased risk for preterm delivery and cesarean sections. It should be noted that the preterm births were due to iatrogenic labor induction due to worsening renal disease, mainly proteinuria. Since it is not unusual for proteinuria to increase during pregnancy in women with pre-existing renal disease, it is difficult to evaluate whether increased proteinuria implies true progression in renal disease with expected histological changes or hemodynamic/hormonal effects of
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pregnancy. Aggravation of the proteinuria and renal function before the 20th gestational week is generally the consequence of the underling renal disease, while in later weeks it should be differentiated from the development of pre-eclampsia. Our data demonstrate that the severity of proteinuria near delivery did not predict permanent renal deterioration. Moreover, when proteinuria was aggravated without hypertension/pre-eclampsia or a rise in serum creatinine/decreased creatinine clearance, the prognosis of renal function post-pregnancy as well as neonatal outcome was good. Nevertheless, in cases of decreased creatinine clearance or the presence of chronic hypertension before pregnancy, the prognosis of renal function post-pregnancy was less favorable. It should be noted that those findings are not specific for Alport syndrome but will also hold true for other kidney diseases [16]. This means that pre-pregnancy renal function is a more relevant predictor for the renal outcome post-pregnancy than the specific underline etiology. In light of these observations, when proteinuria is present without hypertension or impaired creatinine clearance, prolongation of the pregnancy to term or at least until documented fetal lung maturity, and labor induction between the 37th and 38th gestational week, in an effort to avoid the complication of pre-eclampsia, should be considered. The strengths of this study are the fact that this is the largest cohort with Alport syndrome that has ever been described during pregnancy and this is also the first study to combine all the available reports in order to draw conclusions regarding the pregnancies and renal outcomes in this rare disease. The limitation of this study is the small number of available patients for analysis.
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Since the literature describes only a handful of cases, pre-pregnancy consultation regarding pregnancy and postpartum early and late complications to the fetus and mother is difficult, and any conclusion should be made with caution. That being said, the available data suggest that the predictive factors for pregnancy complications in Alport syndrome are similar to those of other kidney diseases and consist of advanced age, pre-pregnancy basal kidney function, chronic hypertension, and pre-eclampsia. Consequently, delivery at a young age before kidney function deterioration seems advisable. In summary, although the information regarding pregnancies with Alport syndrome is limited and should benefit from further research, the available data suggest that the prognosis of young patients with CKD stage G1 without hypertension or proteinuria within the nephrotic range before pregnancy is good. However, the physician should inform the patient about the risk for preterm delivery and cesarean section as well as the risk for renal deterioration, particularly if the pregnancy is complicated with preeclampsia. Compliance with ethical standards Details of ethics approval Informed consent was obtained from the patient treated at our institution. All the information regarding the patients in this study is presented anonymously. This study was approved by the ethics committee. Conflict of interest of interest.
The authors declare that they have no conflict
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MATERNAL-FETAL MEDICINE
Pregnancy outcomes in patients with Alport syndrome Enav Yefet1 • David Tovbin2,3 • Zohar Nachum1,3
Received: 25 March 2015 / Accepted: 14 September 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose To analyze the maternal and obstetric outcomes of patients with Alport syndrome. Methods We describe the pregnancy course of 8 pregnancies of three family members with the autosomal dominant (the rarest) form of Alport syndrome. We also analyzed 10 previously reported pregnancies with other Alport mutations in order to explore risk factors for unfavorable obstetric outcomes and maternal renal deterioration. Results In 13 pregnancies (72 %), renal function did not deteriorate permanently. All of these women had prepregnancy mild chronic kidney disease (CKD stage G1). In all of them, only a transient increase in proteinuria was recorded and in one case there was a transient decrease in the estimated glomerular filtration rate. In four other pregnancies (22 %), renal function deteriorated following pregnancy. All of them were complicated with preeclampsia. One woman had pre-pregnancy CKD-G2A3 and chronic hypertension. Two women had CKD-G1A3 of whom one had pre-pregnancy proteinuria near the nephrotic range. In the fourth case, renal function deterioration was reported without information on the exact prepregnancy renal function. In the last case, CKD-G2 was reported after pregnancy without information on CKD stage prior to pregnancy. Severe proteinuria did not imply a & Enav Yefet [email protected] 1
Department of Obstetrics and Gynecology, Emek Medical Center, Afula, Israel
2
Department of Nephrology, Emek Medical Center, Afula, Israel
3
Rappaport Faculty of Medicine, Technion, Haifa, Israel
permanent renal function deterioration if it developed during pregnancy. Ten pregnancies ended with preterm birth (56 %). Two stillbirths were reported (11 %); however, only one was attributed to maternal health deterioration. Conclusion Data regarding pregnancy outcomes in Alport syndrome is limited. The outcome seems favorable when pre-pregnancy kidney function is normal or near normal and when chronic hypertension/pre-eclampsia is absent. Keywords Alport syndrome Kidney disease Nephritis Pregnancy Renal failure
Introduction Alport syndrome is a genetically heterogeneous disease that results from mutations in genes encoding the alpha-3, alpha-4, and alpha-5 chains of type IV collagen, which comprises the basement membrane of the glomeruli, the inner ear, and the eye. X-linked (80 %), autosomal recessive (15 %), and autosomal dominant (5 %) forms have been identified. The classical presentation (X-linked) includes glomerular disease that progresses to end-stage renal disease (ESRD), sensorineural hearing loss, and ocular abnormalities. The autosomal forms are clinically similar to the X-linked forms; however, the deterioration of renal function is slower. The initial renal manifestation of Alport syndrome is asymptomatic microscopic hematuria. The blood pressure and serum creatinine are normal in early childhood, but progressive renal insufficiency, hypertension, and increasing proteinuria develop. ESRD usually occurs between the ages of 16 and 35, but the course might be slow in some families. Diagnosis is made
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by either renal or skin biopsy and confirmed genetically [1– 4]. Since the majority of the cases involve males (Xlinked), the data in the literature regarding the pregnancy course of patients with Alport syndrome are scant and even the little we know comes from a few anecdotal incidents documented in case reports [5–12]. The objective of the present manuscript was to characterize the effect of Alport syndrome on pregnancy course and vice versa. This manuscript comprises two parts: in the first part, we describe, in detail, the course of 8 pregnancies of 3 family members with the autosomal dominant form of Alport syndrome. To our knowledge, this is the first report in the literature of pregnancies of patients with this mutation and the largest series of pregnancies with Alport syndrome in general. In the second part, we conducted a literature search for additional pregnancies of patients with Alport syndrome (X-linked and autosomal recessive forms) and analyzed their pregnancies together with our cases in an effort to elucidate possible courses and prognostic factors in such cases.
Patients and methods Data collection of a family with the autosomal dominant form of Alport syndrome Family tree The family tree (pedigree) of the described family (Fig. 1) was built based on the clinically affected individuals. For purposes of description, the third daughter (patient II-4), who was treated in our institution, is referred to as the patient in the text, and the other affected individuals are
referred to as the mother (patient I-1) and oldest sister (patient II-2). Patient III-1 is healthy without microhematuria or proteinuria. The clinical and genetic status of the others in the third generation (III) is not known. Alport syndrome diagnosis and family characteristics The family origin was Kazakhstan. The family tree is described in Fig. 1. As can be seen, the mother and two daughters were clinically affected. The presenting symptom of the mother was non-progressive microhematuria. The oldest sister was affected more severely and presented with microhematuria that later progressed to kidney damage manifested by proteinuria. At the age of 14, she underwent kidney biopsy, which disclosed thin basement membrane consistent with Alport syndrome. The second daughter was healthy and was not tested for Alport syndrome. The third daughter (our patient) has suffered from persistent microhematuria since childhood. Altogether, by the evaluation of the genealogical tree, the modes of inheritance match the autosomal dominant mode with an incomplete penetrance. Alport syndrome was also identified by genetic analysis in the cases of the mother and oldest sister. Genetic analysis was done by the Department of Human Genetics of the University Medical Center Go¨ttingen, Germany. Blood samples were taken from the mother and oldest sister; both were found to be heterozygous for the autosomal dominant mutation in c2135G[T (Pg712V) in exon 29 of COL4A3 gene. The mutation in the COL4A5 gene (X-linked) was negative. Pregnancy documentation and management The third sister (patient II-4 in Fig. 1) was a patient in the Maternal-Fetal Medicine Department in our hospital (Emek Medical Center, Afula, Israel). Clinical assessments as well as laboratory investigations were acceptable and described thoroughly. Information regarding the other family members was collected by meticulous interviews as well as official documentations. Literature search for other reports of pregnancies with Alport syndrome
Fig. 1 The family tree (pedigree) of Alport syndrome-affected individuals with the autosomal dominant mutation c2135G[T (Pg712V) in exon 29 of COL4A3 gene. Circles represent females, squares represent males. Filled symbols indicate clinically affected individuals with Alport syndrome. Asterisks represent genetically confirmed Alport syndrome
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We searched PubMed, Medline, and Google Scholar for additional reports using the phrases ‘‘Alport or hereditary nephritis and Pregnancy’’ without limitations except for English language. We added, as appropriate, articles found through the references of included articles. We found 10 additional pregnancies of women with Alport syndrome and their details are described together with our series.
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Renal functions are presented as serum creatinine, proteinuria in 24-h urine collection, and estimated glomerular filtration rate (eGFR). The latter was calculated according to the chronic kidney disease Epidemiology Collaboration group (CKD-EPI) equation [13]. Please note that during pregnancy, eGFR calculated by the CKD-EPI equation underestimates the actual GFR, which returns to prepregnancy levels during the puerperium in healthy individuals [14, 15]. Creatinine clearance during the 2nd and 3rd trimesters is presented if available.
Results Pregnancy courses of family members with the autosomal dominant form of Alport syndrome Tables 1, 2, and 3 summarize the main clinical features and pregnancy outcomes of the mother (patient I-1), oldest sister (patient II-2), and our patient (patient II-4). Patients’ renal function following pregnancies is also described. Mother (patient I-1) The mother was healthy and suffered only from non-progressive persistent microhematuria. The mother’s first pregnancy was terminated in the third trimester due to fetal death of unknown cause. Afterward, she delivered three girls without complications. Laboratory assessment during pregnancies was normal. Oldest sister (patient II-2) The oldest sister had suffered from microhematuria since early childhood, and proteinuria developed a few years later. She had two spontaneous miscarriages. In the third pregnancy, she underwent labor induction at 35 weeks of gestation due to increasing blood pressure (pre-eclampsia). She delivered a healthy baby boy. During pregnancy her kidney function progressively deteriorated and 6 years later she began peritoneal dialysis. The third sister (patient II-4) Our patient had suffered from persistent microhematuria since childhood. Blood pressure and urea levels were normal. Figure 2 summarizes her kidney function profile according to the serum creatinine and proteinuria. Overall, renal function profile is compatible with CKD stage 1A3 according to the KDIGO 2012 criteria [13]. Her first pregnancy was unremarkable except for protein ?2 in urine dipstick throughout the pregnancy. Blood
pressure and creatinine were normal. A 24-h urine collection for protein was not performed. She delivered vaginally a 3500 g baby boy at 40 weeks of gestation without complications. Her second pregnancy was 5 years later. During that pregnancy, proteinuria progressively increased until it reached the nephrotic range of 3.6 g/24 h. Blood pressure and creatinine levels were normal. Due to proteinuria and deterioration of renal function, labor induction was performed at 39 weeks of gestation and proteinuria returned to pre-pregnancy levels. Her third pregnancy 4 years later was unremarkable until the third trimester except for progressively increasing proteinuria, which reached 3.9 g/24 h at 36 weeks of gestation (Fig. 2). Ultrasound directed to the kidney and urinary system was unremarkable. At 35.4 gestational weeks, she was admitted to the Maternal-Fetal Medicine Department due to headache and blurred vision. Physical examination disclosed pitting edema ?2 confined to the lower extremities. Blood pressure as well as creatinine, urea, uric acid, liver function, and CBC were normal. Fundoscopy was unremarkable. Ultrasonography assessment disclosed an appropriate for gestational age fetus with normal amniotic fluid volume and biophysical profile. Due to the worsening proteinuria and patient’s request, fetal lung maturity was confirmed with amniocentesis for lamellar bodies and labor induction was performed at 36.2 weeks without complications. After several weeks, proteinuria returned to pre-pregnancy levels (Fig. 2). Additional cases from the literature and data analysis The literature describes 10 pregnancies with Alport syndrome with variable pregnancy courses and post-pregnancy sequelae. Patient and pregnancy characteristics are summarized in Tables 1, 2, and 3. It should be noted that some of the cases were not genetically confirmed. None of the cases was reported to be of the autosomal dominant form of Alport syndrome. Only one case describes two consecutive pregnancies for a single patient. Together with our own series, 18 pregnancies are available for analysis. Renal outcomes Twelve pregnancies (67 %) began with CKD stage G1 and did not deteriorate (except for transient increase of the proteinuria). In one additional case (case 9), eGFR decreased but returned to pre-pregnancy level later on. Altogether, renal function did not deteriorate from stage G1 in 13 cases (72 %).
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Arch Gynecol Obstet Table 1 Patients’ characteristics and baseline renal functions in pregnancies with Alport syndrome Patient (references)
Mutation
Age (years)
Pregnancy no.
1 [6]
X-linkedc
35
2 [7]
X-linkedc
N/A
3 [5]
X-linkedc
Baseline renal functiona BP
Cr (mg/dl)
CCT (mL/ min)
Proteinuria (g/24 h)
eGFR CKD-EPI (mL/min/1.73 m2)b
CKD staging
1
N/A
0.7
85.1
0.2
113
G1A2
1
N/A
0.8
N/A
N/A
123
G1
29
1
140/90
1.0–1.2
57.8
1.0–2.0
68
G2A3
4 [9] (1st pregnancy)
X-linked
c
19
1
110/60
0.59
122
1.0–2.0
133
G1A3
4 [11] (2nd pregnancy)
X-linkedc
21
2
118/62
0.67
N/A
1
126
G1A3
5 [8]
Autosomal recessive
19
1
Normal
0.7–1.0
173
2.0–2.3
100
G1A3
6 [8]
Autosomal recessive
16
1
Normal
0.5–0.8
143
0.7–0.9
132d
G1A3
7 [10]
X-linked
38
1
N/A
N/A
N/A
N/A
N/A
N/A
8 [10]
X-linked
26
1
Normal
Normal
N/A
3.26
9 [12]
X-linked
20
1
116/78
0.7
NA
1.04
I-1
Autosomal dominant
N/A
1
Normal
20
2
27 28
3 4
II-2
Autosomal dominant
27
3 (after 2 spontaneous early miscarriages)
N/A
II-4
Autosomal dominantc
20
1
Normal
25 29
G1A3 125
G1A3 G1
At least 0.5
N/A
N/A
Normal
150 mg/dl in urinalysis
N/A
G1A3
2
N/A
Normal
At least 0.5
N/A
G1A3
3
0.58
162
0.63
126
G1A3
BP blood pressure (mmHg), CKD chronic kidney disease, CCT creatinine clearance test, Cr serum creatinine, eGFR CKD-EPI estimated glomerular filtration rate calculated with the chronic kidney disease Epidemiology Collaboration group equation, min minute, N/A not available, P proteinuria a
Renal function was evaluated before pregnancy or at the 1st trimester
b
CKD-EPI was calculated according to the serum creatinine value
c
Diagnosis was not genetically confirmed
d
According to pediatric formulas, the eGFR is 98.48 mL/min/1.73 m using the Bedside Schwartz equation, and 102.54 mL/min/1.73 m using the Counahan–Barratt equation
In 4 cases (22 %), renal function deteriorated following pregnancy (cases 2, 3, and 8, and patient II-2). All of those cases were complicated with pre-eclampsia. In cases 3 and 8, the baseline kidney disease was impaired according to the CKD staging (case 3) and baseline proteinuria was close to the nephrotic range (case 8). Baseline renal functions are not available for patient II-2. Only case 2 (6 %) demonstrated deterioration in renal function from CKD stage G1. In case 7, CKD stage G2 was reported after pregnancy without information on CKD stage prior to pregnancy. Notably, this woman was older than the others (38 years).
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The degree of proteinuria near delivery was not associated with permanent renal deterioration. Obstetric outcomes Eleven cases (61 %) were delivered preterm. Seven cases (39 %) had cesarean delivery, none due to fetal distress. Five cases (28 %) were complicated with pre-eclampsia. Stillbirth occurred in two cases (11 %); however, it was related to the renal disease in only one case. Only one case of intrauterine growth restriction (6 %) was reported. All the live born were reported to be in good health immediately after delivery.
G1A2
G1
G2A3 ? HTN
G1A3
G1A3
G1A3
G1A3
N/A
G1A3
1 [6]
2 [7]
3 [5]
4 [9]
4 [11]
5 [8]
6 [8]
7 [10]
8 [10]
CKD staging
Patient (references)
32
33
30
36
32
Through all trimesters
31–39
25
33
N/A
Hypertension (preeclampsia)
Normal
Normal
Normal
102–123/ 58–78
100–110/ 70–74
242/109
136/92
0.7
N/A
N/A
0.53 (28 weeks), reported normal at delivery
0.51
0.67–0.70
0.54–0.7
6.6
1.4–1.7
N/A
86.3
168 (28 weeks), reported normal at delivery
185 (28 weeks), reported normal at delivery
N/A
97–137
N/A
N/A
50
CCT (mL/min)
Proteinuria (g/24 h) 6
N/A
22 months
22 months
[7
6 months
6 months
2 months
6 months
6 months
N/A
3.4-7
10.6
9
0.8–2.0
1.42–2.22
15
N/A
22 months post-partum serum creatinine concentration was 1.48 mg/dl, eGFR CKDEPI—49 mL/min/1.73 m2 and proteinuria returned to 3.21 g/24 h
Proteinuria gradually improved (0.99 g/24 h), eGFR CKD-EPI 81 mL/ min/1.73 m2
Proteinuria reverted to prepregnancy values (1.4 g/ 24 h) when examined 6 months after delivery
Proteinuria first increased to 12.2 g/24 h and then reverted to prepregnancy values (1.8 g/ 24 h) when examined 6 months after delivery
Proteinuria, creatinine level, and blood pressure remained stable in a 2-month follow-up
Six months after delivery proteinuria remained (1.5 g/24 h), eGFR CKD-EPI—133 mL/min/ 1.73 m2 consisted with CKD G1A3
Hemodialysis was needed 48 h post-partum until the end of the reported time of follow-up
Improved
Improved
Post-partum renal function
Duration of follow-up after delivery
Cr (mg/dl)
Gestational week at examination BP
Renal function in follow-up after delivery
Renal function during pregnancy (2nd or 3rd trimester)
Table 2 Renal effects during and after pregnancies in women with Alport syndrome
G3aA3
G2A3
81
49
G1A3
G1A3
G1A3
G1A3
G5
CKD staging
N/A
N/A
N/A
133
N/A
N/A
N/A
eGFR CKDEPI (mL/min/ 1.73 m2)a
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123
G1A3
G1
N/A
G1A3
9 [12]
I-1
II-2
II-4
Normal
Normal 111/71
N/A
35
Hypertension
Normal
162/111
40
35
N/A
29
0.7
0.68
0.9
Elevated
1.53
146
171
N/A
Decreased
N/A
CCT (mL/min)
Proteinuria (g/24 h)
3.905
See Fig. 1
See Fig. 1
See Fig. 1
*0.5 to 1.5 (?2 in dipstick) 3.6
6 years
24 h
Deteriorated
15
Proteinuria reverted to prepregnancy values
Proteinuria reverted to prepregnancy values
Kidney function continued to deteriorate until peritoneal dialysis 6 years later Proteinuria reverted to prepregnancy values as well as creatinine and eGFREPI
Blood pressure became normal. Proteinuria decreased to 0.75 g/day and the serum creatinine decreased to 1.1 mg/dl on the day after delivery (eGFR CKD-EPI — 49 mL/min/1.73 m2). Serum creatinine was reported to return to baseline levels
Post-partum renal function
Duration of follow-up after delivery
Cr (mg/dl)
Gestational week at examination
BP
Renal function in follow-up after delivery
Renal function during pregnancy (2nd or 3rd trimester)
90
103
106
N/A
N/A
N/A
eGFR CKDEPI (mL/min/ 1.73 m2)a
G1A3
G1A3
G1A3
G5
G1
G1A3
CKD staging
a
CKD-EPI was calculated according to the serum creatinine value
BP blood pressure (mmHg), CKD chronic kidney disease, CCT creatinine clearance test, Cr serum creatinine, eGFR CKD-EPI estimated glomerular filtration rate calculated with the chronic kidney disease Epidemiology Collaboration group equation, HTN hypertension, min minute, N/A not available, P proteinuria
CKD staging
Patient (references)
Table 2 continued
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Arch Gynecol Obstet Table 3 Pregnancy and obstetric outcomes in women with Alport syndrome Patient [ref]
CKD staging
Gestational week at delivery
Mode of delivery
Birth weight (g)
gender
Apgar score at 1/5 min
Labor induction
Indication for deliverya
1 [6]
G1A2
32.2
CS
1820, AGA
Male
N/A
No
Renal function deterioration (mainly proteinuria)
2 [7]
G1
35.3
VD
1888, AGA
Female
N/A
Yes
3 [5]
G2A3 ? HTN
25.5
VD
400, SGA
Female
0
Yes
Renal function deterioration and preeclampsia Renal function deterioration and preeclampsia
4 [9]
G1A3
39.2
CS
2868, AGA
Male
8 after 5 min
No
Labor began spontaneously. CS was performed due to labor dystocia
4 [11]
G1A3
37.1
CS
2458, AGA
Female
N/A, reported as a healthy infant
No
Labor began spontaneously. CS was performed due to previous CS
5 [8]
G1A3
32
CS
1830, AGA
Female
5/8
No
CS due to renal function deterioration (severe proteinuria)
6 [8]
G1A3
36
CS
2335, AGA
Female
7/9
Yes
CS was performed due to labor dystocia
7 [10]
N/A
34
CS
2165, AGA
Male
9 after 5 min
No
Renal function deterioration (mainly proteinuria)
8 [10]
G1A3
33
VD
2400, AGA
Male
9 after 5 min
Yes
Renal function deterioration and pre-eclampsia
9 [12]
G1A3
29
CS
N/A
N/A
Healthy neonate
Yes
Acute renal failure and preeclampsia. Cesarean section was performed due to failed induction
I-1
G1
*28
VD
N/A
N/A
0/0 stillborn
Yes
stillborn
Term
VD
N/A
Female
N/A
No
Not applicable
Term
VD
N/A
Female
N/A
No
Not applicable
Term
VD
N/A
Female
N/A
No
Not applicable
35
VD
N/A
Male
Healthy
Yes
Labor induction due to aggravating hypertension (pre-eclampsia)
II-2
N/A
II-4
G1A3
40
VD
3500, AGA
Male
Healthy
No
Not applicable
39
VD
3100, AGA
Female
Healthy
Yes
Labor induction due to aggravating proteinuria
36.2
VD
2686, AGA
Female
9/10
Yes
Labor induction due to aggravating proteinuria
AGA appropriate for gestational age, CS cesarean section, CKD chronic kidney disease, HTN hypertension, N/A not available, SGA small for gestational age, VD vaginal delivery a
In cases of delivery due to renal deterioration see Table 2; Fig. 2 for specific details
Discussion Presented here are three patients with the autosomal dominant type of Alport syndrome. Genetic confirmation was available for the mother and the oldest sister. The third sister refused to undergo either biopsy or genetic diagnosis;
however, her family history and clinical signs were highly suggestive of Alport syndrome. Interestingly, though these patients share an identical mutation, the prognosis ante-partum and post-partum differed. Moreover, in the case of the third daughter, the course of pregnancies differed as the first one ended
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Fig. 2 Kidney function profile of patient II-4. Solid line represents serum creatinine (mg/dl) levels. Dashed line represents protein (in mg) in a 24-h urine collection. Gray rectangle represents the periods during which the woman was pregnant
uneventfully at term with mild proteinuria, the second required induction of labor at term due to aggravation of the proteinuria, and the third prompted preterm delivery due to early marked proteinuria. Since kidney function is known to deteriorate with age, this might serve as an explanation for this observation. In a 4-year follow-up, renal function according to eGFR by CKD-EPI deteriorated to 90 mL/min/1.73 m2, which is the lower limit of CKD stage G1 [13]. This indolent course is probably related to the natural course of the disease and not related directly to her last pregnancy. In addition, while in the mother and younger sister (our patient) renal function did not deteriorate substantially following pregnancy, in the oldest sister renal function deteriorated markedly to ESRD. Pre-pregnancy basal renal function and different genetic penetrance might play a role in this observation. Ten pregnancies of 9 patients from the literature are also described. Analysis of all the pregnancies with Alport syndrome suggests that older age, pre-pregnancy renal function impairment, chronic hypertension, and the development of pre-eclampsia are risk factors for renal function deterioration following pregnancy. Those factors were shown to be risk factors for unfavorable pregnancy outcomes in other renal diseases as well [16]. Moreover, patients with Alport syndrome are at increased risk for preterm delivery and cesarean sections. It should be noted that the preterm births were due to iatrogenic labor induction due to worsening renal disease, mainly proteinuria. Since it is not unusual for proteinuria to increase during pregnancy in women with pre-existing renal disease, it is difficult to evaluate whether increased proteinuria implies true progression in renal disease with expected histological changes or hemodynamic/hormonal effects of
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pregnancy. Aggravation of the proteinuria and renal function before the 20th gestational week is generally the consequence of the underling renal disease, while in later weeks it should be differentiated from the development of pre-eclampsia. Our data demonstrate that the severity of proteinuria near delivery did not predict permanent renal deterioration. Moreover, when proteinuria was aggravated without hypertension/pre-eclampsia or a rise in serum creatinine/decreased creatinine clearance, the prognosis of renal function post-pregnancy as well as neonatal outcome was good. Nevertheless, in cases of decreased creatinine clearance or the presence of chronic hypertension before pregnancy, the prognosis of renal function post-pregnancy was less favorable. It should be noted that those findings are not specific for Alport syndrome but will also hold true for other kidney diseases [16]. This means that pre-pregnancy renal function is a more relevant predictor for the renal outcome post-pregnancy than the specific underline etiology. In light of these observations, when proteinuria is present without hypertension or impaired creatinine clearance, prolongation of the pregnancy to term or at least until documented fetal lung maturity, and labor induction between the 37th and 38th gestational week, in an effort to avoid the complication of pre-eclampsia, should be considered. The strengths of this study are the fact that this is the largest cohort with Alport syndrome that has ever been described during pregnancy and this is also the first study to combine all the available reports in order to draw conclusions regarding the pregnancies and renal outcomes in this rare disease. The limitation of this study is the small number of available patients for analysis.
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Since the literature describes only a handful of cases, pre-pregnancy consultation regarding pregnancy and postpartum early and late complications to the fetus and mother is difficult, and any conclusion should be made with caution. That being said, the available data suggest that the predictive factors for pregnancy complications in Alport syndrome are similar to those of other kidney diseases and consist of advanced age, pre-pregnancy basal kidney function, chronic hypertension, and pre-eclampsia. Consequently, delivery at a young age before kidney function deterioration seems advisable. In summary, although the information regarding pregnancies with Alport syndrome is limited and should benefit from further research, the available data suggest that the prognosis of young patients with CKD stage G1 without hypertension or proteinuria within the nephrotic range before pregnancy is good. However, the physician should inform the patient about the risk for preterm delivery and cesarean section as well as the risk for renal deterioration, particularly if the pregnancy is complicated with preeclampsia. Compliance with ethical standards Details of ethics approval Informed consent was obtained from the patient treated at our institution. All the information regarding the patients in this study is presented anonymously. This study was approved by the ethics committee. Conflict of interest of interest.
The authors declare that they have no conflict
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